Prostate Cancer

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A Randomized Clinical Trial of Exercise vs. Usual Care Among Men Opting for Active Surveillance for Prostate Cancer


Condition: Localized Prostate Cancer, Active Surveillance for Prostate Cancer

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT02435472

Sponsor: University of California, San Francisco

Eligibility:

  • Age: minimum 18 Years maximum N/A
  • Gender: Male

Inclusion Criteria:

  • ARM A and ARM B:
  • Histologically-documented localized (stage < T3) prostate adenocarcinoma
  • Patient has selected active surveillance as their management strategy for low- or low-intermediate risk prostate cancer as defined below
  • >= 10 core prostate biopsy completed prior to randomization with Gleason sum =< 6 with no pattern 4, or Gleason 3+4 in < 34% of all cores
  • Diagnostic or most recent prostate specific antigen (PSA) =< 15 ng/ml, or PSA density (PSAD) < 0.15
  • Low to moderate fitness level at baseline (to be assessed via interview with the exercise staff and through the CPET)
  • Clearance based on medical chart review and normal electrocardiogram (ECG) (administered by a trained health professional) to undergo a symptom-limited cardiopulmonary exercise test and aerobic training intervention
  • Able to achieve and complete an acceptable cardiopulmonary exercise test defined as follows: achieving peak or plateau in oxygen consumption concurrent with increased power output; a respiratory exchange ratio >= 1.1 or volitional exhaustion-rating of perceived exertion > 19
  • English-speaking
  • A priori, we will allow men with concurrent benign prostatic hyperplasia (prostate volume > 50 g) to have a PSA between 10-15 ng/ml; and include men with low volume Gleason 3+4 disease, because such men have similar outcomes on active surveillance to those with Gleason =< 3+3; also a priori, we will allow men with < than a 10 core biopsy at the discretion of the urologist if s/he classifies the patient as "low-risk" and a good candidate for active surveillance based on other favorable features (e.g., tumor molecular tests, prostate imaging, etc.) NON-CANCER CONTROL GROUP (EXPLORATORY ARM C):
  • Healthy males age 20-35 or >=60 yrs.
  • No history of prostate cancer or other cancer.
  • Medical clearance based on medical chart review and normal ECG (administered by a trained health professional) to undergo a symptom-limited cardiopulmonary exercise test and aerobic training intervention OR medical clearance based on medical chart review and sub-maximal exercise testing for the remote aerobic training intervention.
  • English-speaking.
  • Low to moderate fitness level at baseline (to be assessed via interview with the exercise staff and through the CPET; similar to Arms A and B); subjects will be frequency-matched to subjects in the prostate cancer exercise intervention group (Arm A) to have a similar distribution of body mass index and facilitate comparisons between these two groups. NON-RANDOMIZED OBSERVATIONAL COMPONENT ELIGIBILITY:
  • Histologically-documented localized (stage < T3) prostate adenocarcinoma.
  • Undergoing or initiating active surveillance.
  • Medical clearance based on medical chart review and normal ECG (administered by a trained health professional) to undergo a symptom-limited cardiopulmonary exercise test and aerobic training intervention.
  • English-speaking. Exclusion Criteria
  • Any prior or concurrent treatment for prostate cancer
  • Use of finasteride or dutasteride within 3 weeks or 6 months, respectively, of study entry
  • Uncontrolled illness, physical disability, or other contraindication to aerobic exercise training including, but not limited to:
  • Acute myocardial Infarction (within 5 days of any planned study procedure)
  • Unstable angina
  • Uncontrolled arrhythmia causing symptoms or hemodynamic compromise
  • Recurrent syncope
  • Active endocarditis
  • Acute myocarditis or pericarditis
  • Symptomatic severe aortic stenosis
  • Uncontrolled heart failure
  • Acute (within 3 months) pulmonary embolus or pulmonary infarction
  • Thrombosis of lower extremities
  • Suspected dissecting aneurysm
  • Uncontrolled asthma
  • Pulmonary edema
  • Room air desaturation at rest =< 85%
  • Respiratory failure
  • Acute non-cardiopulmonary disorders that may affect exercise performance or be aggravated by exercise (ie infection, renal failure, thyrotoxicosis)
  • Mental impairment leading to inability to cooperate NON-RANDOMIZED OBSERVATIONAL AND INTERVENTION COMPONENTS (ARM C): The same

Exclusion Criteria:

  • Any prior or concurrent treatment for prostate cancer
  • Use of finasteride or dutasteride within 3 weeks or 6 months, respectively, of study entry
  • Uncontrolled illness, physical disability, or other contraindication to aerobic exercise training including, but not limited to:
  • Acute myocardial Infarction (within 5 days of any planned study procedure)
  • Unstable angina
  • Uncontrolled arrhythmia causing symptoms or hemodynamic compromise
  • Recurrent syncope
  • Active endocarditis
  • Acute myocarditis or pericarditis
  • Symptomatic severe aortic stenosis
  • Uncontrolled heart failure
  • Acute (within 3 months) pulmonary embolus or pulmonary infarction
  • Thrombosis of lower extremities
  • Suspected dissecting aneurysm
  • Uncontrolled asthma
  • Pulmonary edema
  • Room air desaturation at rest =< 85%
  • Respiratory failure
  • Acute non-cardiopulmonary disorders that may affect exercise performance or be aggravated by exercise (ie infection, renal failure, thyrotoxicosis)
  • Mental impairment leading to inability to cooperate NON-RANDOMIZED OBSERVATIONAL AND INTERVENTION COMPONENTS (ARM C): The same exclusion criteria apply as above. Additionally, • Should have no prior history of cancer, except for non-melanoma skin cancer

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Evaluation of PSMA-based PET as an Imaging Biomarker of Androgen Receptor Signaling in High-Risk Localized and Locally Advanced Prostate Cancer


Condition: Advanced Prostate Cancer

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT02420977

Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Phase: Early Phase 1

Eligibility:

  • Age: minimum 18 Years maximum 100 Years
  • Gender: Male

Inclusion Criteria:

  • Men 18 years of age or greater with recently diagnosed prostate cancer with planned radiation and ADT.

Key Inclusion Criteria:

  • (the entire list of inclusion and exclusion criteria will appear later in section 4 of the protocol)
  • Newly diagnosed prostate cancer pathologically proven by prostate biopsy
  • Prostate biopsy histology grade ≥ Gleason 8-10
  • Patients considered as candidates for and medically fit to undergo radiation and ADT
  • At least 10 days after most recent prostate biopsy

Exclusion Criteria:

  • will appear later in section 4 of the protocol)
  • Newly diagnosed prostate cancer pathologically proven by prostate biopsy
  • Prostate biopsy histology grade ≥ Gleason 8-10
  • Patients considered as candidates for and medically fit to undergo radiation and ADT
  • At least 10 days after most recent prostate biopsy Exclusion Criteria:
  • Prior pelvic external beam radiation therapy or brachytherapy
  • Chemotherapy for prostate cancer
  • Hormone deprivation therapy
  • Investigational therapy for prostate cancer
  • Hemorrhagic cystitis or active prostatitis

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A Phase I/II Study of Enzalutamide in Combination With Indomethacin in Castration-Resistant Prostate Cancer (CRPC)


Condition: Metastatic Prostate Carcinoma, Recurrent Prostate Carcinoma, Stage IV Prostate Cancer

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT02935205

Sponsor: Mamta Parikh

Phase: Phase 1/Phase 2

Eligibility:

  • Age: minimum 19 Years maximum N/A
  • Gender: Male

Inclusion Criteria:

  • Patients must have histologically or cytologically confirmed prostate cancer (CaP); CaP can be recurrent disease after definitive therapy (radical prostatectomy or radiation therapy) for localized CaP, or metastatic CaP
  • Patients must have CaP deemed to be castration-resistant by one or more of the following criteria (despite androgen deprivation when applicable):
  • Progression of unidimensionally measurable disease assessed within 42 days prior to initial administration of drug
  • Progression of evaluable but not measurable disease assessed within 42 days prior to initial administration of drug for PSA evaluation and for imaging studies (e.g, bone scans)
  • Rising PSA, defined as at least two consecutive rises in PSA to be documented over a reference value (measure 1); the first rising PSA (measure 2) should be taken at least 7 days after the reference value; a third confirmatory PSA measure (2nd beyond the reference level) should be greater than the second measure, and it must be obtained at least 7 days after the 2nd measure; if this is not the case, a fourth PSA measurement is required to be taken and be greater than the second measure
  • Measurable disease is not required
  • Patients who have measurable disease must have had X-rays, scans or physical examinations used for tumor measurement completed within 28 days prior to initial administration of drug
  • Patients must have non-measurable disease (such as nuclear medicine bone scans) and non-target lesions (such as PSA level) assessed within 28 days prior to initial administration of drug
  • Soft tissue disease that has been radiated within two months prior to registration is not assessable as measurable disease; soft tissue disease that has been radiated two or more months prior to registration is assessable as measurable disease provided that the lesion has progressed following radiation; as the biology of previously irradiated tumors may be different from non-irradiated tumors, patients must have at least one measurable lesion outside the previously irradiated region in order to be considered to have measurable disease
  • If PSA is the only indicator of disease and patients do not have any metastatic disease, PSA value must be 5.0 or higher
  • Patients must have been surgically or medically castrated; if the method of castration was luteinizing hormone-releasing hormone (LHRH) agonists (leuprolide or goserelin) or antagonists (degarelix), then the patient must be willing to continue the use of LHRH agonists or antagonists; serum testosterone must be at castration levels (< 50 ng/dL) within 3 months prior to registration
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
  • Life expectancy of greater than 6 months
  • Leukocytes >= 3,000/mcL
  • Absolute neutrophil count >= 1,500/mcL
  • Platelets >= 100,000/mcL
  • Total bilirubin within normal institutional limits
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 1.5 x institutional upper limit of normal
  • Creatinine =< 1.5 x institutional upper limit of normal
  • Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of enzalutamide administration
  • Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

  • Patients who have had chemotherapy or radiotherapy within 4 weeks prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier
  • Patients who are receiving any other investigational agents within the preceding 4 weeks
  • Patients on herbs or other alternative medicines for the treatment of prostate cancer, including but not limited to saw palmetto, PC-SPES
  • Patient has received enzalutamide or ketoconazole for the treatment of prostate cancer; however, previous treatment with other hormonal therapy (bicalutamide, abiraterone, flutamide, and nilutamide) or chemotherapy (docetaxel, cabazitaxel, or mitoxantrone) is allowed
  • Other malignancies within the past 3 years except for adequately treated basal or squamous cell carcinomas of the skin or other stage 0 or I cancers
  • Patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to enzalutamide or indomethacin
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
  • Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible
  • Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of drugs (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection)
  • Patients with an active bleeding diathesis
  • History of noncompliance to medical regimens
  • Patients unwilling to or unable to comply with the protocol
  • Patients with symptomatic metastatic prostate cancer such as moderate to severe pain, impaired organ function, or spinal cord compression will be excluded from this study unless these issues have been taken care of
  • Patients with a history of seizure disorder, underlying brain injury with loss of consciousness, transient ischemic attack within the past 12 months, cerebral vascular accident, brain metastases, brain arteriovenous malformation
  • Patients with a history of peptic ulcer disease or gastrointestinal bleeding

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A Multi-Center Prospective Single Arm Intervention Trial Evaluating Focal Therapy Using High Intensity Focused Ultrasound (Sonablate 500) for Localized Prostate Cancer


Condition: Male Erectile Disorder, Prostate Cancer, Therapy-related Toxicity, Urinary Incontinence

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT01194648

Sponsor: University College, London

Eligibility:

  • Age: minimum N/A maximum 90 Years
  • Gender: Male

Criteria: 1. Histologically proven prostate cancer on trans-rectal or transperineal template prostate biopsies. 2. Prostate biopsy (either TRUS or MRI Targeted or Template): - TRUS biopsy: up to burden bilateral disease with maximum 3mm one biopsy on non-dominant side is allowable. - MRI targeted and/or Template biopsy within 12 months of entry showing: - unilateral disease minimum 3mm of Gleason 3+3 or any Gleason 3+4 or 4+3 but not exceeding Gleason 4+3 overall OR - bilateral disease presence of clinically significant cancer on only one side (as determined by histological rules described above) Gleason ≤7 which is concordant with the MRI findings. 3. Stage T1-T2cN0M0 disease, as determined by local guidelines (radiological T3a permitted). 4. Serum PSA /=10 years. 6. Signed informed consent by patient. 7. An understanding of the English language sufficient to understand

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Quality of Life in Patients With Clinically Localized Prostate Cancer Treated With Stereotactic Body Radiation Therapy (SBRT)


Condition: Prostate Cancer, Localized Malignant Neoplasm

Study Type: Observational

Clinical Trials Identifier NCT 8-digits: NCT01766492

Sponsor: Georgetown University

Phase:

Eligibility:

  • Age: minimum 18 Years maximum 99 Years
  • Gender: Male

Inclusion Criteria:

  • Histologically confirmed adenocarcinoma of prostate
  • Signed study-specific consent
  • Prostate Specific Antigen (PSA) within 60 days of registration

Exclusion Criteria:

  • Prior pelvic radiotherapy
  • Prior radical prostate surgery
  • Medical or psychiatric illness that would interfere with treatment or follow up
  • Implanted hardware adjacent to the prostate that would prohibit appropriate treatment planning and/or treatment delivery

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International Randomised Study of Laparoscopic Prostatectomy vs Stereotactic Body Radiotherapy (SBRT) and Conventionally Fractionated Radiotherapy vs SBRT for Early Stage Organ-Confined Prostate Cancer


Condition: Prostate Cancer

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT01584258

Sponsor: Royal Marsden NHS Foundation Trust

Phase: Phase 3

Eligibility:

  • Age: minimum 18 Years maximum N/A
  • Gender: Male

Inclusion Criteria:

  • All of the following criteria are mandatory for inclusion:
  • Histological confirmation of prostate adenocarcinoma with a minimum of 10 biopsy cores taken within 18 months of randomisation.
  • Gleason score ≤ 3+4
  • Men aged ≥18
  • Clinical and MRI stage T1c -T2c, N0-X, M0-X (TNM 6th Edition [72], See Appendix 1)
  • PSA ≤ 20 ng/ml
  • Pre-enrollment PSA must be completed within 60 days of randomisation
  • Patients belonging in one of the following risk groups according to the National Comprehensive Cancer Network (www.nccn.org):
  • Low risk: Clinical stage T1-T2a and Gleason ≤ 6 and PSA < 10 ng/ml, or
  • Intermediate risk includes any one of the following:
  • Clinical stage T2b orT2c
  • PSA 10-20 ng/ml or
  • Gleason 3+4
  • WHO performance status 0
  • 2
  • Prostate volume ≤ 90 cc measured within 6 months of randomisation (height*width*length *π/6)
  • Ability of the research subject to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

  • One of the following criteria is sufficient for exclusion:
  • Clinical stage T3 or greater
  • Gleason score ≥ 4 + 3
  • High risk disease defined by National Comprehensive Cancer Network (www.nccn.org)
  • Previous malignancy within the last 2 years (except basal cell carcinoma or squamous cell carcinoma of the skin), or if previous malignancy is expected to significantly compromise 5 year survival
  • Prior pelvic radiotherapy
  • Prior androgen deprivation therapy (including LHRH agonists and antagonists and anti-androgens)
  • Any prior active treatment for prostate cancer. Patients previously on active surveillance are eligible if they continue to meet all other

Eligibility Criteria:

  • .
  • Life expectancy <5 years
  • Bilateral hip prostheses or any other implants/hardware that would introduce substantial CT artifacts
  • Medical conditions likely to make radiotherapy inadvisable eg inflammatory bowel disease, significant urinary symptoms
  • Anticoagulation with warfarin/ bleeding tendency making fiducial placement or surgery unsafe in the opinion of the clinician (see section 11, Treatment).
  • Participation in another concurrent treatment protocol for prostate cancer

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Prospective Evaluation of Truebeam STX Stereotactic Body Radiosurgery for Low and Intermediate Risk Prostate Cancer


Condition: Prostate Neoplasms

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT01581749

Sponsor: Albert DeNittis

Phase: Phase 4

Eligibility:

  • Age: minimum 21 Years maximum N/A
  • Gender: Male

Inclusion Criteria:

  • histologically proven prostate adenocarcinoma within 1 year of enrollment
  • Low risk: Gleason
  • Intermediate risk:Gleason 10 & < or =20 & Clinical Stage T1b- T2b, Nx or NO, Mx or M0
  • ECOG Performance Status 0-1
  • No prior prostate radiation or other definitive therapy

Exclusion Criteria:

  • implanted hardware or other material that would prohibit treatment planning or delivery
  • chemotherapy for a malignancy within the previous 5 years
  • history of an invasive malignancy (other than this prostate cancer,or basal or squamous skin cancers) within prior 5 years
  • hormone ablation for 2 months prior to treatment or during treatment

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Phase III Trial of Docetaxel vs. Docetaxel and Radium-223 for Metastatic Castration-Resistant Prostate Cancer (mCRPC)


Condition: Prostate Cancer

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT03574571

Sponsor: Memorial Sloan Kettering Cancer Center

Phase: Phase 3

Eligibility:

  • Age: minimum 18 Years maximum N/A
  • Gender: Male

Inclusion Criteria:

  • Willing and able to provide written informed consent (ICF) and HIPAA authorization for the release of personal health information. A signed informed consent must be obtained before screening procedures are performed. NOTE: HIPAA authorization may be either included in the informed consent or obtained separately.
  • Males 18 years of age and above
  • Histological or cytological proof of prostate cancer
  • Documented progressive mCRPC based on at least one of the following criteria: 1. PSA progression defined as 25% increase over baseline value with an increase in the absolute value of at least 1.0 ng/mL that is confirmed by another PSA level with a minimum of a 1 week interval and a minimum PSA of 1.0 ng/mL. 2. Soft-tissue progression defined as an increase ≥ 20% in the sum of the LD of all target lesions based on the smallest sum LD since treatment started or the appearance of one or more new lesions. 3. Progression of bone disease (evaluable disease) or two or more new bone lesions by bone scan.
  • Two or more bone lesions
  • ECOG 0- 1
  • Normal organ function with acceptable initial laboratory values within 14 days of randomization:
  • Albumin > 30 g/L
  • ANC ≥ 1.5 x 10^9/L
  • Hemoglobin ≥ 10 g/dL
  • Platelet count ≥ 100 x 10^9/L
  • Creatinine ≤ 1.5 x the institutional upper limit of normal (ULN)
  • Bilirubin ≤ ULN (unless documented Gilbert's disease)
  • SGOT (AST) ≤ 1.5 x ULN
  • SGPT (ALT) ≤ 1.5 x ULN
  • WBC count ≥ 3 x 10^9/L
  • Subjects must agree to use a medically acceptable method of birth control (e.g., spermicide in conjunction with a barrier such as a condom) or sexual abstinence for the duration of the study, including 30 days after the last dose of study drug. Sperm donation is prohibited during the study and for 30 days after the last dose of study drug. Female partners must use hormonal or barrier contraception unless postmenopausal or abstinent.
  • Serum testosterone < 50 ng/dL. Subjects must continue primary androgen deprivation with an LHRH analogue (agonist or antagonist) if they have not undergone orchiectomy.
  • All acute toxic effects of any prior treatment have resolved to NCI-CTCAE v4.0 Grade 1 or less.
  • Willing and able to comply with the protocol, including follow-up visits and examinations

Exclusion Criteria:

  • Received any other investigational therapeutic agents or other anticancer therapies within 4 weeks prior to randomization.
  • Received external beam radiotherapy within the 4 weeks prior to randomization.
  • Has an immediate need for external beam radiotherapy.
  • Has received any systemic bone-seeking radiopharmaceutical in the past.
  • Has received any prostate cancer directed chemotherapy in the castration resistant setting. Subjects who have received up to 6 prior doses of docetaxel in the castration sensitive setting are permitted if they have not experienced disease progression within 36 weeks of last treatment with docetaxel.
  • Has received four or more systemic anticancer regimens for mCRPC.
  • Treatment with docetaxel or abiraterone for non-castrate metastatic disease is permissible and does not count towards the lines of therapy for mCRPC
  • A 'line' is a regimen. Combinations of hormones and other types of therapies count as single lines.
  • Has known Grade ≥3 docetaxel-related toxicities or docetaxel toxicity related dose interruption or discontinuation.
  • Has received blood transfusions or growth factors within the last 4 weeks prior to randomization.
  • Symptomatic nodal disease (i.e., scrotal, penile, or leg edema).
  • Has visceral metastases with ≥ 3 lung and/or liver metastases or individual lesion ≥2 cm, as assessed by CT scan or MRI of the chest/abdomen/pelvis within the last 8 weeks prior to randomization.
  • Symptomatic loco-regional disease that causes ongoing Grade 3 or Grade 4 urinary or rectal symptoms.
  • Subjects with a "currently active" second malignancy other than non-melanoma skin cancers or non-invasive bladder cancers or other in-situ or non-invasive malignancies. Subjects are not considered to have a "currently active" malignancy if they have completed therapy and are free of disease for ≥ 3 years.
  • Has imminent or established cord compression based on clinical findings and/or MRI.
  • Known bone marrow dysplasia
  • Has received any of the following in the 4 weeks prior to randomization: 5-alpha-reductase inhibitors, herbal medications, natural hormonally active foods (e.g., phytoestrogens) or other food supplements known to alter PSA in humans
  • Any other serious illness or medical condition that would, in the opinion of the investigator, make this protocol unreasonably hazardous, including but not limited to:
  • Uncontrolled infection
  • NYHA III or IV heart failure
  • Crohn's disease or those with ulcerative colitis who have not undergone a colectomy
  • Known active infection with HIV, Hepatitis B or Hepatitis C

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Phase 1b/2 Study of BXCL701, a Small Molecule Inhibitor of Dipeptidyl Peptidases, Administered in Combination With the Anti-Programmed Cell Death 1 Monoclonal Antibody Pembrolizumab in Patients With mCRPC Either Small Cell Neuroendocrine Prostate Cancer or Adenocarcinoma Phenotype


Condition: Prostate Cancer, Neuroendocrine Tumors, Small Cell Carcinoma

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT03910660

Sponsor: BioXcel Therapeutics Inc

Phase: Phase 1/Phase 2

Eligibility:

  • Age: minimum 18 Years maximum N/A
  • Gender: Male

Inclusion Criteria:

  • All patients must satisfy the following inclusion and exclusion criteria to be eligible for entry into the trial. 1. Patient has evidence of progressive, metastatic castration-resistant disease, as defined by PCWG3 criteria. a. Patients with de novo small cell prostate cancer are not required to have received androgen deprivation therapy (ADT). 2. Progression during or following completion of at least 1 prior line of systemic therapy for locally advanced or metastatic prostate cancer. 3. Phases 2a and 2b Only: SCNC
  • Cohort A of Phase 2a only: 1. Patient has histologic evidence of SCNC either with archival tissue or a fresh tumor biopsy obtained during screening. Tumor biopsy tissue must be submitted for a central laboratory pathology review; however, enrollment can proceed if SCNC is determined by a local pathology review. 2. Patient has previously received at least 1 prior line of cytotoxic chemotherapy. Patients who either have refused chemotherapy or are considered unsuitable for chemotherapy may be eligible following discussion with the sponsor. 3. Must be willing to undergo metastatic tumor biopsy during Screening. Requirement may be waived in patients without safely accessible lesion or for patients with evaluable archival metastatic tumor tissue 4. Has measurable disease per RECIST 1.1 criteria. Adenocarcinoma
  • Cohort B of Phase 2a; randomized population for Phase 2b 1. Patient has histologically or cytologically confirmed adenocarcinoma of the prostate without small cell neuroendocrine features. 2. Patients with soft tissue disease must provide a fresh core or excisional biopsy or archival tissue from a site not previously irradiated for central pathology review; however enrollment may proceed if predominant adenocarcinoma without small cell neuroendocrine features is determined by local pathology review. 3. Has been treated with at least 1 but no more than 2 second generation AR pathway target agents (e.g., abiraterone acetate and/or enzalutamide or other next generation agent) and at least 1 regimen/line of taxane containing chemotherapy in the mCSPC or mCRPC setting. Patients with known actionable mutations should have progressed on applicable standard care targeted therapy or have documented intolerance to or be unsuitable for such therapy. 4. RECIST 1.1 measurable disease or detectable bone metastases by whole body bone scintigraphy. 4. Patient has serum testosterone <50 ng/dL during Screening except for those with de novo small cell prostate cancer. a. Patients with treatment-emergent SCNC without a history of bilateral orchiectomy are required to remain on luteinizing hormone-releasing hormone (LHRH) analog during the course of protocol therapy except for patients with de novo small cell prostate cancer. 5. Patient has Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. 6. Patient is ≥18 years of age. 7. Patient's acute toxic effects of previous anticancer therapy have resolved to ≤Grade 1 except for Grade 2-3 peripheral neuropathy or any grade of alopecia. 8. Patient has adequate baseline organ function, as demonstrated by the following: 1. Serum creatinine ≤1.5 times institutional upper limit of normal (ULN) or calculated creatinine clearance >50 mL/min; 2. Serum albumin ≥2.5 g/dL; 3. Total bilirubin ≤1.5 × ULN; 4. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 × institutional ULN (patients with hepatic metastases must have AST/ALT ≤5 × ULN). 9. Patient has adequate baseline hematologic function, as demonstrated by the following: 1. Absolute neutrophil count (ANC) ≥1.5 × 109/L. 2. Hemoglobin ≥8 g/dL and no red blood cell transfusions during the prior 14 days. 3. Platelet count ≥100 × 109/L and no platelet transfusions during the prior 14 days. 10. Male patients and their female partners of childbearing potential must agree and commit to use a barrier contraception throughout the duration of the study until at least 6 months following the last dose of study drug, in addition to their female partners using either an intrauterine device or hormonal contraception and continuing until at least 6 months following the last dose of study drug. This criterion may be waived for male patients who have had a vasectomy >6 months before signing the informed consent form. Exception: In the United States, female partners of study participants are not required to use contraception as a condition of their partners' eligibility, but female partners with child bearing potential should consider use of effect methods of contraception for the duration of their male partners' study participation and for at least 6 months following the last dose of study medication. 11. Patient has signed informed consent prior to initiation of any study-specific procedures or treatment. 12. Patient is able to adhere to the study visit schedule and other protocol requirements, including follow-up for overall survival (OS).

Exclusion Criteria:

  • to be eligible for entry into the trial. 1. Patient has evidence of progressive, metastatic castration-resistant disease, as defined by PCWG3 criteria. a. Patients with de novo small cell prostate cancer are not required to have received androgen deprivation therapy (ADT). 2. Progression during or following completion of at least 1 prior line of systemic therapy for locally advanced or metastatic prostate cancer. 3. Phases 2a and 2b Only: SCNC
  • Cohort A of Phase 2a only: 1. Patient has histologic evidence of SCNC either with archival tissue or a fresh tumor biopsy obtained during screening. Tumor biopsy tissue must be submitted for a central laboratory pathology review; however, enrollment can proceed if SCNC is determined by a local pathology review. 2. Patient has previously received at least 1 prior line of cytotoxic chemotherapy. Patients who either have refused chemotherapy or are considered unsuitable for chemotherapy may be eligible following discussion with the sponsor. 3. Must be willing to undergo metastatic tumor biopsy during Screening. Requirement may be waived in patients without safely accessible lesion or for patients with evaluable archival metastatic tumor tissue 4. Has measurable disease per RECIST 1.1 criteria. Adenocarcinoma
  • Cohort B of Phase 2a; randomized population for Phase 2b 1. Patient has histologically or cytologically confirmed adenocarcinoma of the prostate without small cell neuroendocrine features. 2. Patients with soft tissue disease must provide a fresh core or excisional biopsy or archival tissue from a site not previously irradiated for central pathology review; however enrollment may proceed if predominant adenocarcinoma without small cell neuroendocrine features is determined by local pathology review. 3. Has been treated with at least 1 but no more than 2 second generation AR pathway target agents (e.g., abiraterone acetate and/or enzalutamide or other next generation agent) and at least 1 regimen/line of taxane containing chemotherapy in the mCSPC or mCRPC setting. Patients with known actionable mutations should have progressed on applicable standard care targeted therapy or have documented intolerance to or be unsuitable for such therapy. 4. RECIST 1.1 measurable disease or detectable bone metastases by whole body bone scintigraphy. 4. Patient has serum testosterone <50 ng/dL during Screening except for those with de novo small cell prostate cancer. a. Patients with treatment-emergent SCNC without a history of bilateral orchiectomy are required to remain on luteinizing hormone-releasing hormone (LHRH) analog during the course of protocol therapy except for patients with de novo small cell prostate cancer. 5. Patient has Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. 6. Patient is ≥18 years of age. 7. Patient's acute toxic effects of previous anticancer therapy have resolved to ≤Grade 1 except for Grade 2-3 peripheral neuropathy or any grade of alopecia. 8. Patient has adequate baseline organ function, as demonstrated by the following: 1. Serum creatinine ≤1.5 times institutional upper limit of normal (ULN) or calculated creatinine clearance >50 mL/min; 2. Serum albumin ≥2.5 g/dL; 3. Total bilirubin ≤1.5 × ULN; 4. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 × institutional ULN (patients with hepatic metastases must have AST/ALT ≤5 × ULN). 9. Patient has adequate baseline hematologic function, as demonstrated by the following: 1. Absolute neutrophil count (ANC) ≥1.5 × 109/L. 2. Hemoglobin ≥8 g/dL and no red blood cell transfusions during the prior 14 days. 3. Platelet count ≥100 × 109/L and no platelet transfusions during the prior 14 days. 10. Male patients and their female partners of childbearing potential must agree and commit to use a barrier contraception throughout the duration of the study until at least 6 months following the last dose of study drug, in addition to their female partners using either an intrauterine device or hormonal contraception and continuing until at least 6 months following the last dose of study drug. This criterion may be waived for male patients who have had a vasectomy >6 months before signing the informed consent form. Exception: In the United States, female partners of study participants are not required to use contraception as a condition of their partners' eligibility, but female partners with child bearing potential should consider use of effect methods of contraception for the duration of their male partners' study participation and for at least 6 months following the last dose of study medication. 11. Patient has signed informed consent prior to initiation of any study-specific procedures or treatment. 12. Patient is able to adhere to the study visit schedule and other protocol requirements, including follow-up for overall survival (OS). Exclusion Criteria: 1. Patient has received treatment with >2 cytotoxic chemotherapy regimens for castration-resistant prostate cancer (CRPC). Chemotherapy in the hormone-sensitive setting does not count in this assessment provided the last dose was >6 months before study entry. A change in chemotherapy agents due to intolerance after brief exposure may not count in this assessment, pending review with Medical Monitor. 2. Patient has received external-beam radiation or another systemic anticancer therapy within 14 days or 5 half-lives, whichever is shorter, prior to study treatment. 3. Patient has received treatment with an investigational systemic anticancer agent within 14 days prior to study drug administration. 4. Patient has received prior treatment with an anti-PD-1, anti-PD-L1, anti-programmed death ligand 2 (PD-L2) agent or with an agent directed to another co-inhibitory T-cell receptor (e.g., cytotoxic T lymphocyte-associated antigen 4 [CTLA-4], OX-40, CD137) or requires concomitant treatment with DPP4 inhibitors. 5. Patient has an additional active malignancy that may confound the assessment of the study endpoints. If the patient has a past cancer history (active malignancy within 2 years prior to study entry) with substantial potential for recurrence, this must be discussed with the sponsor before study entry. Patients with the following concomitant neoplastic diagnoses are eligible: non-melanoma skin cancer and carcinomas in situ (including transitional cell carcinoma, anal carcinoma, and melanoma in situ). 6. Patient has clinically significant cardiovascular disease (e.g., uncontrolled or any New York Heart Association Class 3 or 4 congestive heart failure, uncontrolled angina, history of myocardial infarction, unstable angina or stroke within 6 months prior to study entry, uncontrolled hypertension or clinically significant arrhythmias not controlled by medication). 7. QT interval corrected for heart rate using Bazett's formula (QTcB) >480 msec at Screening. 8. Patient has uncontrolled, clinically significant pulmonary disease (e.g., chronic obstructive pulmonary disease, pulmonary hypertension) that in the opinion of the investigator would put the patient at significant risk for pulmonary complications during the study. 9. Patient has brain or leptomeningeal metastases that are symptomatic and progressive on imaging. Patients with a history of central nervous system (CNS) metastases must have received appropriate treatment. Central nervous system imaging is not required prior to study entry unless there is a history of CNS involvement or clinical suspicion of CNS involvement. Imaging of patients with a prior history of CNS metastases should be compared to prior imaging to discern disease progression. 10. Patient has an active autoimmune disease or Grade ≥3 non-infectious pneumonitis that has required systemic treatment in the past 2 years (i.e., with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) or treatment with drugs (e.g., neomercazol, carbimazole) that function to decrease the generation of thyroid hormone by a hyperfunctioning thyroid gland (e.g., in Graves' disease) is not considered a form of systemic treatment of an autoimmune disease. 11. Patient has a diagnosis of immunodeficiency or is receiving systemic steroid therapy at a prednisone equivalent dose of >10 mg daily for at least 1 week or other form of immunosuppressive therapy within 7 days prior to Cycle 1 Day 1 (C1D1). 12. Patient has uncontrolled intercurrent illness including, but not limited to, uncontrolled infection, suspected or active SARS-CoV-2 (COVID-19) infection, disseminated intravascular coagulation, or psychiatric illness/social situations that would limit compliance with study requirements. 13. Patient has known positive status for human immunodeficiency virus, active or chronic Hepatitis B, or Hepatitis C. Screening is not required. 14. Patient has any medical condition which, in the opinion of the investigator, places the patient at an unacceptably high risk for toxicity. 15. Any dysphagia, odynophagia, esophageal dysmotility or stricture, known GI malabsorption syndrome, or intractable diarrhea that may significantly alter the absorption of orally administered study drug. 16. Patients with history of symptomatic orthostatic hypotension within 3 months prior to enrollment. Orthostatic hypotension is defined as a drop in systolic blood pressure (BP) of ≥ 20 mmHg or diastolic BP of ≥ 10 mmHg with assumption of an upright posture.

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Randomized Phase 2 Study: Neoadjuvant Conditioning of Prostate Cancer Tumor Microenvironment Using a Novel Chemokine-Modulating Regimen


Condition: Prostate Adenocarcinoma, Stage I Prostate Cancer AJCC v8, Stage II Prostate Cancer AJCC v8, Stage IIA Prostate Cancer AJCC v8, Stage IIB Prostate Cancer AJCC v8, Stage IIC Prostate Cancer AJCC v8, Stage III Prostate Cancer AJCC v8, Stage IIIA Prostate Cancer AJCC v8, Stage IIIB Prostate Cancer AJCC v8, Stage IIIC Prostate Cancer AJCC v8

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT03899987

Sponsor: Roswell Park Cancer Institute

Phase: Phase 2

Eligibility:

  • Age: minimum 18 Years maximum N/A
  • Gender: Male

Inclusion Criteria:

  • Histologically confirmed, localized prostate adenocarcinoma patients who are planning to have a radical prostatectomy.
  • Diagnostic prostate biopsy must have been obtained within 6 months patients who had biopsies at outside facilities may be eligible if tissue availability and adequacy can be confirmed by pathology.
  • Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
  • Platelet >= 75,000/uL.
  • Hemoglobin >= 9 g/dL.
  • Hematocrit >= 27%.
  • Absolute neutrophil count (ANC) >= 1500/uL.
  • Creatinine < institutional upper limit of normal (ULN) OR creatinine clearance >= 50 mL/min for patients with creatinine levels greater than ULN.
  • Total bilirubin =< 1.5 X institutional ULN.
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 1.5 X institutional ULN.
  • Serum amylase and lipase =< 1.5 X institutional ULN.
  • Negative hepatitis panel for patients with a history of Hepatitis
  • Participant must understand the investigational nature of this study and sign an Independent Ethics Committee/Institutional Review Board approved written informed consent form prior to receiving any study related procedure.

Exclusion Criteria:

  • Patients currently treated with systemic immunosuppressive agents, including steroids, are ineligible until 3 weeks after removal from immunosuppressive treatment.
  • Patients who received hormonal therapy, 5-alpha reductase inhibitors (such as finasteride, dutasteride), chemotherapy, radiotherapy, major surgery, or biologic therapy within 3 weeks of protocol treatment.
  • Patients with active prostatitis.
  • Patients with active autoimmune disease or history of transplantation.
  • Patients with comorbid medical conditions that render them unfit for surgery.
  • Metastatic disease based on preoperative imaging.
  • Cardiac risk factors including:
  • Patients experiencing cardiac event(s) (acute coronary syndrome, myocardial infarction, or ischemia) within 3 months of signing consent
  • Patients with a New York Heart Association classification of III or IV.
  • History of upper and lower gastrointestinal ulceration, upper gastrointestinal bleeding, or perforation within the past 3 years.
  • History of bleeding disorders, known lesions at risk for bleeding, or history of recent clinically significant bleed or hemorrhage (<3months).
  • Prior allergic reaction or hypersensitivity to aspirin, or other nonsteroidal antiinflammatory drugs (NSAIDs).
  • Patients are ineligible if they plan on use of other NSAIDs at any dose during the trial. Patients who agree to stop regular NSAIDs are eligible and no wash out period is required.
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
  • Unwilling or unable to follow protocol requirements.
  • Any condition which in the investigator?s opinion deems the participant an unsuitable candidate to receive study drug.

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Phase II Trial of Rucaparib in Patients With Metastatic Hormone-Sensitive Prostate Cancer Harboring Germline DNA Repair Gene Mutations (TRIUMPH)


Condition: Prostate Cancer Metastatic

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT03413995

Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Phase: Phase 2

Eligibility:

  • Age: minimum 18 Years maximum N/A
  • Gender: Male

Inclusion Criteria:

  • Willing and able to provide written informed consent and HIPAA authorization for the release of personal health information.
  • Males aged 18 years of age and above
  • Histological or cytologic proof of adenocarcinoma of the prostate
  • Germline mutation in one or more homologous recombination DNA-repair genes (BRCA1, BRCA2, ATM, CHEK2, NBN, RAD50, RAD51C, RAD51D, PALB2, MRE11, FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM) as documented by a clinical CLIA-grade, genetic test (including but not limited to Invitae, Color Genomics, etc)
  • All patients must be ineligible for or have declined androgen deprivation therapy (ADT)-based systemic treatment
  • Absolute PSA ≥2.0 ng/ml at screening.
  • Radiographic evidence of metastatic disease by CT scan and bone scan, performed within the prior 8 weeks.
  • Serum testosterone ≥ 100 ng/dl.
  • Participants must have normal organ and bone marrow function measured within 28 days prior to administration of study treatment as defined below:
  • Hemoglobin ≥ 10.0 g/dL with no blood transfusion in the past 28 days
  • Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
  • Platelet count ≥ 100 x 109/L
  • Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN)
  • Aspartate aminotransferase (AST) (Serum Glutamic Oxaloacetic Transaminase (SGOT)) / Alanine aminotransferase (ALT) (Serum Glutamic Pyruvate Transaminase (SGPT))
  • Participants must have creatinine clearance estimated using the Cockcroft-Gault equation of ≥51 mL/min:
  • Estimated creatinine clearance = (140-age [years]) x weight (kg) serum creatinine (mg/dL) x 72
  • ECOG Performance Status <2
  • Participants must have a life expectancy ≥ 12 months.
  • Male participants and their partners, who are sexually active and of childbearing potential, must agree to the use of two highly effective forms of contraception in combination [see appendix E for acceptable methods], throughout the period of taking study treatment and for 6 months after last dose of study drug to prevent pregnancy in a partner.

Exclusion Criteria:

  • Current active second malignancy (history of non-melanoma skin cancers and superficial bladder cancers are allowed)
  • Prior ADT in the past 6 months. Prior ADT in context of neoadjuvant/adjuvant primary is allowed; prior ADT for biochemical recurrence is also allowed, as long as no ADT has been administered in past 6 months and testosterone has recovered (>100 ng/dl). The total duration of prior ADT should not exceed 24 months.
  • Prior oral anti-androgen (e.g. bicalutamide, nilutamide, enzalutamide, apalutamide), or androgen synthesis inhibitor (e.g. abiraterone, orteronel) in the past 6 months is not permitted. 5-alpha reductase inhibitor therapy (e.g. finasteride, dutasteride) is allowed, as long as subject has been stable on medication for past 6 months.
  • Presence of visceral (i.e. lung or liver) metastases >3cm in long-axis dimension.
  • Pain due to bone metastases requiring narcotic analgesics.
  • Prior treatment with intravenous chemotherapy.
  • Use of any prohibited concomitant medications (Appendix B: Medications With the Potential for Drug-Drug Interactions) within the prior 2 weeks.
  • Involvement in the planning and/or conduct of the study (applies to both Clovis Oncology staff and/or staff at the study site)
  • Previous enrollment in the present study
  • Participation in another clinical study with an investigational product during the last 1 month.
  • Any previous treatment with a PARP inhibitor, including rucaparib.
  • Resting ECG with QTc > 480 msec on 2 or more time points within a 24 hour period or family history of long QT syndrome
  • Persistent toxicities (>Common Terminology Criteria for Adverse Event (CTCAE) grade 2) caused by previous cancer therapy, excluding alopecia.
  • Patients with myelodysplastic syndrome/acute myeloid leukemia or with features suggestive of MDS/AML.
  • Major surgery within 2 weeks of starting study treatment, and patients must have recovered from any effects of any major surgery.
  • Poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 6 months) myocardial infarction, uncontrolled major seizure disorder, extensive interstitial bilateral lung disease, or any psychiatric disorder that prohibits obtaining informed consent.
  • Unable to swallow orally administered medication or gastrointestinal disorders likely to interfere with absorption of the study medication.
  • Immunocompromised patients, e.g., patients who are known to be serologically positive for HIV. Known active hepatitis (i.e. Hepatitis B or C) due to risk of transmitting the infection through blood or other body fluids
  • Known hypersensitivity to rucaparib or any of the excipients of the product.
  • Whole blood transfusions in the last 30 days prior to entry to the study.

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Cabazitaxel With Abiraterone Versus Abiraterone Alone Randomized Trial for Extensive Disease Following Docetaxel: The CHAARTED2 Trial


Condition: Castration Levels of Testosterone, Castration-Resistant Prostate Carcinoma, Metastatic Prostate Carcinoma in the Soft Tissue, Prostate Carcinoma Metastatic in the Bone, Stage IV Prostate Adenocarcinoma AJCC v7

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT03419234

Sponsor: ECOG-ACRIN Cancer Research Group

Phase: Phase 2

Eligibility:

  • Age: minimum 18 Years maximum N/A
  • Gender: Male

Inclusion Criteria:

  • Histologically confirmed diagnosis of prostate cancer (adenocarcinoma of the prostate)
  • Previous chemotherapy with at least 3 cycles of docetaxel for hormone-sensitive metastatic prostate cancer
  • Metastatic disease as evidenced by the presence of soft tissue and/or bone metastases on imaging studies (CT/magnetic resonance imaging [MRI] of abdomen/pelvis, bone scintigraphy or NaF PET/CT)
  • Ability to swallow abiraterone acetate tablets as a whole
  • All patients must be receiving standard of care androgen deprivation treatment (surgical castration versus LHRH agonist or antagonist treatment); subjects receiving LHRH agonist or antagonist must continue treatment throughout the time on this study
  • Patients must have castrate serum level of testosterone of < 50 ng/dL (< 1.73 nmol/L)
  • Patients must have progressive disease while receiving androgen deprivation therapy defined by any one of the following as per the Prostate Cancer Clinical Trials Working Group 3 (PCWG3) criteria for PSA, measurable disease or non-measurable (bone) disease during treatment with ADT:
  • PSA: At least two consecutive rises in serum PSA, obtained at a minimum of 1-week intervals, with the final value >= 2.0 ng/mL
  • Measurable disease (by RECIST 1.1): > 20% increase in the sum of the longest diameters of all measurable lesions or the development of new measurable lesions; the short axis of a target lymph node must be more that 15 mm to be assessed for change in size
  • Non-measurable (bone) disease: The appearance of two or more new areas of uptake on bone scan (or NaF PET/CT) consistent with metastatic disease compared to previous imaging during castration therapy; the increased uptake of pre-existing lesions on bone scan will not be taken to constitute progression, and ambiguous results must be confirmed by other imaging modalities (e.g. X-ray, CT or MRI)
  • Patients may or may not have been treated previously with a nonsteroidal antiandrogen, such as flutamide, bicalutamide or nilutamide; for patients previously treated with an antiandrogen, they must be off treatment for at least 4 weeks (for flutamide) or 6 weeks (for bicalutamide or nilutamide) prior to registration and must have shown PSA progression after discontinuing the anti-androgen
  • Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
  • Absolute neutrophil count (ANC) >= 1500/mm^3
  • Hemoglobin (HgB) >= 9.0 gr/dL
  • Platelets >= 100,000/mm^3
  • Creatinine < 2.0 mg/dL
  • Patients must be informed of the experimental nature of the study and its potential risks, and must sign an Institutional Review Board (IRB)-approved written informed consent form indicating such an understanding
  • Patients with resected or irradiated brain metastases or those treated with stereotactic radiation therapy are eligible to enroll, provided that they do not require treatment with steroids that exceeds 10 mg of prednisone daily or equivalent
  • Sexually active males must use an accepted and effective method of double barrier contraception or abstain from sexual intercourse for the duration of their participation in the study and for 26 weeks after the last dose of study drug
  • NaF PET/CT OPTIONAL SUB-STUDY

Eligibility Criteria:

  • Ability to lie still for imaging
  • Weight =< 300 lbs (pounds)

Exclusion Criteria:

  • Any prior chemotherapy or androgen receptor (AR)-directed therapy for CRPC, (e.g. docetaxel, cabazitaxel, mitoxantrone, abiraterone acetate, ketoconazole, or enzalutamide); previous treatment with radium-223 or sipuleucel-T is allowed
  • Pure small cell or other variant (non-adenocarcinoma) prostate cancer histology for which treatment with abiraterone would not be considered appropriate
  • Patients may not be receiving other therapeutic investigational agents or be receiving concurrent anticancer therapy other than standard androgen deprivation therapy; concurrent treatment with agents to prevent skeletal-related events (such as zoledronic acid or denosumab) will be allowed as long as it was initiated prior to study entry
  • Any medical condition for which prednisone (corticosteroid) is contraindicated
  • If total bilirubin is > upper limit of normal (ULN) (NOTE: in subjects with Gilbert?s syndrome, if total bilirubin is > ULN, measure direct and indirect bilirubin and if direct bilirubin is within normal range, subject may be eligible) or
  • Alanine (ALT) or aspartate (AST) aminotransferase > 1.5 x ULN
  • Active infection requiring treatment with antibiotics
  • History of adrenal insufficiency or hypoaldosteronism
  • Myocardial infarction or arterial thrombotic event within 6 months, heart failure of New York Heart Association class II or higher, uncontrolled angina, severe uncontrolled ventricular arrhythmia
  • External beam radiation therapy within 4 weeks of registration
  • Prior history of allergic reactions to G-CSF
  • Prior history of allergic reactions to docetaxel and/or to medications formulated with polysorbate 80
  • History of active malignancy; patients with a history of cancer that has been adequately treated and are free of disease recurrence for 3 years or more are allowed to participate; patients with non-melanoma skin cancers or carcinoma in situ of the bladder that have been adequately excised are eligible to participate
  • Life expectancy of < 12 months at screening
  • Grade >= 2 neuropathy

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Bone Response After Luteinizing Hormone-releasing Hormone Analogue and Enzalutamide +/- Zoledronic Acid in Prostate Cancer Patients With Hormone Sensitive Metastatic Bone Disease: a Prospective, Phase II, Randomized, Multicenter Study


Condition: Prostate Cancer, Bone Metastases

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT03336983

Sponsor: Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia

Phase: Phase 2

Eligibility:

  • Age: minimum 18 Years maximum N/A
  • Gender: Male

Inclusion Criteria:

  • 1. Histological diagnosis of prostate carcinoma, 2. Age > 18 years, 3. Metastatic disease documented as the presence of bone lesions on bone scan associated or not to soft tissue lesions measurable at computed tomography (CT) scan or Magnetic Resonance Imaging (MRI), 4. No previous hormone or chemotherapeutic treatments given for prostate carcinoma (patients that are receiving LHRH-A therapy for less than 4 months are admitted), 5. Eastern Cooperative Oncology Group (ECOG) performance status of 0
  • 1, 6. Expected life expectancy ≥ 6 months, 7. Subject capable to swallow the Study's medication and to comply with the Study's requirements, 8. Signed informed consent.

Exclusion Criteria:

  • 1. Presence of active serious disease, active infection or co-comorbidity that may prevent the study enrollment make (at the discretion of the clinical Investigator), 2. Known or suspected brain metastases or active leptomeningeal dissemination, 3. History of other malignant neoplasm during the previous 5 years, different from the non-melanoma skin carcinoma, 4. Absolute Neutrophil Count (ANC) < 1.500/µL, platelet < 100.000/µL, or hemoglobin < 5,6 mmol/L (< 9 g/dL) at Screening Visit (notably: patients must not receive neither any growth factor during the previous 7 days nor any blood transfusion during the 28 days preceding the hematology sampling performed at Screening), 5. Total bilirubin, alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2,5 x upper limit of normal (ULN) at Screening Visit, 6. Creatinine > 177 µmol/L (> 2 mg/dL) at Screening Visit, 7. Albumin ≤ 30 g/L (≤ 3,0 g/dL) at Screening Visit, 8. History of seizures or any other seizure-predisposed pathology; history of loss of consciousness or transitory ischaemic attack during the 12 months preceding the Screening visit, 9. Clinically significant cardiovascular disease including:
  • myocardial infarction (6 months preceding the screening)
  • uncontrolled angina (3 months preceding the screening)
  • Congestive heart failure New York Heart Association (NYHA) class 3 or 4, congestive heart failure NYHA class 3 or 4 in the past, unless a screening echocardiogram or multi-gated acquisition scan performed within three months results in a left ventricular ejection fraction that is ≥ 45%;
  • History of clinically significant ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, torsades de pointes);
  • History of Mobitz II second degree or third degree heart block without a permanent pacemaker in place;
  • Hypotension as indicated by systolic blood pressure < 86 millimeters of mercury (mmHg) at the Screening visit;
  • Bradycardia as indicated by a heart rate of < 50 beats per minute on the Screening ECG;
  • Uncontrolled hypertension as indicated by systolic blood pressure > 170 mmHg or diastolic blood pressure > 105 mmHg at the Screening visit; 10. Gastrointestinal disorder affecting absorption (e.g., gastrectomy, active peptic ulcer disease within last 3 months); 11. Major surgery within 4 weeks of enrollment (Day 1 Visit); 12. Radiation therapy for treatment of the primary tumor within 3 weeks of enrollment (Day 1 visit); 13. Use of herbal products that may have hormonal anti-prostate cancer activity and/or are known to decrease Prostate-specific antigen (PSA) levels (e.g., saw palmetto) or systemic corticosteroids greater than the equivalent of 10 mg of prednisone per day within four weeks of enrollment (Day 1 visit); 14. Any condition or reason that, in the opinion of the Investigator, interferes with the ability of the patient to participate in the trial, which places the patient at undue risk, or complicates the interpretation of safety data.

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A Phase 2 Trial of Radium Ra 223 Dichloride in Combination With Androgen Deprivation Therapy and Stereotactic Body Radiation Therapy for Patients With Oligometastatic Castration Sensitive Prostate Cancer


Condition: Prostate Adenocarcinoma

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT03361735

Sponsor: City of Hope Medical Center

Phase: Phase 2

Eligibility:

  • Age: minimum 18 Years maximum N/A
  • Gender: All

Inclusion Criteria:

  • Documented informed consent of participant and/or legally authorized representative
  • Agreement to provide archival primary or metastatic tumor tissue if available
  • Eastern Cooperative Oncology Group (ECOG) =< 2
  • Life expectancy > 12 months
  • Histologic diagnosis of prostate adenocarcinoma * Pure small cell carcinoma will be excluded; however, component of neuroendocrine /small cell differentiation will be allowed provided that adenocarcinoma constitutes majority of the tissue specimen
  • Stage M1 * Metastatic disease can be documented by bone scan or computed tomography (CT) scan or magnetic resonance imaging (MRI) or positron emission tomography (PET)/CT or the combination of these tests
  • Up to 4 metastatic lesions:
  • Must have at least 1 bone lesion AND each non-visceral lesion should be less than 5 cm
  • Visceral lesions will be limited to one lung lesion (< 2 cm) or one lymph node; no liver lesions allowed; lymph nodes allowed provided they are not in a field of prior radiation, and if amenable to SBRT (to be reviewed by principal investigator [PI])
  • Two lesions can be in close proximity (i.e. within 5 cm of each other) if they meet radiation SBRT normal tissue toxicity requirements
  • If have untreated primary prostate cancer: must undergo debulking prostatectomy
  • If had prior definitive radiation therapy to the prostate: no evidence of locally persistent or recurrent prostate cancer on digital rectal exam (DRE) and imaging studies (CT or MRI); retreatment to local residual-recurrent disease will result in potential eligibility to be reviewed by PI on a case-by-case basis
  • Does not have castration resistant disease * Castration resistance defined as progression of disease despite serum testosterone level of < 50 ng/dL
  • PSA >= 0.2 prior to start of androgen deprivation treatment
  • Initiated 28 (+ 7) days of androgen deprivation therapy (ADT) prior to day 1 of protocol therapy * Only luteinizing hormone-releasing hormone (LHRH) agonist/antagonist treatment is considered ADT, bicalutamide or other antiandrogens used alone do not count
  • May have received prior hormonal therapy in the context of definitive treatment of a primary tumor * Patients may have had one prior systemic non-chemotherapeutic treatment (i.e. immunotherapy, receptor tyrosine kinase inhibitor, antiangiogenic agent, differentiating agent) for recurrent or metastatic disease
  • Must have refused standard of care chemotherapy for metastatic disease
  • Recovered from all acute side-effects (except alopecia) related to previous systemic therapy
  • Absolute neutrophil count (ANC) >= 1,500/mm^3 (to be performed within 14 days prior to day 1 of protocol therapy) * NOTE: growth factor support is not permitted to normalize baseline ANC parameters, however subsequent growth factor administration is permitted as standard supportive care
  • Platelets >= 100,000/mm^3 (to be performed within 14 days prior to day 1 of protocol therapy) * NOTE: transfusion of blood products are not allowed to normalize baseline blood parameters, however subsequent transfusions are allowed per standard supportive care guidelines
  • Hemoglobin (HgB) >= 9.0 g/dL (to be performed within 14 days prior to day 1 of protocol therapy) * NOTE: transfusion of blood products are not allowed to normalize baseline blood parameters, however subsequent transfusions are allowed per standard supportive care guidelines
  • Total serum bilirubin =< 2 x upper limit of normal (ULN) (to be performed within 14 days prior to day 1 of protocol therapy)
  • Aspartate aminotransferase (AST) =< 2.5 x ULN (to be performed within 14 days prior to day 1 of protocol therapy)
  • Alanine aminotransferase (ALT) =< 2.5 x ULN (to be performed within 14 days prior to day 1 of protocol therapy)
  • Creatinine =< 2.5 mg/dL (to be performed within 14 days prior to day 1 of protocol therapy)

Exclusion Criteria:

  • Prior radium Ra 223 dichloride
  • Prior or concomitant chemotherapy for metastatic or recurrent disease with the following exceptions:
  • Prior chemotherapy for local primary disease is permitted
  • Bisphosphonates or receptor activator of nuclear factor kappa-Β (RANK) ligand inhibitors are allowed at doses and schedule consistent with the treatment or prevention of osteoporosis
  • Prior radiation treatment for metastatic disease
  • Concomitant radiation treatment to primary prostate site
  • Orchiectomy
  • Unstable medical comorbidities (i.e. uncontrolled cardiac comorbidities)
  • Metastases that in the judgment of investigator-radiologist are not amenable to SBRT
  • History of brain metastases or who currently have treated or untreated brain metastases
  • Uncontrolled human immunodeficiency virus (HIV) infection
  • Any other condition that would, in the investigator's judgement, contraindicate the patient's participation in the clinical study due to safety concerns with clinical study procedures
  • Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)

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A Phase II Study of Neoadjuvant Androgen Deprivation Therapy Combined With Enzalutamide and Abiraterone Using Multiparametric MRI and 18F-DCFPyL-PET/CT in Newly Diagnosed Prostate Cancer


Condition: Castrate Sensitive Prostate Cancer

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT03860987

Sponsor: National Cancer Institute (NCI)

Phase: Phase 2

Eligibility:

  • Age: minimum 18 Years maximum N/A
  • Gender: Male

Inclusion Criteria:

  • 1. Patients must have histologically or cytologically confirmed prostate cancer confirmed by the Laboratory of Pathology, NCI, OR documented histopathological confirmation of prostate cancer from a CLIA-certified laboratory. 2. Must have previously untreated (with definitive therapy ie: surgery, systemic treatment or radiation therapy) prostate cancer with intermediate or high risk features defined as:
  • Intermediate risk (patient must have at least one of the features listed below):
  • PSA level is between 10 and 20 ng/ml,
  • Gleason score is 7, OR
  • Stage T2b or T2c,
  • High risk (patient must have at least one of the features listed below):
  • PSA > 20 at the time of diagnosis,
  • Gleason 8 or higher,
  • Seminal vesicle involvement,
  • Possible (on MRI) extra-capsular extension (T3 disease), OR
  • Clinical stage T4 3. Patients must be eligible for and must be planning to undergo radical prostatectomy 4. Patients must have testosterone levels greater than or equal to 100 ng/dL 5. Men age greater than or equal to18 years. Children are excluded because prostate cancer is not common in pediatric populations. Women are not eligible because this disease occurs only in men. 6. ECOG performance status 0-1. 7. Patients must have adequate organ and marrow function, and other laboratory parameters as defined below:
  • hemoglobin greater than or equal to 9 g/dL
  • total bilirubin within normal institutional limits
  • AST(SGOT)/ALT(SGPT) less than or equal to 3 X institutional upper limit of normal
  • creatinine within normal institutional limits; OR,
  • creatinine clearance greater than or equal to 30 mL/min/1.73 m2 for patients with creatinine levels above institutional normal (calculated via EGFR) 8. Lesions within prostate must be detectable on MRI for biopsy. 9. The effects of enzalutamide and abiraterone on the developing human fetus are unknown. For this reason and because androgen receptor antagonists as well as other therapeutic agents used in this trial are known to be teratogenic, male participants and their female partners of child bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence). Male participants should use a condom if having intercourse with a pregnant woman. Additionally, a condom plus another effective method of birth control is recommended during therapy and for 3 months after treatment for male participants having intercourse with a woman of reproductive potential. Should a woman become pregnant or suspect she is pregnant while her partner is participating in this study, she should inform her treating physician immediately and her partner should inform the study team. 10. Ability of subject to understand and the willingness to sign a written informed consent document. 11. Willingness to adhere to protocol requirements (e.g., required biopsies). 12. Willingness to travel to NIH for follow-up visits.

Exclusion Criteria:

  • 1. Patients who are receiving any other investigational agents (in the past 28 days) or herbal medications (within 1 day prior to registration). 2. Patients with evidence of distant metastatic disease beyond N1 (regional) lymph nodes on conventional imaging studies (e.g., CT, MRI or Bone Scan). 3. Patients who have received any prior definitive therapy (ie: surgery, systemic treatment or radiation therapy) for prostate cancer. 4. History of allergic reactions attributed to compounds of similar chemical or biologic composition to enzalutamide, abiraterone or other agents used in study. 5. Clinically significant cardiac disease, e.g., New York Heart Association (NYHA) classes III-IV; uncontrolled angina, uncontrolled arrhythmia or uncontrolled hypertension (greater than or equal to 160/100 mmHg on two consecutive readings), myocardial infarction in the previous 6 months as confirmed by an electrocardiogram (ECG). 6. Contraindication to biopsy:
  • Bleeding disorders for which a prostate biopsy would pose a bleeding risk
  • PT/PTT greater than or equal to 1.5 times the upper limit of normal
  • Artificial heart valve 7. Contraindication to MRI:
  • Patients weighing more than the weight limit or unable to fit the scanner
  • Allergy to MR contrast agent
  • Patients with pacemakers, cerebral aneurysm clips, shrapnel injury or implantable electronic device 8. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, or psychiatric illness/social situations that would limit compliance with study requirements. 9. HIV-positive patients on antiretroviral therapy are ineligible because of potential pharmacokinetic interactions with study drugs. However, patients with long-standing (>5 years) HIV on antiretroviral therapy > 1 month (undetectable HIV viral load and CD4 count > 150 cells/microliter) may be eligible if the PI determines no anticipated clinically significant drug-drug interactions. 10. Patients undergoing active treatment for Hepatitis B or C infections. 11. Patients who have taken medications that are strong inhibitors or inducers of CYP3A4 or PgP within 14 days prior to enrollment and need to remain on these medications. 12. Other medications used for urinary symptoms including 5-alpha reductase inhibitors (finasteride and dutasteride) and alternative medications known to alter PSA (e.g., phytoestrogens and saw palmetto) cannot be taken while patients are receiving enzalutamide and abiraterone. 13. Contraindication to steroid use. 14. Patients with malignancy within the past 3 years for which study drugs or a prostatectomy is a contraindication.

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PEACE V: A Randomized Phase II Trial for the Salvage Treatment of OligoRecurrent Nodal Prostate Cancer Metastases (STORM)


Condition: Prostate Cancer, Prostate Cancer Metastatic, Metastatic Cancer, Oligometastatic Cancer

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT03569241

Sponsor: University Ghent

Phase: Phase 2

Eligibility:

  • Age: minimum 18 Years maximum N/A
  • Gender: Male

Inclusion Criteria:

  • Histologically proven initial diagnosis of adenocarcinoma of the prostate
  • Biochemical relapse of prostate cancer following radical local prostate treatment (radical prostatectomy, primary radiotherapy or radical prostatectomy +/- prostate bed adjuvant/ salvage radiotherapy) according to the EAU guidelines 2016.
  • Following radical prostatectomy, patients with a biochemical relapse are eligible in case a nodal relapse is detected in the pelvis even in the absence of prior postoperative prostate bed radiotherapy (adjuvant or salvage).
  • In case of a suspected local recurrence following primary radiotherapy, a biopsy should confirm local recurrence and patients with a confirmed local recurrence are eligible in case they also undergo a local salvage therapy. If imaging rules out local relapse, patients are eligible.
  • Nodal relapse in the pelvis on choline, PSMA or FACBC PET-CT with a maximum of 3 positive nodal lymph nodes. The upper limit of the pelvis is defined as the aortic bifurcation.
  • WHO performance state 0-1
  • Age >18 years
  • Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial
  • Before patient registration/randomization, written informed consent must be given according to ICH/GCP, and national/local regulations.

Exclusion Criteria:

  • Bone or visceral metastases
  • Para-aortic lymph node metastases (above the aortic bifurcation)
  • Local relapse in the prostate gland or prostate bed not suitable for a curative treatment
  • Previous irradiation of the pelvic and or para-aortic nodes
  • Serum testosterone level <50ng/dl or 1.7 nmol/L at time of randomization
  • Symptomatic metastases
  • Lymph node metastases in previously irradiated areas resulting in dose constraint violation
  • Contraindications to pelvic radiotherapy (chronic pelvic inflammatory bowel disease)
  • Contraindications to androgen deprivation therapy
  • PSA rise while on active treatment with (LHRH-agonist, LHRH-antagonist, anti-androgen, estrogen
  • Previous treatment with cytotoxic agent for PCa
  • Treatment during the past month with products known to influence PSA levels (e.g. fluconazole, finasteride, corticosteroids,…)
  • Other active malignancy, except non-melanoma skin cancer or other malignancies with a documented disease-free survival for a minimum of 3 years before randomization.

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High Dose Testosterone + Carboplatin in Men With Advanced Prostate Cancer


Condition: Castration-resistant Prostate Cancer, Homologous Recombination Deficiency

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT03522064

Sponsor: St Vincent's Hospital, Sydney

Phase: Phase 2

Eligibility:

  • Age: minimum 18 Years maximum N/A
  • Gender: Male

Inclusion Criteria:

  1. Males with histologically confirmed adenocarcinoma of the prostate
  2. Confirmed HRD (Homologous recombination defect) in germline and/or somatic DNA analysis (tumour or blood), by a validated assay (see Appendix 1). Mutations in HR genes not listed in appendix 1 will be considered in literature suggests pathogenicity. A maximum of 10 uncharacterised or heterozygous mutations will be included.
  3. Age ≥ 18 years
  4. ECOG performance status ≤ 1
  5. Rising PSA confirmed on two sequential tests ≥1 week apart and a minimum value of 2 ug/L despite castrate levels of testosterone
  6. Serum testosterone < 1.7 nmol/L and on an LHRH agent or post orchidectomy ≥ 1 year.
  7. Washout of ≥ 4 weeks from prior line of treatment, radiotherapy or surgery (aside from LHRH agent)
  8. Adequate bone marrow function (platelets > 100 x 109/L, ANC > 1.5 x 109/L, Hb >100)
  9. Adequate liver function (ALT/AST < 1.5 x ULN, bilirubin < 2 x ULN)
  10. Adequate renal function (creatinine clearance > 50 ml/min)
  11. Adequate cardiac function and reserve after cardiology assessment
  12. Archived tissue sample available or willingness to undergo fresh biopsy
  13. Willing and able to comply with all study requirements, including treatment, timing and/or nature of required assessments
  14. Signed, written informed consent

Exclusion Criteria:

  1. Contraindications to investigational product
  2. Pain due to metastatic prostate cancer requiring opioid analgesics
  3. Evidence of disease progression in sites or extent that, in the opinion of the investigator, would put the patient at risk from testosterone therapy and its potential for initial tumour flare (eg: femoral metastasis at risk of fracture, ureteric obstruction due to nodal disease or cord compression due to spinal metastases).
  4. Previous treatment with platinum chemotherapy and/or a PARP inhibitor. However up to 8 men with prior treatment to these agents will be included as an exploratory cohort.
  5. Life expectancy of less than 3 months.
  6. Brain metastases or leptomeningeal disease
  7. History of thromboembolic event and not currently on anticoagulation
  8. Prior myocardial infarction or unstable angina within 2 years of study entry
  9. Haematocrit ≥ 50%, untreated severe obstructive sleep apnoea or poorly controlled heart failure (NYHA >1)
  10. History of another malignancy within 5 years prior to registration. Patients with a past history of adequately treated carcinoma-in-situ, basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or superficial transitional cell carcinoma of the bladder are eligible. Patients with a history of other malignancies are eligible if they have been continuously disease free for at least 5 years after definitive primary treatment.
  11. Concurrent illness, including severe infection that may jeopardize the ability of the patient to undergo the procedures outlined in this protocol with reasonable safety.
  12. Presence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule, including alcohol dependence or drug abuse.

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An Open-Label Multi-Center Phase II Study of Neoadjuvant Atezolizumab-Based Combination Therapy in Men With Localized Prostate Cancer Prior to Radical Prostatectomy


Condition: Prostate Adenocarcinoma, Prostate Cancer, Localized Prostate Cancer

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT03821246

Sponsor: Lawrence Fong

Phase: Phase 2

Eligibility:

  • Age: minimum 18 Years maximum N/A
  • Gender: Male

Inclusion Criteria:

  • 1. Histologically confirmed adenocarcinoma of the prostate. a. Subjects with small cell or neuroendocrine PC are not eligible. 2. Eligible for radical prostatectomy as determined by urologic oncology surgeon, and subject consents to proceeding with radical prostatectomy. a. Deemed by urologic oncology surgeon to be appropriate for a "window-of-opportunity"study. 3. Only patients with high-risk disease are eligible for the safety lead-in for each cohort. Patients with intermediate-risk disease will be included after interim analyses is complete for the corresponding cohort and the PI has determined that it is safe to do so. 4. Availability of a representative tumor specimen that is suitable for the planned study analyses, as determined by the Principal Investigator. 1. A formalin-fixed paraffin-embedded (FFPE) tumor specimen in a paraffin block (preferred) or at least 15 slides containing unstained, freshly cut, serial sections should be submitted along with an associated pathology report prior to study treatment. If only 10-14 slides are available, the patient may still be eligible for the study, after Principal Investigator approval has been obtained. 2. If archival tumor tissue is unavailable or is determined to be unsuitable for required testing, tumor tissue must be obtained from a biopsy performed at screening. Refer to Section 6.3 for additional information on tumor specimens collected at screening. 5. Subjects have not received any prior systemic or locally directed therapy for PC (see exclusion criteria). 6. Age >= 18 years 7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 8. Requirements for organ and marrow function:
  • Hemoglobin >= 9 g/dL
  • Participants must not have been transfused within 2 weeks prior to screening to meet this criterion
  • Absolute neutrophil count >= 1,500/microliter (uL) without granulocyte colonystimulating factor support
  • Absolute lymphocyte count >= 500/uL
  • Platelets >= 100,000/uL without transfusion
  • Total bilirubin < 1.5 x institutional upper limit of normal (ULN) (known Gilbert disease: < 3 x ULN)
  • Alkaline phosphatase < 2 x institutional ULN
  • Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase (SGOT)) =< 2 x institutional ULN
  • Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase (SGPT)) =< 2 x institutional ULN
  • International normalized ratio (INR) or activated partial thromboplastin time (aPTT) < 1.5 x institutional ULN for subjects not receiving therapeutic anticoagulation
  • Creatinine clearance >= 30 mL/min (calculated using the Cockcroft-Gault formula)
  • Serum creatinine <=1.6 mg/dL (141 μmol/L) in female patients and ≤1.9 mg/dL (168 μmol/L) in male patients . Patients with serum creatinine values exceeding limits may be eligible for the study if their estimated glomerular filtration rates (GFR) are >30 9. Testosterone level > 150 ng/dL. 10. Contraception: agreement to remain abstinent or use contraceptive measures, and agreement to refrain from donating sperm as defined below: 1. With female partners of childbearing potential: men must remain abstinent or use a condom plus an additional contraceptive method that together result in a failure rate of < 1% per year during the treatment period and for 4 months after the last dose of study treatment. Men must refrain from donating sperm during the same period 2. With pregnant female partners: men must remain abstinent or use a condom during the treatment period and for 4 months after the last dose of study treatment to avoid exposing the embryo 3. Abstinence: the reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception 11. For patients receiving therapeutic anticoagulation: stable anticoagulant regimen > 3 months. 12. Ability to understand a written informed consent document, and the willingness to sign it. 13. Ability to comply with the study protocol, in the investigator's judgment. Exclusion Criteria: 1. Evidence of metastatic disease as determined by standard staging scans. a. Staging scans should be performed per urologic standard of care for patients undergoing radical prostatectomy [per American Urological Association (AUA)/National Comprehensive Cancer Network (NCCN) guidelines]. 2. Not a candidate for radical prostatectomy as determined by treating urologic oncology surgeon 3. Any prior systemic therapy for PC, including antiandrogens, androgen deprivation therapy [gonadotropin-releasing hormone (GnRH) agonist or antagonist], chemotherapy, targeted therapy, immunotherapy, OR radiopharmaceuticals. a. Subjects who are on finasteride or dutasteride must discontinue therapy and undergo a washout period of 6 weeks to become eligible for the study. Screening procedures should begin following the washout period 4. Prior radiotherapy for PC. 5. Any history of prior malignancy, except: 1. Non-melanoma skin cancer treated with curative intent 2. Carcinoma-in-situ (CIS) treated with curative intent, without evidence of recurrence or disease progression for 3 years 3. Appropriately treated Stage I uterine cancer 4. All other cancer: treated with curative intent and without evidence of disease on standard of care follow-up for 5 years 6. Active or history of autoimmune disease or immune deficiency, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjogren's syndrome, Guillain-Barre syndrome, or multiple sclerosis, with the following exceptions: 1. Subjects with a history of autoimmune-related hypothyroidism who are on thyroid-replacement therapy, with a stable dose > 3 months, are eligible for the study 2. Subjects with controlled type 1 diabetes mellitus who are on an insulin regimen, with a Glycated hemoglobin (hemoglobin A1C) < 7.0 are eligible for the study. All subjects with controlled type 2 diabetes mellitus are eligible for the study 3. Subjects with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis are excluded from the study) are eligible for the study provided all of the following conditions are met:
  • Rash covers < 10% of body surface area
  • Disease is well controlled at baseline and requires only low-potency topical steroids
  • No occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high-potency or oral corticosteroids within the previous 12 months 7. History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or any evidence of active, non-infectious pneumonitis requiring corticosteroids. 8. History of prior positive human immunodeficiency virus (HIV) test. 9. Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (chronic or acute). 1. Subjects with a past or resolved HBV infection are eligible for this study. 2. HCV positivity is defined as having a positive HCV antibody test followed by a positive HCV ribonucleic acid (RNA) test at screening; the HCV RNA test will only be performed for subjects who have a positive HCV antibody test. 10. Significant cardiovascular disease, such as New York Heart Association class III or greater cardiac disease, myocardial infarction, or cerebrovascular accident within 3 months prior to initiation of study treatment, unstable arrhythmia, or unstable angina. 11. Active chronic obstructive pulmonary disease (COPD) requiring use of home oxygen (O2) or systemic steroid therapy > 10 mg prednisone (or equivalent) daily. 12. Asthma requiring systemic corticosteroids > 10 mg prednisone (or equivalent) daily. Inhaled corticosteroids for the treatment of asthma are permitted. 13. Major surgical procedure (including joint surgery) other than for diagnosis within 4 weeks prior to initiation of study treatment, or anticipation of need for a major surgical procedure during the course of the study a. Placement of central venous access catheter (e.g., port or similar) is not considered a major surgical procedure and is therefore permitted. 14. Severe infection within 4 weeks prior to initiation of study treatment, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia. 15. Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug, may affect the interpretation of the results, or may render the patient at high risk from treatment complications. 16. Prior allogeneic stem cell or solid organ transplantation. 17. Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study treatment, or anticipation of need for such a vaccine during the course of the study or within 5 months after the last dose of atezolizumab. Note: Because IL-6 inhibition may interfere with the normal immune response to new antigen, patients should be brought up to date on all recommended vaccinations, except for live vaccines, prior to initiation of therapy with tocilizumab to maximize vaccine response. 18. Treatment with investigational therapy within 28 days prior to initiation of study treatment. 19. Prior treatment with adenosine-axis inhibitors, cluster of differentiation 137 (CD137) agonists or immune checkpoint blockade therapies, including anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), ant-PD-1, and anti-PD-L1 therapeutic antibodies. 20. Treatment with systemic immunostimulatory agents [including, but not limited to, interferon and interleukin 2 (IL-2)] within 4 weeks or five half-lives of the drug (whichever is longer) prior to initiation of study treatment. 21. Treatment with systemic immunosuppressive medication (including, but not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor (TNF)- agents) within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressive medication during the course of the study, with the following exceptions: 1. Patients who receive acute, low-dose systemic immunosuppressant medication or a one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of corticosteroids for a contrast allergy) are eligible for the study 2. Patients who receive mineralocorticoids (e.g., fludrocortisone), corticosteroids for chronic obstructive pulmonary disease (COPD) or asthma (=< 10 mg prednisone or equivalent), or low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency (=< 10 mg prednisone or equivalent) are eligible for the study. 22. History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins. 23. Known hypersensitivity to Chinese hamster ovary cell products or to any component of the atezolizumab formulation. 24. Known allergy or hypersensitivity to any of the study drugs of their excipients. 25. Previous treatment with any cell-depleting therapies, including investigational agents or approved therapies, some examples include: CAMPATH, anti-cluster of differentiation 4 (CD4), anti-cluster of differentiation 5 (CD5), anti-cluster of differentiation 3 (CD3), anti-Cluster of Differentiation 19 (CD19) and anti-Cluster of Differentiation 20 (CD20). 26. Treatment with intravenous gamma globulin, plasmapheresis or Prosorba column within 6 months of baseline. 27. Previous treatment with tocilizumab (an exception to this criterion may be granted for single dose exposure upon application to the Sponsor-Investigator on a case-by-case basis). 28. Any previous treatment with alkylating agents such as chlorambucil, or with total lymphoid irradiation. 29. History of severe allergic or anaphylactic reactions to human, humanized or murine monoclonal antibodies. 30. Evidence of serious uncontrolled concomitant, nervous system, pulmonary, renal, hepatic, endocrine (include uncontrolled diabetes mellitus) or gastrointestinal disease (including complicated diverticulitis, ulcerative colitis, or Crohn's disease). 31. Any history of recent serious bacterial, viral, fungal, or other opportunistic infections. 32. Primary or secondary immunodeficiency (history of or currently active) unless related to primary disease under investigation. 33. Any medical or psychological condition that in the opinion of the principal investigator would interfere with safe completion of the trial. 34. Pregnant women or nursing (breast feeding) mothers. 35. Neuropathies or other conditions that might interfere with pain evaluation unless related to primary disease under investigation. 36. Patients with lack of peripheral venous access Additional Exclusion Criteria for Cohort B (atezolizumab + etrumadenant): 37. Treatment with known P-glycoprotein (P-gp) substrates with a narrow therapeutic window, administered orally (e.g., digoxin) within 4 weeks or 5 half-lives of the drug (whichever is longer) prior to initiation of study treatment. 38. Treatment with known strong CYP3A4 inducers (e.g., rifampin, phenytoin, carbamazepine, phenobarbital, and St. John's Wort) and strong CYP3A4 inhibitors (eg,clarithromycin, grapefruit juice, itraconazole, ketoconazole, posaconazole, telithromycin,and voriconazole) within 4 weeks or 5 half-lives of the drug (whichever is longer) prior to initiation of study treatment. 39. Treatment with known breast cancer resistance protein (BCRP) substrates with a narrow therapeutic window, administered orally (e.g., prazosin, rosuvastatin) within 4 weeks or 5 half-lives of the drug (whichever is longer) prior to initiation of study treatment. Additional

Exclusion Criteria:

  • ). 6. Age >= 18 years 7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 8. Requirements for organ and marrow function:
  • Hemoglobin >= 9 g/dL
  • Participants must not have been transfused within 2 weeks prior to screening to meet this criterion
  • Absolute neutrophil count >= 1,500/microliter (uL) without granulocyte colonystimulating factor support
  • Absolute lymphocyte count >= 500/uL
  • Platelets >= 100,000/uL without transfusion
  • Total bilirubin < 1.5 x institutional upper limit of normal (ULN) (known Gilbert disease: < 3 x ULN)
  • Alkaline phosphatase < 2 x institutional ULN
  • Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase (SGOT)) =< 2 x institutional ULN
  • Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase (SGPT)) =< 2 x institutional ULN
  • International normalized ratio (INR) or activated partial thromboplastin time (aPTT) < 1.5 x institutional ULN for subjects not receiving therapeutic anticoagulation
  • Creatinine clearance >= 30 mL/min (calculated using the Cockcroft-Gault formula)
  • Serum creatinine <=1.6 mg/dL (141 μmol/L) in female patients and ≤1.9 mg/dL (168 μmol/L) in male patients . Patients with serum creatinine values exceeding limits may be eligible for the study if their estimated glomerular filtration rates (GFR) are >30 9. Testosterone level > 150 ng/dL. 10. Contraception: agreement to remain abstinent or use contraceptive measures, and agreement to refrain from donating sperm as defined below: 1. With female partners of childbearing potential: men must remain abstinent or use a condom plus an additional contraceptive method that together result in a failure rate of < 1% per year during the treatment period and for 4 months after the last dose of study treatment. Men must refrain from donating sperm during the same period 2. With pregnant female partners: men must remain abstinent or use a condom during the treatment period and for 4 months after the last dose of study treatment to avoid exposing the embryo 3. Abstinence: the reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception 11. For patients receiving therapeutic anticoagulation: stable anticoagulant regimen > 3 months. 12. Ability to understand a written informed consent document, and the willingness to sign it. 13. Ability to comply with the study protocol, in the investigator's judgment. Exclusion Criteria: 1. Evidence of metastatic disease as determined by standard staging scans. a. Staging scans should be performed per urologic standard of care for patients undergoing radical prostatectomy [per American Urological Association (AUA)/National Comprehensive Cancer Network (NCCN) guidelines]. 2. Not a candidate for radical prostatectomy as determined by treating urologic oncology surgeon 3. Any prior systemic therapy for PC, including antiandrogens, androgen deprivation therapy [gonadotropin-releasing hormone (GnRH) agonist or antagonist], chemotherapy, targeted therapy, immunotherapy, OR radiopharmaceuticals. a. Subjects who are on finasteride or dutasteride must discontinue therapy and undergo a washout period of 6 weeks to become eligible for the study. Screening procedures should begin following the washout period 4. Prior radiotherapy for PC. 5. Any history of prior malignancy, except: 1. Non-melanoma skin cancer treated with curative intent 2. Carcinoma-in-situ (CIS) treated with curative intent, without evidence of recurrence or disease progression for 3 years 3. Appropriately treated Stage I uterine cancer 4. All other cancer: treated with curative intent and without evidence of disease on standard of care follow-up for 5 years 6. Active or history of autoimmune disease or immune deficiency, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjogren's syndrome, Guillain-Barre syndrome, or multiple sclerosis, with the following exceptions: 1. Subjects with a history of autoimmune-related hypothyroidism who are on thyroid-replacement therapy, with a stable dose > 3 months, are eligible for the study 2. Subjects with controlled type 1 diabetes mellitus who are on an insulin regimen, with a Glycated hemoglobin (hemoglobin A1C) < 7.0 are eligible for the study. All subjects with controlled type 2 diabetes mellitus are eligible for the study 3. Subjects with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis are excluded from the study) are eligible for the study provided all of the following conditions are met:
  • Rash covers < 10% of body surface area
  • Disease is well controlled at baseline and requires only low-potency topical steroids
  • No occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high-potency or oral corticosteroids within the previous 12 months 7. History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or any evidence of active, non-infectious pneumonitis requiring corticosteroids. 8. History of prior positive human immunodeficiency virus (HIV) test. 9. Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (chronic or acute). 1. Subjects with a past or resolved HBV infection are eligible for this study. 2. HCV positivity is defined as having a positive HCV antibody test followed by a positive HCV ribonucleic acid (RNA) test at screening; the HCV RNA test will only be performed for subjects who have a positive HCV antibody test. 10. Significant cardiovascular disease, such as New York Heart Association class III or greater cardiac disease, myocardial infarction, or cerebrovascular accident within 3 months prior to initiation of study treatment, unstable arrhythmia, or unstable angina. 11. Active chronic obstructive pulmonary disease (COPD) requiring use of home oxygen (O2) or systemic steroid therapy > 10 mg prednisone (or equivalent) daily. 12. Asthma requiring systemic corticosteroids > 10 mg prednisone (or equivalent) daily. Inhaled corticosteroids for the treatment of asthma are permitted. 13. Major surgical procedure (including joint surgery) other than for diagnosis within 4 weeks prior to initiation of study treatment, or anticipation of need for a major surgical procedure during the course of the study a. Placement of central venous access catheter (e.g., port or similar) is not considered a major surgical procedure and is therefore permitted. 14. Severe infection within 4 weeks prior to initiation of study treatment, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia. 15. Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug, may affect the interpretation of the results, or may render the patient at high risk from treatment complications. 16. Prior allogeneic stem cell or solid organ transplantation. 17. Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study treatment, or anticipation of need for such a vaccine during the course of the study or within 5 months after the last dose of atezolizumab. Note: Because IL-6 inhibition may interfere with the normal immune response to new antigen, patients should be brought up to date on all recommended vaccinations, except for live vaccines, prior to initiation of therapy with tocilizumab to maximize vaccine response. 18. Treatment with investigational therapy within 28 days prior to initiation of study treatment. 19. Prior treatment with adenosine-axis inhibitors, cluster of differentiation 137 (CD137) agonists or immune checkpoint blockade therapies, including anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), ant-PD-1, and anti-PD-L1 therapeutic antibodies. 20. Treatment with systemic immunostimulatory agents [including, but not limited to, interferon and interleukin 2 (IL-2)] within 4 weeks or five half-lives of the drug (whichever is longer) prior to initiation of study treatment. 21. Treatment with systemic immunosuppressive medication (including, but not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor (TNF)- agents) within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressive medication during the course of the study, with the following exceptions: 1. Patients who receive acute, low-dose systemic immunosuppressant medication or a one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of corticosteroids for a contrast allergy) are eligible for the study 2. Patients who receive mineralocorticoids (e.g., fludrocortisone), corticosteroids for chronic obstructive pulmonary disease (COPD) or asthma (=< 10 mg prednisone or equivalent), or low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency (=< 10 mg prednisone or equivalent) are eligible for the study. 22. History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins. 23. Known hypersensitivity to Chinese hamster ovary cell products or to any component of the atezolizumab formulation. 24. Known allergy or hypersensitivity to any of the study drugs of their excipients. 25. Previous treatment with any cell-depleting therapies, including investigational agents or approved therapies, some examples include: CAMPATH, anti-cluster of differentiation 4 (CD4), anti-cluster of differentiation 5 (CD5), anti-cluster of differentiation 3 (CD3), anti-Cluster of Differentiation 19 (CD19) and anti-Cluster of Differentiation 20 (CD20). 26. Treatment with intravenous gamma globulin, plasmapheresis or Prosorba column within 6 months of baseline. 27. Previous treatment with tocilizumab (an exception to this criterion may be granted for single dose exposure upon application to the Sponsor-Investigator on a case-by-case basis). 28. Any previous treatment with alkylating agents such as chlorambucil, or with total lymphoid irradiation. 29. History of severe allergic or anaphylactic reactions to human, humanized or murine monoclonal antibodies. 30. Evidence of serious uncontrolled concomitant, nervous system, pulmonary, renal, hepatic, endocrine (include uncontrolled diabetes mellitus) or gastrointestinal disease (including complicated diverticulitis, ulcerative colitis, or Crohn's disease). 31. Any history of recent serious bacterial, viral, fungal, or other opportunistic infections. 32. Primary or secondary immunodeficiency (history of or currently active) unless related to primary disease under investigation. 33. Any medical or psychological condition that in the opinion of the principal investigator would interfere with safe completion of the trial. 34. Pregnant women or nursing (breast feeding) mothers. 35. Neuropathies or other conditions that might interfere with pain evaluation unless related to primary disease under investigation. 36. Patients with lack of peripheral venous access Additional Exclusion Criteria for Cohort B (atezolizumab + etrumadenant): 37. Treatment with known P-glycoprotein (P-gp) substrates with a narrow therapeutic window, administered orally (e.g., digoxin) within 4 weeks or 5 half-lives of the drug (whichever is longer) prior to initiation of study treatment. 38. Treatment with known strong CYP3A4 inducers (e.g., rifampin, phenytoin, carbamazepine, phenobarbital, and St. John's Wort) and strong CYP3A4 inhibitors (eg,clarithromycin, grapefruit juice, itraconazole, ketoconazole, posaconazole, telithromycin,and voriconazole) within 4 weeks or 5 half-lives of the drug (whichever is longer) prior to initiation of study treatment. 39. Treatment with known breast cancer resistance protein (BCRP) substrates with a narrow therapeutic window, administered orally (e.g., prazosin, rosuvastatin) within 4 weeks or 5 half-lives of the drug (whichever is longer) prior to initiation of study treatment. Additional Exclusion Criteria for Cohort C (atezolizumab + tocilizumab): 40. Known active infection or history of recurrent bacterial, viral, fungal, mycobacterial or other infections, including, but not limited to, TB (i.e., has signs and symptoms of TB) and atypical mycobacterial disease, hepatitis B and C, and herpes zoster, but excluding fungal infections of nail beds.

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PLATI-PARP: A Phase 2 Study of Induction Docetaxel and Carboplatin Followed by Maintenance Rucaparib in Treatment of Patients With Metastatic Castration Resistant Prostate Cancer With Homologous Recombination DNA Repair Deficiency


Condition: ATM Gene Mutation, BRCA1 Gene Mutation, BRCA2 Gene Mutation, Castration Levels of Testosterone, Castration-Resistant Prostate Carcinoma, Homologous Recombination Deficiency, Prostate Carcinoma Metastatic in the Bone, PSA Level Greater Than or Equal to Two, PSA Progression, Stage IV Prostate Adenocarcinoma AJCC v7

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT03442556

Sponsor: University of Washington

Phase: Phase 2

Eligibility:

  • Age: minimum 18 Years maximum N/A
  • Gender: Male

Inclusion Criteria:

  • Signed informed consent form (ICF) providing agreement to adhere to the dosing schedule, report for all trial visits and authorization, use and release of health and research trial information
  • Histologically or cytologically confirmed adenocarcinoma of the prostate (excluding predominant small cell histology)
  • Ongoing gonadal androgen deprivation therapy with gonadotropin-releasing hormone (GnRH) analogues, antagonists or orchiectomy; patients who have not had an orchiectomy must be maintained on effective GnRH analogue/antagonist therapy
  • Castration resistant prostate cancer as defined by serum testosterone < 50 ng/ml and PSA level of at least 2 ng/ml that has risen on at least 2 successive occasions at least 1 week apart
  • Presence of metastatic disease on bone or computed tomography (CT) scan
  • Evaluable disease progression by modified RECIST 1.1 (Response Evaluation Criteria in Solid Tumors)
  • Bone disease on bone scan
  • Prior therapy with sipuleucel-T, abiraterone, enzalutamide, docetaxel, and/or cabazitaxel; there is no limit to the number of prior treatment regimens in the castration resistant setting, so long as prior therapy does not include platinum chemotherapy or a PARP inhibitor; prior platinum chemotherapy in the hormone sensitive setting is permitted, so long as it has been at least 6 months since last dose
  • Eastern Cooperative Oncology Group (ECOG) performance status of =< 1
  • Life expectancy >= 12 weeks
  • No prior malignancy is allowed except:
  • Adequately treated basal cell or squamous cell skin cancer or
  • In situ carcinoma of any site or
  • Other adequately treated malignancy for which the patient has been disease-free for at least one year (any prior chemotherapy is allowed)
  • Documented evidence of at least ONE or MORE of the following: * Pathogenic mutation or inactivating alteration of a gene involved in homologous recombination repair in the tumor
  • Note, that if this alteration is identified in a circulating tumor deoxyribonucleic acid (ctDNA) assay, the variant-allele fraction must be > 20% to indicate relevance to predominant tumor clone
  • Mutation in one or more other genes involved in homologous DNA recombination repair in the tumor may be included at investigator's discretion
  • Homologous recombination repair deficiency by genomic signature in the tumor by BROCA-HR, Foundation One or equivalent assay
  • Presence of pathogenic or likely pathogenic germline mutation/variant in BRCA2, BRCA1, ATM or PALB2
  • Note: Germline mutations in other HR genes will be considered at investigator's discretion)
  • Absolute neutrophil count (ANC) >= 1.5 x 10^9/L (within 14 days of first dose of study drug)
  • Platelets > 100 x 10^9/L (within 14 days of first dose of study drug)
  • Hemoglobin >= 9 g/dL (within 14 days of first dose of study drug)
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3 x ULN; if liver metastases, then =< 5 x ULN (within 14 days of first dose of study drug)
  • Bilirubin =< 1.5 x ULN (< 2 x ULN if hyperbilirubinemia is due to Gilbert's syndrome) (within 14 days of first dose of study drug)
  • Serum creatinine =< 1.5 x ULN or estimated glomerular filtration rate (GFR) >= 45 mL/min using the Cockcroft Gault formula (within 14 days of first dose of study drug)

Exclusion Criteria:

  • Currently receiving active therapy for other neoplastic disorders
  • Symptomatic and/or untreated central nervous system (CNS) metastases; patients with asymptomatic previously treated CNS metastases are eligible provided they have been clinically stable for at least 4 weeks
  • Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness, active or symptomatic viral hepatitis or chronic liver disease
  • Clinically significant heart disease as evidenced by myocardial infarction, or arterial thrombotic events in the past 6 months, severe or unstable angina, or New York Heart Association (NYHA) class II-IV heart disease or cardiac ejection fraction measurement of < 35 % at baseline
  • Treatment with an investigational therapeutic drug within 30 days of cycle 1
  • Prior therapy with a PARP inhibitor (e.g., olaparib, talazoparib, veliparib, niraparib, rucaparib)
  • Prior therapy with a platinum chemotherapy (e.g. cisplatin, carboplatin, oxaliplatin) in the castration resistant setting; (prior platinum chemotherapy in the hormone sensitive setting is permitted, so long as time since last dose is 6 months or greater)
  • Active, ongoing toxicity (Common Terminology Criteria for Adverse Events [CTCAE] grade 2 or higher) from prior therapy
  • Presence of dementia, psychiatric illness, and/or social situations limiting compliance with study requirements or understanding and/or giving of informed consent
  • Pre-existing duodenal stent and/ or any gastrointestinal disorder or defect that would, in the opinion of the Investigator, interfere with absorption of rucaparib
  • Any condition(s), medical or otherwise, which, in the opinion of the investigators, would jeopardize either the patient or the integrity of the data obtained

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BRCAAway: A Randomized Phase II Trial of Abiraterone, Olaparib, or Abiraterone + Olaparib in Patients With Metastatic Castration-Resistant Prostate Cancer With DNA Repair Defects


Condition: Prostate Cancer Metastatic Castration-Resistant, Abnormal DNA Repair, Metastatic Prostate Carcinoma, Stage IV Prostate Cancer

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT03012321

Sponsor: Northwestern University

Phase: Phase 2

Eligibility:

  • Age: minimum 18 Years maximum N/A
  • Gender: Male

Inclusion Criteria:

  • Ability to understand and the willingness to sign a written informed consent document that is approved by the local institutional review board and HIPAA authorization for the release of personal health information.
  • Histological or cytological proof of prostate adenocarcinoma (Note: small-cell carcinoma of the prostate is not permitted)
  • Documented progressive mCRPC based on at least one of the following criteria: 1. PSA progression defined as 25% increase over baseline value with an increase in the absolute value of at least 2.0 ng/mL that is confirmed by another PSA level with a minimum of a 1 week interval and a minimum PSA of 2.0 ng/mL. 2. Progression of bidimensionally measurable soft tissue or nodal metastasis assessed within one month prior to registration by a CT scan or MRI. 3. Progression of bone disease (evaluable disease) (new bone lesion(s)) by bone scan.
  • Agree to undergo a biopsy of at least one metastatic site (fresh biopsy of primary prostate only allowed if there is clear local disease and no other measurable disease site or biopsiable bone lesion.) to determine DNA repair defects. (Please refer to the Laboratory Manual for specific procedures). However: 1. Adequate archival metastatic or primary disease tumor tissue can be used if available in lieu of a new biopsy. These patients will only be eligible for protocol therapy if the biopsy has tumor that is positive for DNA repair defects. 2. Patients with known DNA damage repair defects based on prior appropriately validated metastatic or prostate tissue analysis may be used in lieu of new biopsy/analysis based on central site evaluation of quality of the biopsy and analysis. 3. Patients with known germline DNA repair defects are eligible without a biopsy. However it will be highly desirable that they undergo a metastatic (or fresh prostate biopsy if there is clear local disease and no other measurable disease site or biopsiable bone lesion) disease biopsy to better define the scope of the DNA repair defects in the current disease context.
  • ECOG status of 0-2 (Appendix A: Performance Status Criteria).
  • Adequate organ function as defined below obtained within 14 days of registration: ANC > or = 1500/µl Hemoglobin ≥ 10.0 g/dL WBC > 3x10^9/L Platelet count 100,000/µl Creatinine ≥51 mL/min estimated using the Cockcroft-Gault equation Potassium ≥ 3.5 mmol/L (within institutional normal range) Bilirubin within normal institutional limits (or <2X the upper limit of normal (ULN) in those with Gilbert's disease) AST (SGOT) / ALT (SGPT) ≤ 1.5x institutional ULN unless liver metastases are present in which case it must be ≤ 5x ULN
  • The effects of abiraterone, olaparib or the combination of both on the developing human fetus at the recommended therapeutic dose are unknown. Men must agree to use adequate contraception prior to study entry, for the duration of study participation and for at least 3 months thereafter.
  • Patients must discontinue antiandrogen therapy (i.e., flutamide, bicalutamide, nilutamide) for at least 4 weeks prior to registration with no evidence of a falling PSA after washout.
  • Serum testosterone < 50 ng/dL. Patients must continue primary ADT with an LHRH analogue (agonist or antagonist) if they have not undergone orchiectomy.
  • Able to take oral medication without crushing, dissolving or chewing tablets.
  • Patients must have a life expectancy ≥ 6 months.
  • Patients may have received prior radiation therapy or surgery. However, at least 14 days must have elapsed since completion of radiation therapy or surgery and patient must have recovered from all side effects at the time of registration (e.g. back to baseline or grade 1) .
  • Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.

Exclusion Criteria:

  • Prior exposure to CYP17 (other than ketoconazole) or PARP inhibitors for prostate cancer. Patients with prior exposure to ketoconazole are eligible.
  • Prior chemotherapy for castration resistant disease. Chemotherapy given in the hormone-sensitive setting is permissible if stopped at least 4 weeks prior to registration. Note: Patients can receive a stable dose of bisphosphonates for bone metastases, including zoledronic acid, or denosumab before and during the study as deemed appropriate by the treating physician.
  • Prior exposure to enzalutamide, ARN-509 or other investigational AR-directed therapy in the setting of mCRPC.
  • Patients with a currently active second malignancy excluding non-melanomatous skin cancer or superficial transitional cell carcinoma. Note: Patients are not considered to have a "currently active" malignancy if they have completed all therapy and are now considered without evidence of disease for 1 year.
  • Patients receiving any other investigational agents. Any prior investigational agents must be stopped at least 14 days (2 week washout) prior to registration.
  • Patients who have received itraconazole, ketoconazole, or fluconazole within 3 weeks prior to registration or those who have not recovered (i.e., back to baseline or Grade 1) from AEs due to agents administered more than 3 weeks earlier.
  • Patients with a history of active seizures (or a single confirmed seizure event) in the last 2 years from the time of registration.
  • Patients with a history of pituitary or adrenal dysfunction or active or symptomatic viral hepatitis or chronic liver disease are not eligible.
  • Patients with active brain metastases. A scan to confirm the absence of brain metastases is not required for asymptomatic patients.
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to olaparib or abiraterone.
  • Patients considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction, unstable spinal cord compression (untreated or unstable within at least 28 days prior to registration), superior vena cava syndrome, and extensive bilateral lung disease on HRCT scan or any psychiatric disorder that prohibits obtaining informed consent.
  • Patients with prolonged pre-existing hematological toxicities including known indicators of bone marrow failure or abnormality.
  • Patients with myelodysplastic syndrome / acute myeloid leukemia.
  • Patients may continue on a daily Multi-Vitamin, calcium and Vitamin D, but all other herbal, alternative and food supplements (i.e. PC-Spes, Saw Palmetto, St John's Wort, etc.) must be discontinued before starting protocol treatment. Hormonal-acting agents such as DES are forbidden during the trial and must be stopped prior to starting protocol treatment. No washout period will be required. Patients on megesterol acetate for hot flashes are allowed to continue therapy.
  • Patients must stop taking ritonavir, idinavir, saquinavir, telithromycin, clarithromycin and nelfinavir 1 week prior to registration. Note: topical ketoconazole is permitted.
  • Patients must stop taking phenytoin, rifampicin, rifapentine, rifabutin, carbamazepine, nevirapine, modafinil and St John's Wort (Hypericum perforatum) 3 weeks prior to registration. Patients must stop taking phenobarbitone 5 weeks prior to registration. Patients must stop taking all strong CYP3A4 inhibitors, including clarithromycin, telithromycin, nefazodone, itraconazole, ketoconazole, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, and tipranavir, prior to registration.
  • Patients must not be planning to receive any concurrent cytotoxic chemotherapy, surgery or radiation therapy during protocol treatment.
  • Use of any prohibited concomitant medications within 7 days of registration.
  • Patients who are HIV-positive on combination antiretroviral therapy because of the potential for pharmacokinetic interactions with olaparib. In addition these patients are at increased risk of lethal infections when treated with marrow suppressive therapy.
  • Patients with known active Hepatitis B or Hepatitis C.
  • Patients with baseline moderate to severe hepatic impairment (Child-Pugh Class B and C).
  • Persistent toxicities (≥CTCAE Grade 2), with the exception of alopecia, caused by previous cancer therapy.
  • Resting ECG with QTc > 470msec on 2 or more time points within a 24 hour period or of long QT syndrome.
  • Patients with significant cardiac history including:
  • Severe or unstable angina pectoris
  • Uncontrolled hypertension (defined as systolic BP ≥ 160 mmHg or diastolic BP ≥ 95 mmHg). Note
  • Patients with a history of hypertension are allowed provided blood pressure is controlled by anti-hypertensive treatment
  • Atrial fibrillation or other cardiac arrhythmia requiring therapy.
  • Heart disease as evidenced by myocardial infarction, or aterial thrombotic events in the past 6 months
  • Class II-IV heart failure (as defined by New York Heart Association) or a cardiac ejection fraction measurement of less than 50% at baseline
  • Blood transfusion within 30 days of consent.
  • Previous allogeneic bone marrow transplant.
  • Major surgery within 14 days of registration and patients must have recovered from any effects of any major surgery.
  • Patients with any condition likely to interfere with absorption of the study medication.
  • No other condition which, in the opinion of the Investigator, would preclude participation in this trial.
  • Patients who have noncanonical DNA repair defects and extensive visceral disease or symptomatic bone disease requiring urgent tumor response.

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