Prostate Cancer

Condition: Prostate Cancer

Study Type: Observational

Clinical Trials Identifier NCT 8-digits: NCT04100811

Sponsor: miR Scientific LLC

Phase:

Eligibility:

• Age: minimum 45 Years maximum N/A
• Gender: Male

Inclusion Criteria:

1. Males ≥ 45 years old
2. Males with clinical suspicion of prostate cancer, including but not limited to elevated PSA level, suspicious DRE, family history of prostate cancer, and/or germline mutation, who as a result undergo TRUS- or MRI-guided core-needle biopsy and PSA recording (for NCCN group label).
3. Signed informed consent prior to initiation of any study-related procedures.
4. The patient provided a voided urine sample within 30 days prior to biopsy being performed and prior to DRE (if any). This collection must be ≥ 1 hour after the last urination.

Exclusion Criteria:

1. Persons previously diagnosed with prostate cancer.
2. Persons who have previously undergone a 12 core or fusion biopsy in the last 12 months
3. Persons who have had a DRE within 72 hours of the urine collection
4. Persons incapable of providing informed consent.
5. Persons presenting with clinical symptoms of urinary tract infection, including prostatitis at the time of enrollment.
6. Persons with prior history of invasive treatment for benign prostatic hyperplasia within 3-6 months of study enrollment.
7. Patients treated with a 5-alpha-reductase inhibitor, Saw Palmetto for BPH or male pattern baldness within 3 months of the urine collection.

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Condition: Prostate Cancer, Radiotherapy Side Effects, Volatile Organic Compounds, DNA Damage

Study Type: Observational

Clinical Trials Identifier NCT 8-digits: NCT04081428

Sponsor: NHS Lothian

Phase:

Eligibility:

• Age: minimum 18 Years maximum 80 Years
• Gender: Male

Inclusion Criteria:

• Low risk prostate cancer T1-2, PSA<10ng/ml, Gleason score (GS) 3+3=6
• Intermediate risk prostate cancer T1-T2, PSA 10-20ng/ml,GS ≤7(3+4=7 only)
• World Health Organisation (WHO) performance status 0-2
• Prostate volume ≤90cc
• International Prostate Symptom Score (IPSS) ≤20
• Peak urinary flow rate (Q-max) >10cc/sec
• Urinary residual <250mls total
• No prior Trans Urethral Resection of the Prostate (TURP)
• No previous pelvic radiotherapy
• Able to give informed consent
• Aged between 18-85 years of age

Exclusion Criteria:

• Inflammatory bowel disease
• Previous androgen deprivation therapy
• History of urinary retention

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Condition: Prostate Cancer, PSA, Infection

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT04081636

Sponsor: Albany Medical College

Eligibility:

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

Inclusion Criteria:

• All patients who are scheduled to undergo prostate biopsy for suspected prostate cancer as part of their regular medical care
• Either with or without an MRI

Exclusion Criteria:

• Patients with no access to rectum (due to previous rectal surgery)
• Any abnormalities of the perineal skin (e.g. infection)
• Patients whose procedure requires sedation or general anesthesia

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Condition: Prostate Cancer

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT04083937

Sponsor: University Hospital Heidelberg

Eligibility:

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

Inclusion Criteria:

• histology-proven prostate cancer with Gleason Score and PSA-value;
• indication for prostate bed irradiation (adjuvant/ salvage) after prostatectomy;
• Karnofsky-Index ≥ 70%
• age ≥ 18 years

Exclusion Criteria:

• androgen deprivation therapy
• lymphatic spread
• macroscopic tumor/ R2
• stage IV (M1)
• previous irradiation

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Condition: Metastatic Prostate Cancer

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT04179864

Sponsor: Epizyme, Inc.

Phase: Phase 1/Phase 2

Eligibility:

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

Inclusion Criteria:

• 1. Age at the time of consent ≥ 18 years. 2. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1 (Appendix 3. Life expectancy of > 3 months. 4. Histologically or cytologically confirmed adenocarcinoma of the prostate. Small cell or neuroendocrine tumors of the prostate are also permitted. 5. Progressive disease in the setting of medical or surgical castration (ie, castration- resistant prostate cancer [CRPC]) by PCWG3 criteria for study entry.
• Evidence of disease progression by rising PSA or
• Soft tissue progression per RECIST 1.1 or
• Evidence of disease progression by observation of 2 new bone lesions since the initiation of last systemic therapy. 6. Metastatic prostate cancer disease, documented by the following imaging • Bone lesions on bone scan (per PCWG3) or by soft tissue disease (per RECIST 1.1) by CT/MRI imaging Must have undergone bilateral orchiectomy or be willing to continue GnRH analogue or antagonist. 7. Prior treatment with a second-generation androgen inhibitor as follows:
• For phase 1b, EITHER Previously untreated with or progressed on a second generation androgen inhibitor (abiraterone, enzalutamide, or apalutamide) OR progressed on a second generation inhibitor (inhibitor (abiraterone, enzalutamide, or apalutamide)
• For phase 2 randomized component (i.e, enzalutamide- containing treatment arms) of the study, previously progressed on abiraterone.

Exclusion Criteria:

• 1. Known symptomatic brain metastases 2. Treatment with any of the following for prostate cancer within the indicated timeframe prior to day 1 of starting study treatment:
• First generation: AR antagonists (eg, bicalutamide, nilutamide, flutamide) within 4 weeks.
• 5-alpha-reductase inhibitors, ketoconazole, estrogens (including diethylstilbesterol), or progesterones within 2 weeks.
• Chemotherapy (except as permitted in inclusion criteria #10) within 3 weeks.
• Prior radionuclide therapy within 4 weeks.
• Another interventional product or standard agent in a clinical study within 28 days prior to the first planned dose of Tazemetostat
• For phase 2 subjects to be randomized to one of the enzalutamide treatment arms only, prior treatment with the second-generation androgen antagonist including enzalutamide, apalutamide, darolutamide, and proxalutamide, etc. 3. Severe concurrent disease, infection, or comorbidity that, in the judgment of the Investigator, would make the subject inappropriate for enrollment 4. Has had prior exposure to tazemetostat or other inhibitor(s) of enhancer of zeste homologue-2.

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Condition: Prostate Adenocarcinoma, PSA Level Greater Than or Equal to 0.5, PSA Level Less Than Ten

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT04175431

Sponsor: University of Washington

Phase: Phase 2

Eligibility:

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

Inclusion Criteria:

• Patient must have histologically or cytologically documented evidence of prostate adenocarcinoma
• Patient must previously have undergone radical prostatectomy
• Patient must previously have undergone either adjuvant or salvage radiation therapy to the prostatic fossa +/- whole pelvis
• PSA doubling time must be calculated utilizing all PSA measurements from most recent biochemically-recurred (BCR). PSA doubling time must be > 3 months and < 18 months. The Memorial Sloan Kettering PSA doubling time calculator should be used
• Patient must have no previous evidence of radiographically detectable metastatic prostate cancer by conventional CT and bone scan imaging
• Patient must have total testosterone level > 120 ng/dL demonstrated within 28 days of enrollment
• Patient must have Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Absolute neutrophil count (ANC) >= 1.0 X 10^9/L
• Platelet count >= 100 X 10^9/L
• Hemoglobin >= 9 g/dL
• Potassium >= 3.5
• Serum bilirubin =< 1.5 X upper limit of normal (ULN) or =< 3 X ULN for patients with documented Gilbert's syndrome
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3 X ULN
• Creatinine clearance (Cr Cl) >= 30 mL/min as estimated by the Cockcroft-Gault criteria or as determined by 24 hour Cr Cl measurement
• Patient must be able to understand and authorize informed consent

Exclusion Criteria:

• Chronic active hepatitis B or C
• History of a second, non-prostate malignancy that required systemic therapy in the last 2 years except cancer in situ of bladder and non-melanomatous cancers of the skin
• Patient with a serious underlying medical condition that would otherwise impair the patient's ability to undergo fluciclovine PET/CT imaging or receive subsequent treatment
• Any condition that would alter the patient's mental status, prohibiting understanding and/or authorization of informed consent
• Expected lifespan of less than 12 weeks
• Inability to lay still for imaging
• Weight > 300 lbs. (due to equipment specifications)
• Any other underlying medical condition that, in the opinion of the investigator, would impair the ability of the patient to receive or tolerate the planned treatment and/or follow up

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Condition: Prostate Cancer Metastatic

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT03951831

Sponsor: Mark Stein

Phase: Phase 2

Eligibility:

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

Inclusion Criteria:

• 1. Be willing and able to provide written informed consent for the trial. 2. Age ≥18 years of age on day of signing informed consent. 3. Have life expectancy > 12 months. 4. Have a performance status of 0 or 1 using the Eastern Cooperative Oncology Group (ECOG) Performance Scale. 5. Have histologically or cytologically confirmed prostate cancer from prostate biopsy, radical prostatectomy, TURP or from biopsy of a metastatic site. Rarely pathology is not available but if clinical situation confirms prostate cancer (such as prior response to androgen ablation and/or metastatic disease typical of prostate cancer, i.e. involving bone or pelvic/extra pelvic lymph nodes or para-aortic lymph nodes, AND an elevated serum concentration of PSA typical of prostate cancer) pathology is not required and patient can be enrolled after discussed with study PI.. 6. Have metastatic disease that is either measurable or evaluable (non-measurable). 7. Have evaluable (non-measurable) or measurable disease, based on RECIST 1.1, with at least one lesion amenable to biopsy. 8. Have testosterone level ≥ 150ng/dL. 9. Have not been on androgen deprivation therapy or novel hormonal agents (e.g., abiraterone, enzalutamide, apalutamide) for at least 6 months prior to enrollment in trial and must not have exceeded 24 months of therapy 10. Have not received any adjuvant or neoadjuvant chemotherapy or immunotherapy. 11. Have not had prior bilateral surgical orchiectomy. 12. Have not received palliative radiation within 14 days of starting ADT on study treatment. 13. Have adequate organ and marrow function as defined below:
• Leukocytes ≥3,000/microliters (mcL)
• Absolute Neutrophil Count ≥1,500/mcL
• Platelets ≥100,000
• Hemoglobin ≥ 8.0g/dL (without transfusion in past 2 weeks)
• Prothrombin time (PT)/international normalized ratio (INR), partial thromboplastin time (PTT) ≤ 1.5 upper limit of normal (ULN) (except if on therapeutic anticoagulation in which case the patient can be enrolled if stable and anti-coagulation levels are appropriate for their condition per good clinical practice).
• Aspartate aminotransferase (AST)(SGOT)/ alanine aminotransferase (ALT)(SGPT) ≤2.5 × institutional ULN
• Total bilirubin within normal institutional limits. Note: Patients with hyperbilirubinemia clinically consistent with an inherited disorder of bilirubin metabolism (e.g. Gilbert's syndrome) will be eligible at the discretion of the treating physician and/or the principal investigator.
• Creatinine clearance of ≥ 30 mL/min. Creatinine clearance (CrCl) should be calculated at screening using the Cockcroft-Gault formula. 14. Agree to undergo serial tumor biopsies, unless medically contraindicated in the opinion of the treating physician, and discussed with the principal investigator 15. The effects of REGN2810 on the developing human fetus are unknown. For this reason and because REGN2810 agents [as well as other therapeutic agents used in this trial] are known to be teratogenic, 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 REGN2810 administration. 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.

Exclusion Criteria:

1. The subject must be excluded from participating in the trial if the subject:
2. Received ADT or other hormonal agents within 6 months prior to entering the study or in the metastatic setting with the exception of 5-alpha reductase inhibitors (e.g. finasteride and dutasteride) and first-generation androgen receptor inhibitor (e.g. bicalutamide) in setting of normal testosterone. Advise subject to continue the 5-alpha reductase inhibitor for the duration of the study if already started. Advise subject to stop the androgen receptor inhibitor for duration of the study
3. Received prior immunotherapy (including inhibitors of programmed cell death protein 1 (anti-PD-1), anti-PD-L1, anti-CTLA4, or Sipuleucel-T).
4. Received prior chemotherapy for prostate cancer treatment.
5. Received radiation within 2 weeks prior to entering study.
6. Is receiving any other investigational agents concurrently.
7. Had a solid organ or hematologic transplant.
8. Has active autoimmune disease that has required systemic treatment in 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, etc.) is not considered a form of systemic treatment.
9. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment.
10. Has a diagnosed malignant disease, other than the tumor type being treated in this study. Note: Patients with a prior or concurrent malignancy of low metastatic potential that does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen may be included (e.g., patients with a history of nonmelanoma skin cancer, carcinoma in situ of the cervix, early stage cancers treated with curative intent, non-muscle invasive bladder cancer, stage I renal cancer)Has a known history of, or any evidence of, interstitial lung disease or active noninfectious pneumonitis.
11. Peripheral neuropathy must be ≤ grade 1
12. Has an active infection requiring systemic therapy.
13. Has a history of current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator, including dialysis.
14. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
15. Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies). Note: HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with REGN28
16. In addition, these patients are at increased risk of lethal infections when treated with immunotherapy and marrow-suppressive therapy. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated.
17. Has untreated active Hepatitis B. Note: To qualify for enrollment, antiviral therapy for HBV must be given for at least 3 months, and HBV viral load must be less than 100 IU/mL prior to first dose of study drug. Those on active HBV therapy with viral loads under 100 IU/mL should stay on the same therapy throughout trial treatment. Those subjects who are anti-HBc (+), and negative for HBsAg, and negative for anti-HBs, and have an HBV viral load under 100 IU/mL do not require HBV anti-viral prophylaxis, but need close monitoring.
18. Has dual infection with HBV/HCV or other hepatitis combinations at study entry.
19. Has received a live vaccine within 30 days of planned start of study therapy (Cycle 1, Day 1). Note: The killed virus vaccines used for seasonal influenza vaccines for injection are allowed; however intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed.
20. Patients with a history of severe hypersensitivity reaction to docetaxel or other drugs formulated with polysorbate 80 must be excluded.

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Condition: Prostate Cancer

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT03934840

Sponsor: Masonic Cancer Center, University of Minnesota

Phase: Phase 2

Eligibility:

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

Inclusion Criteria:

• Willing and able to provide, or have a legally authorized representative provide, written informed consent and HIPAA authorization for the release of personal health information. A signed informed consent must be obtained before screening procedures are performed.
• Histologically confirmed prostate cancer.
• High volume metastatic disease (defined as the presence of visceral metastases or ≥3 bone lesions).
• ADT for ≤3 months by day 1 of study chemotherapy; Prior episodes of ADT are allowed (i.e. ADT used previously in courses of radiation).
• Testosterone <50 ng/dL. Patients must continue primary ADT with an LHRH analogue if they have not undergone orchiectomy.
• ECOG Performance Status 0 or 1 (see Appendix A)
• Patient has adequate bone marrow and organ function as defined by the following laboratory values:
• Absolute neutrophil count ≥ 1.5 × 10^9/L
• Platelets ≥ 100 × 10^9/L
• Hemoglobin ≥ 9 g/dl
• Serum creatinine ≤ 1.5mg/dL or estimated creatinine clearance ≥ 50 ml/min
• In the absence of liver metastases, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <2.5 x ULN. If the patient has liver metastases, ALT and AST <5 x ULN
• Total bilirubin < ULN; or total bilirubin ≤3.0 x ULN or direct bilirubin ≤1.5 x ULN in patients with well-documented Gilbert's Syndrome.
• Sexually active males must use a condom during intercourse while taking study drugs and for 30 days after stopping treatment and should not father a child in this period. A condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid. Fertile males must use a condom with spermicide (double barrier method).
• Age ≥ 18 years

Exclusion Criteria:

• Prior exposure to any chemotherapy, PARPi, or immunotherapy for prostate cancer.
• Prior abiraterone or enzalutamide, unless therapy was for < 2 weeks
• Radiation therapy (including palliative radiotherapy to a metastatic lesion) within 14 days or major surgery (e.g., open abdominal, pelvic, thoracic, orthopedic or neurosurgery) within 28 days of the date of the first dose.
• Other systemic therapies for prostate cancer within 28 days or 5 half-lives, whichever is shorter, prior to day 1 of chemotherapy (with the exception of anti-androgens like bicalutamide).
• PSA <2.0 ng/mL at diagnosis.
• If present, peripheral neuropathy must be ≤ Grade 1
• Patients with an active second malignancy that could, in the investigator's opinion, potentially interfere with the patient's ability to participate and/or complete this trial.
• Patients with central nervous system (CNS) involvement unless they meet ALL of the following criteria:
• At least 4 weeks from prior therapy completion (including radiation and/or surgery) prior to starting the study treatment
• Clinically stable CNS tumor at the time of screening.
• Baseline screening for CNS metastases is not required unless presence of signs and/or symptoms of involvement
• Patients with severe psychiatric illness/social situations that would limit compliance with study requirements in the judgment of treating investigator.
• Patient has a history of non-compliance to medical regimen or inability to grant consent.

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Condition: Prostate Cancer, Oligometastasis

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT03630666

Sponsor: Institut Cancerologie de l'Ouest

Eligibility:

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

Inclusion Criteria:

• Histologically-proven prostate adenocarcinoma
• Age ≥ 18 years
• Performance Status 0-1
• Prior radical prostate treatment (surgery and/or radiotherapy)
• ≤ 5 metastatic pelvic lymph nodes detected by FCH-PET or PSMA-PET
• Upper limit of metastatic lymph nodes: aortic bifurcation
• If ADT has been previously administered to the patient, at least 12 months must have elapsed between the predicted duration of the last injection and inclusion of the patient in the study. For this category of patients, serum testosterone must be higher than 6 nmol/L (50 ng/L) prior to inclusion
• Biochemical relapse (according to the European Association of Urology guidelines) is defined by : Following radical prostatectomy (RP), biochemical recurrence (BCR) is defined by two consecutive rising PSA values > 0.20 ng/ml After primary radiation therapy (RT), the Radiation Therapy Oncology Group (RTOG) and American Society for Radiation Oncology Phoenix Consensus Conference definition of PSA failure is any PSA increase > 2.00 ng/ml higher than the PSA nadir value, regardless of the serum concentration of the nadir.
• Having given written informed consent prior to any procedure related to the study.
• Patient is willing and able to comply with the protocol for the duration of the study including all scheduled treatment, visits and examinations.
• Patient has valid health insurance
• Subjects who have partners of childbearing potential must be willing to use a method of effective birth control during treatment and for 12 months following completion of treatment with ADT or IG-IMRT.

Exclusion Criteria:

• Bone or visceral metastases
• Para-aortic lymph node metastases (above the aortic bifurcation)
• Presence of more than five metastatic lymph nodes
• Evidence of local intra-prostatic relapse
• Evidence of prostate bed relapse in a previously irradiated region. Prostate bed relapses which have not been previously irradiated will not be excluded
• Evidence of metastasis at initial diagnosis
• Evidence of distant metastases beyond the pelvic lymph nodes
• Previous irradiation of pelvic lymph nodes
• Castration-resistant prostate cancer (CRPC) as defined by : a castrate serum testosterone < 6 nmol/L (50 ng/L)
• Contraindications to pelvic irradiation (e.g. chronic inflammatory bowel disease)
• Contraindications to ADT (known hypersensitivity to any of the study drugs or excipients)
• Severe uncontrolled hypertension defined as systolic BP ≥ 160 mmHg or diastolic BP ≥ 95 mmHg). Patients with a history of hypertension are allowed provided blood pressure is controlled by anti-hypertensive therapy
• Other malignancy treated within the last 5 years (except non-melanoma skin cancer)
• Patients with a biochemical relapse while on active treatment with LHRH-agonist, LHRH-antagonist, anti-androgen, maximal androgen blockade, or oestrogen
• Treatment during the past month with products known to influence PSA levels (such as finasteride)
• In case of previous prostate/prostate bed radiotherapy, PET-positive lymph nodes have to be located outside the previous irradiation field with a maximum of 20 Gy to the PET-positive lymph nodes region
• Patients already included in another therapeutic trial with an experimental drug or having been given an experimental drug within a period of 30 days
• Disorder precluding understanding of trial information or informed consent

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Condition: Prostate Cancer

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT01567800

Sponsor: University Health Network, Toronto

Eligibility:

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

Inclusion Criteria:

• Age => 18 years
• Histologic diagnosis of adenocarcinoma of the prostate
• Bulky intermediate risk, high risk or metastatic prostate cancer Bulky intermediate risk: cT1-2 with >50% of diagnostic biopsy cores containing cancer and Gleason 6 or 7 and prostate specific antigen (PSA) >10 and ≤20 OR High risk: cT1-2 with Gleason score ≥8; or cT1-2 with PSA >20; or cT3 OR N+ and/or M1 disease OR Newly diagnosed hormone-refractory prostate cancer
• Intention to treat using radiotherapy +/- concurrent and adjuvant hormonal therapy
• Intention to treat with radiotherapy, hormonal therapy, other systemic treatment for prostate cancer, or a combination of these according to the Princess Margaret Genitourinary Site policies.
• Previous or concurrent anti-cancer therapy for the PET FAZA target lesion allowed
• Ability to provide written informed consent to participate in the study

Exclusion Criteria:

• Inability to lie supine for more than 60 minutes
• Patients taking the drug disulfiram (Antabuse)
• Contraindications for MRI: only applicable in cases where the PET FAZA target lesion is identified as the prostate gland. Patients with target lesions at other anatomic sites will not undergo MR imaging.
• Patients weighing > 136 kg

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Condition: Prostate Cancer, Prostate Neoplasm

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT03232164

Sponsor: University of Wisconsin, Madison

Phase: Early Phase 1

Eligibility:

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

Inclusion Criteria:

• Prostate cancer pathologically proven by prostate biopsy (newly diagnosed for Sub-Study 1 and 4)
• Prostate biopsy histology grade ≥ Gleason 1, 6, 3+4, or 4+3; positive biopsy >2 cores
• Any PSA permitted
• Two consecutive rising PSA values (Sub-Study 3 only)
• Castrate-levels of testosterone
• total testosterone < 50 ng/dL (Sub-Study 3 only)
• Patients considered as candidates for and medically fit to undergo prostatectomy
• At least 7 days after most recent prostate biopsy
• Imaging evidence of suspected metastatic disease, including CT, bone scan, MRI, ultrasound or other PET modalities (Sub-Study 3 only)
• New diagnosis of prostate cancer undergoing additional biopsy evaluation (Sub--Study 4 only)
• Karnofsky performance status of at least 70 (Sub-Study 4 only)
• General health and anatomy suitable to undergo transrectal ultrasound-MRI fusion biopsy of the identified lesions and standard 12 core sextent biopsy (Sub-Study 4 only)

Exclusion Criteria:

• Prior pelvic external beam radiation therapy or brachytherapy
• Chemotherapy for prostate cancer
• Androgen deprivation therapy for prostate cancer
• Investigational therapy for prostate cancer (Sub-Study 3 Only)
• Unable to lie flat during or tolerate PET/CT
• Prior history of any other malignancy within the last 2 years, other than skin basal cell or cutaneous superficial squamous cell carcinoma that has not metastasized and superficial bladder cancer.
• No prostatectomy scheduled more than 12 hours post imaging (Sub-Study 1 only)
• Serum creatinine > 2 time the upper limit of normal
• Total bilirubin > 3 times the upper limit of normal
• Liver Transaminases > 5 times the upper limit of normal

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Condition: Prostate Cancer

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT03315871

Sponsor: National Cancer Institute (NCI)

Phase: Phase 2

Eligibility:

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

Inclusion Criteria:

• Histopathological documentation of prostate cancer confirmed in either the Laboratory of Pathology at the National Institutes of Health (NIH) Clinical Center, or Walter Reed National Military Medical Center prior to enrollment. If no pathologic specimen is available, participants may enroll with a pathologist s report showing a histologic diagnosis of prostate cancer and a clinical course consistent with the disease.
• Recovery to baseline from acute toxicity related to prior therapy, including surgery and radiation. (28 days removed from last systemic therapy, 14 days removed from last radiation therapy).
• Hepatic function eligibility parameters (within 16 days before starting therapy): --Bilirubin less than or equal to ULN (OR in participants with Gilbert s syndrome, a total bilirubin less than or equal to 3.0), AST and ALT less than or equal to 1.5 times upper limit of normal.
• Adequate renal function defined by an estimated creatinine clearance > 50 mL/min according to the Cockcroft-Gault formula or by measure of creatinine clearance from 24 hour urine collection.
• No other active malignancies within the past 36 months (with the exception of nonmelanoma skin cancers or carcinoma in situ of the bladder) or life-threatening illnesses.
• Willing to travel to the NIH for follow-up visits.
• 18 years of age or older.
• Able to understand and sign informed consent.
• The effects Prostvac and CV301 on the developing human fetus are unknown. For this reason, men must agree to use highly effective contraception (that is, methods with a failure rate of less than 1% per year) prior to study entry, for the duration of study therapy and at least four months after the last treatment administration. 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.
• Additional Inclusion Criteria Specific to Safety Lead-In Cohort
• Castrate testosterone level (<50ng/dl or 1.7nmol /L)
• Progressive disease at study entry defined as one or more of the following criteria occurring in the setting of castrate levels of testosterone:
• Radiographic progression defined as any new or enlarging bone lesions or growing lymph node disease, consistent with prostate cancer OR
• PSA progression defined by sequence of rising values separated by >1 week (2 separate increasing values over a minimum of 2ng/ml (PCWG2 PSA

Eligibility Criteria:

• ). If participants had been on flutamide, PSA progression is documented 4 weeks or more after withdrawal. For participants on bicalutamide or nilutamide disease progression is documented 6 or more weeks after withdrawal. --Participants must agree to continuation of androgen deprivation therapy (ADT) with a gonadotropin-releasing hormone agonist/antagonist or bilateral orchiectomy
• ECOG performance status of 0-2 (Karnofsky >80%).
• Hematological eligibility parameters (within 16 days before starting therapy):
• Granulocyte count greater than or equal to 1000/mm^3
• Platelet count greater than or equal to 100 000/mm^3
• Hgb greater than or equal to 9 g/dL
• PT less than or equal to 1.5 x ULN
• aPTT less than or equal to 1.5 x ULN Additional Inclusion Criteria Specific to Biochemical Recurrence Cohort
• Biochemical progression defined as follows:
• For participants following definitive radiation therapy: a rise in PSA of greater than or equal to 2 ng/mL above the nadir (per RTOG-ASTRO consensus criteria)
• For participants following radical prostatectomy: rising PSA after surgical procedure (participants must have a PSA greater than or equal to 0.8 ng/mL)
• Participants must have a rising PSA as confirmed by 3 values a minimum of 1 week apart over at least a 1 month period of time.
• Participants must have a PSA doubling time of 5-15 months.
• ECOG performance status of 0-1 (Karnofsky greater than or equal to 80%).
• Negative CT scan/MRI and bone scan for metastatic prostate cancer.
• Baseline testosterone greater than or equal to 100 ng/dl.
• PSA less than or equal to 30 ng/mL.
• Hematological eligibility parameters (within 16 days before starting therapy):
• Granulocyte count greater than or equal to 1000/mm3
• Platelet count greater than or equal to 100 000/mm3
• Hgb greater than or equal to 10 g/dL

Exclusion Criteria:

• Immunocompromised status due to:
• Human immunodeficiency virus (HIV) positivity.
• Active autoimmune diseases such as Addison's disease, Hashimoto's thyroiditis, systemic lupus erythematosus, Sjogren syndrome, scleroderma, myasthenia gravis, Goodpasture syndrome or active Grave's disease.
• Participants with a history of autoimmunity that has not required systemic immunosuppressive therapy or does not threaten vital organ function including CNS, heart, lungs, kidneys, skin, and GI tract will be allowed.
• Participants with diabetes type I, vitiligo, or alopecia are allowed.
• Other immunodeficiency diseases
• Splenectomy
• Receipt of any organ transplantation, including allogeneic stem-cell transplantation, but with the exception of transplants that do not require immunosuppression (e.g. corneal transplant, hair transplant).
• Chronic administration (defined as daily or every other day for continued use > 14 days) of systemic corticosteroids within 28 days before the first planned dose of investigational therapy. Use of corticosteroids with minimal systemic absorption (e.g. inhaled steroids, nasal sprays, and topical agents) is allowed.
• Serious intercurrent medical illness that, in the judgment of the investigator, would interfere with participant s ability to carry out the treatment program.
• 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).
• History of prior chemotherapy (chemotherapy allowed for lead-in cohort in castration resistant disease.)
• History of prior immunotherapy within the last 3 years (immunotherapy allowed for lead-in cohort in castration resistant disease.)
• Receipt of an investigational agent within 28 days (or 56 days for an antibody-based therapy) before the first planned dose of study drugs.
• Major surgery within 4 weeks prior to enrollment
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to poxviral vaccines (e.g., vaccinia vaccine)
• Previous serious adverse reactions to smallpox vaccination
• History of allergic reactions attributed to monoclonal antibodies (grade 3)
• Known allergy to eggs, egg products, aminoglycoside antibiotics (e.g. gentamicin or tobramycin).
• History of atopic dermatitis or active skin condition (acute, chronic, exfoliative) that disrupts the epidermis
• Unable to avoid close contact or household contact with the following high-risk individuals for three weeks after the Day 1 vaccination: (a) children less than or equal to 3 years of age, (b) pregnant or nursing women, (c) individuals with prior or concurrent extensive eczema or other eczemoid skin disorders, or (d) immunocompromised individuals, such as those with HIV.
• Participants who test positive for HBV or HCV
• Clinically significant cardiovascular/cerebrovascular disease as follows: cerebral vascular accident/stroke (< 6 months prior to the first planned dose of study drugs), myocardial infarction (< 6 months prior to the first planned dose of study drugs), unstable angina, congestive heart failure (New York Heart Association Classification Class greater than or equal to II), serious cardiac arrhythmia, or uncontrolled hypertension (SBP>170/DBP>105).
• Participants who have received a red cell transfusion within 2 weeks prior to enrollment.
• Participants unwilling to accept blood products as medically indicated.
• Individual tumor lesion(s) in the liver or chest which are 10 cm or larger.

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Condition: Hormone Refractory Prostate Cancer

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT02955082

Sponsor: Institute of Cancer Research, United Kingdom

Phase: Phase 2

Eligibility:

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

Inclusion Criteria:

1. All study participants will be assessed according to the part 1 and/ or part 2 inclusion criteria depending on which part of the study they enter initially. For Part 1 (genetic screening) of the study:
2. Age ≥ 18 years.
3. Recorded diagnosis of prostate cancer with or without histological confirmation. Patients who have not previously undergone a prostate (or metastatic) biopsy but are confirmed to have a raised PSA (>80ng/ml at any time), metastatic disease on imaging and have undergone treatment for mCRPC are eligible.
4. Castration-resistant disease defined as biochemical or radiological progression on/after treatment with orchidectomy or LHRH analogues as per PCWG3 criteria.
5. Confirmed metastatic disease on conventional imaging methods such as CT, bone scan or PET imaging.
6. Current or previous treatment includes at least one of the following:
7. Docetaxel (either in hormone sensitive or resistant setting; Patients who have completed treatment with or are currently undergoing Cabazitaxel chemotherapy are also eligible)
8. Enzalutamide
9. Abiraterone
10. Adequate renal function measured by calculated GFR (Cockcroft-Gault) >30ml/min. If a participant had renal dysfunction that is expected to improve, they may be considered for part 1 of the study.
11. Adequate haematological function to allow study entry in line with local hospital practice or at the investigator's discretion.
12. WHO performance status 0-2 as assessed and documented by study doctor.
13. Life expectancy >12 weeks
14. Participants with stable, treated brain metastases will be eligible providing informed consent can be given and that other sites of measurable disease are present
15. The subject is capable of understanding and complying with the protocol requirements and has signed the BARCODE 2 informed consent form. In addition to the above, for Part 2 of the study:
16. Confirmed pathogenic germline mutation in a DNA repair gene. (Participants with a known germline mutation will need to provide a report from the external laboratory where genetic testing was carried out)
17. Previous treatment with docetaxel and abiraterone or enzalutamide with documented disease progression prior to entry to part 2 (rising PSA and/or radiographic progression). Patients previously treated with cabazitaxel and who have documented disease progression are also eligible.
18. Adequate haematological function: Haemoglobin (Hb) ≥8.0g/dL, neutrophil count ≥1.5x109/L and platelets ≥100x109/L.
19. Adequate liver function: Total bilirubin ≤1.5 x upper limit of normal (ULN) except for participants with known Gilbert's syndrome; AST and ALT ≤ 2.5x ULN in the presence of liver metastases.
20. Adequate renal function: creatinine clearance >30ml/min measured by a glomerular filtration rate (GFR) clearance test. If a measured GFR test is not available, then calculated GFR is acceptable (measured GFR must be carried out by cycle 2 of carboplatin).

Exclusion Criteria:

1. (for part 1 and 2):
2. Critical organ metastases (e.g. spinal metastases with risk of cord compression) as documented on most recent imaging report.
3. Participants with bleeding tumours.
4. Previous treatment with a platinum chemotherapy drug for prostate cancer.
5. Previous treatment with a PARP inhibitor
6. Participants with a history of severe allergic reaction to carboplatin or other platinum-containing compounds
7. Exposure to yellow fever vaccine in the previous 6 months.
8. Participants unfit for chemotherapy or those with ongoing neuropathy >grade 1 (sensory or motor) according to NCI CTCAE V4.
9. Known and documented hearing impairment
10. Other active malignancies or previous malignancies likely, in the PI's opinion, to impact on management of mCRPC.
11. Significant documented cardiovascular disease: severe/unstable angina, myocardial infarction less than 6 months prior to trial entry, arterial thrombotic events less than 6 months prior to trial entry, clinically significant cardiac failure requiring treatment (NYHA II-IV).
12. Cerebrovascular disease (CVA or TIA) in the preceding 2 years to entry to Part 2 of study.
13. Presence of symptomatic brain metastases.

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Condition: Node; Prostate, Bone Metastases, Prostate Cancer Patients

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT03795207

Sponsor: Institut Cancerologie de l'Ouest

Phase: Phase 2

Eligibility:

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

Inclusion Criteria:

• 1. Written informed consent obtained from the patient prior to performing any protocol-related procedures, including screening evaluations 2. Age > or = 18 years at time of study entry 3. Histologically proven diagnosis of prostate cancer (PCa) 4. PCa patients with a biochemical recurrence "Rising PSA" following treatment with curative intent (radical prostatectomy, primary radiotherapy or a combination of both) as defined by the EAU guidelines. 5. A maximum of 5 bone or lymph node metastases, seen only on FCH-PET CT or Ga-PSMA PET CT, not seen on conventional imaging assessments (bone scan or thorax, abdomen and pelvis CT scan). 6. WHO performance state 0-1 7. Controlled primary tumor. In case the PSA > 0,2 ng/ml in the postoperative setting patients are eligible if a multiparametic MRI or PET scan of the prostate bed rules out a local relapse. Patients after primary radiotherapy should undergo MRI of the prostate according to the European Society of Urogenital Radiology (ESUR) guidelines to rule out local relapse. In case of a suspicious lesion, a biopsy should confirm local recurrence and patients should be referred for local salvage prostatectomy when distant metastases are ruled out. If MRI rules out local relapse, patients are eligible. 8. If ADT has been previously administered to the patient, a minimum of 12 months must have elapsed between the predicted duration of the last injection and inclusion of the patient in the study. For this category of patients, serum testosterone has to be higher than 8.5 nmol/l prior to inclusion. 9. Adequate normal organ and marrow function as defined below:
• Haemoglobin ≥9.0 g/dL
• Absolute neutrophil count (ANC) ≥ 1.5 x 103 /L (≥ 1500 per mm3)
• Platelet count ≥ 75 x 109/L (≥75,000 per mm3)
• Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN). This will not apply to patients with confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysishaemolysis or hepatic pathology), who will be allowed only in consultation with their physician.
• AST (SGOT)/ALT (SGPT) ≤2.5 x institutional upper limit of normal unless liver metastases are present, in which case it must be ≤5x ULN
• Measured creatinine clearance (CL) ≥ 40 ml/min or Calculated creatinine CL ≥ 40 ml/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance: Creatinine CL (ml/min) = Weight (kg) x (140
• Age) 72 x serum creatinine (mg/dL) 10. Body weight > 30kg 11. Life expectancy of > 24 months. 12. 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. 13. Social insurance

Exclusion Criteria:

• 1. Serum testosterone level < 8.5 nmol/ml 2. Vertebral metastases with a minimum distance inferior to 5 mm between GTV (gross tumor volume) and spinal cord 3. Visceral metastases 4. Bone metastases seen on bone scan 5. Lymph nodes greater than 20 mm 6. PSA doubling time less than 6 months 7. Spinal cord compression 8. Any unresolved toxicity NCI CTCAE (v4.03) Grade ≥2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria
• Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation with the Study Physician.
• Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab may be included only after consultation with the Study Physician. 9. PSA rise while on active treatment (LHRH-agonist, LHRH-antagonist, anti-androgen, maximal androgen blockade, oestrogen) 10. Lung, Brain, Liver or other visceral metastases 11. Relapsed primary tumor 12. Perihilar lymphnode metastases 13. Previous irradiation of the oligometastatic site using a dose > 20 Gy less than 5 years ago. 14. Previous treatment with a cytotoxic agent for PCa 15. Treatment during the past month with products known to influence PSA levels (e.g. fluconazole, finasteride, corticosteroids...) 16. Particimmunotherapyation in another clinical study with an investigational product during the last 4 weeks 17. Concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study 18. Any prior immune therapy (CTLA-4, PD1 (Programmed cell death )1 or PD-L1 inhibitor, including durvalumab) 19. Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid. The following are exceptions to this criterion:
• Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection)
• Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent
• Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication) 20. Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks of the first dose of study drug 21. Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of Durvalumab. 22. History of allogenic organ transplantation. 23. Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc]). The following are exceptions to this criterion:
• Patients with vitiligo or alopecia
• Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement
• Any chronic skin condition that does not require systemic therapy
• Patients without active disease in the last 5 years may be included but only after consultation with the study physician
• Patients with celiac disease controlled by diet alone 24. Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement 25. History of another primary malignancy except for
• Malignancy treated with curative intent and with no known active disease ≥5 years before the first dose of immunotherapy and of low potential risk for recurrence
• Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
• Adequately treated carcinoma in situ without evidence of disease 26. History of leptomeningeal carcinomatosis 27. History of active primary immunodeficiency 28. Active infection including tuberculosis, hepatitis B (known positive HBV (hepatitis B virus) surface antigen (HBsAg) result), hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies). Patients with a past or resolved HBV (hepatitis B virus) infection (defined as the presence of hepatitis B core antibody [anti-HBc (hepatitis B core antigen)] and absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA. 29. Receipt of live attenuated vaccine within 30 days prior to the first dose of immunotherapy. Note: Patients, if enrolled, should not receive live vaccine whilst receiving immunotherapy and up to 30 days after the last dose of immunotherapy. 30. Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients. 31. Prior randomization or treatment in a previous durvalumab clinical study regardless of treatment arm assignment. 32. Male patients of reproductive potential who are not willing to employ effective birth control from screening to 90 days after the last dose of durvalumab monotherapy, whichever is the longer time period.

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Condition: Prostate Cancer

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT01794403

Sponsor: University of Miami

Eligibility:

• Age: minimum 35 Years maximum 85 Years
• Gender: Male

Inclusion Criteria:

• 1. Histologically proven prostate adenocarcinoma.
• Gleason score 2-7 (reviewed by reference lab at UM).
• Biopsy within one year of date of enrollment. 2. Clinical stage ≤ T2 based on DRE and/or ≤ T3a based on MRI (if done); N0-Nx; M0-Mx (AJCC 7th Edition)
• T-stage and N-stage determined by physical exam and available imaging studies (CT, and/or MRI of the pelvis; see section 4.5). For MRI, questionable extracapsular extension is permitted. To distinguish blood from tumor the ideal study would be to acquire T2, T1 noncontrast and T1 dynamic contrast enhanced sequence, although this is not required. A small amount of extracapsular extension is permitted, as long as it can be included in the clinical target volume (CTV) and the constraints are met.
• M-stage determined by physical exam, CT or MRI. Bone scan not required unless clinical findings suggest possible osseous metastases. 3. Prostate-Specific Antigen (PSA) < 20 ng/ml, obtained no greater than 3 months prior to enrollment. 4. Patients belonging in one of the following risk groups:
• Low:
• Clinical stage* T1-T2; Gleason ≤ 6, PSA ≤ 10 & <50% biopsy cores positive.
• Intermediate:
• Clinical stage T2b-T2c; Gleason ≤ 6, PSA ≤ 10 & <50% biopsy cores positive.
• Clinical stage T1-T2; Gleason ≤ 6, PSA ≤ 10 & ≥50% biopsy cores positive.
• Clinical stage T1-T2; Gleason = 7, PSA ≤ 10 & <50% biopsy cores positive or T1-T2; Gleason ≤ 6 & PSA >10 and < 20 & < 50% biopsy cores positive.
• MRI stage T3a with evidence of extraprostatic extension is allowed.
• Clinical stage is based on digital rectal exam (DRE). Seminal vesicle invasion on MRI is not eligible. T1a should be permitted if subsequent peripheral zone biopsies show tumor. 5. Prostate volume: ≤ 80 cc.
• Determined using: volume = π/6 x length x height x width.
• Measured from CT or MRI ≤90 days prior to enrollment. 6. Zubrod performance status 0-1. 7. No prior total prostatectomy or cryotherapy of the prostate.
• Prior suprapubic prostatectomy, transurethral resection and laser ablation are permitted. 8. No prior radiotherapy to the prostate or lower pelvis. 9. No implanted hardware or other material that would prohibit appropriate treatment planning or treatment delivery, in the investigator's opinion. 10. No chemotherapy for a malignancy in the last 5 years. 11. No history of an invasive malignancy (other than this prostate cancer, or nonmetastatic basal or squamous skin cancers) in the last 5 years. 12. 4-6 months of androgen deprivation therapy (ADT) are allowed for intermediate risk patients. This must be declared prior to randomization. This may not have been started more than 2 months prior to randomization. 13. Patient must be able to have gold fiducial markers placed in the prostate (if on anticoagulants, must be cleared by a primary care physician or cardiologist), or if patient already has fiducial marker placed, they must be in accordance with the protocol specifications (Section 4.2.2). NOTE: If a method of intrafraction prostate tracking is available which does not require fiducial markers, this will be adequate for this trial (i.e. 4D transperitoneal ultrasound, onboard MRI guidance). 14. Ability to understand and the willingness to sign a written informed consent document. 15. Willingness to fill out quality of life/psychosocial forms. 16. Age >= 35 and =< 85 years. 17. IPSS (AUA) score ≤12

Exclusion Criteria:

1. Does not have a diagnosis of prostate adenocarcinoma.
2. Patient has clinical T3a or any evidence of T3b disease.
3. Patient has stage N1 or M1 disease.
4. Patients has a PSA of greater than 20 ng/ml, obtained no greater than 3 months prior to randomization.
5. Patient does not meet any of the risk groups outlined in section 3.1.
6. Prostate volume greater than 80 cc.
7. Zubrod performance status 2 or greater.
8. Prior total prostatectomy.
9. Prior radiation therapy to the prostate or lower pelvis.
10. Implanted hardware which limits treatment planning or delivery (determined by the investigator).
11. Chemotherapy within the past 5 years.
12. Diagnosis of an invasive malignancy within 5 years (other than current prostate cancer or non-metastatic basal or squamous skin cancers or non-metastatic curatively treated papillary thyroid carcinoma).
13. The use of more than 2 months of androgen deprivation therapy (ADT) prior to randomization, or plans for ADT to be continued for greater than 6 months.
14. Inability to have gold fiducial markers placed in the prostate, or fiducial markers already placed that are not in accordance with the protocol (Section 4.2.2). NOTE: If a method of intrafraction prostate tracking is available which does not require fiducial markers, this will be adequate for this trial (i.e. 4D transperitoneal ultrasound, onboard MRI guidance).
15. Unwilling or inability to give informed consent.
16. Not willing to fill out quality of life/psychosocial questionnaires.
17. IPSS score > to
18. Age < 35 and > 85 years.

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Condition: Hormone-Resistant Prostate Cancer, Metastatic Prostate Carcinoma, Prostate Carcinoma Metastatic in the Bone, Stage IV Prostate Cancer

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT02555189

Sponsor: Sidney Kimmel Cancer Center at Thomas Jefferson University

Phase: Phase 1/Phase 2

Eligibility:

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

Inclusion Criteria:

• 1. Willing and able to provide written informed consent and HIPAA authorization for the release of personal health information. NOTE: HIPAA authorization may be either included in the informed consent or obtained separately. Consent and HIPPA authorization must be obtained prior to any screening procedures. 2. Males 18 years of age and above 3. Histological or cytological proof of prostate cancer 4. Documented progressive mCRPC based on at least one of the following criteria:
• PSA progression defined as 25% increase over baseline value with an increase in the absolute value of at least 2 ng/mL that is confirmed by another PSA level with a minimum of a 1 week interval and a minimum PSA of 2 ng/mL.
• 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.
• Progression of bone disease (evaluable disease) or (new bone lesion(s)) by bone scan. 7) Have testosterone < 50 ng/dL. Patients must continue primary androgen deprivation with an LHRH analogue (agonist or antagonist) if they have not undergone orchiectomy 8) ECOG performance status of 0-1 9) Patients on long term (>6 months) anti-androgen therapy (e.g., flutamide, bicalutamide, nilutamide) will need to be off anti-androgen for 4 weeks (wash out period) and show evidence of disease progression off the anti-androgen. Patients that have been on an anti-androgen 6 months or less will need to discontinue anti-androgen therapy prior to enrollment (no wash out period required). 10) Patient has adequate bone marrow and organ function as defined by the following laboratory values:
• Absolute neutrophil count ≥ 1.5 × 109/L.
• Platelets (UNVPLT) ≥ 100 × 109/L.
• Hemoglobin (HGB) ≥ 9 g/dl.
• Potassium (K), total calcium (CA)(corrected for serum albumin), magnesium, sodium (NA) and phosphorus within normal limits for the institution or corrected to within normal limits with supplements before first dose of study medication.
• INR ≤ 1.5.
• Serum creatinine (CREAT) ≤ 1.5 mg/dL or creatine clearance > 50 mL/min.
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x ULN. If the patient has liver metastases, ALT and AST must still be ≤ 2.5 x ULN. Patients with liver metastases and AST/ALT above this limit will not be enrolled..
• Total serum bilirubin ≤ 1.5 x ULN; or total bilirubin (TBILI) ≤ 3.0 x ULN with direct bilirubin within normal range in patients with well documented Gilbert's Syndrome. 11) The effects of ribociclib on the developing human fetus at the recommended therapeutic dose are unknown. Men must agree to use adequate contraception prior to enrollment, for the duration of study participation and for at least 3 months thereafter. 12) Must be able to take oral medication without crushing, dissolving or chewing tablets.

Exclusion Criteria:

• 1. Prior exposure to abiraterone acetate or other specific CYP-17 inhibitors. Abiraterone acetate given in the castration-sensitive setting is permissible if stopped at least 6 months prior to initial protocol treatment. 2. Prior exposure to enzalutamide or other investigational AR directed therapy 3. Prior chemotherapy. 4. Prior isotope therapy with strontium-89, samarium or radium-223 within 12 weeks of enrollment. 5. Administration of antifungal agents (itraconazole, fluconazole, etc) within 4 weeks of enrollment or unrecovered AEs due to agents administered more than 4 weeks of enrollment. 6. History of pituitary or adrenal dysfunction, active or symptomatic viral hepatitis or chronic liver disease. 7. Known symptomatic brain metastases. 8. Use of any prohibited concomitant medications: immunotherapy, 5 alpha reductase inhibitors, spironolactone, diethylstilbestrol (DES), ketoconazole, newer medications targeting ARs. NOTE: Because of the potential for drug-drug interaction, the concurrent use of all other drugs, over-the-counter medications, or alternative therapies must be documented. The principal investigator should be alerted if the patient is taking any agent that interacts with CYP450 system. 9. Treatment-related toxicity from prior therapy > Grade 2. 10. Peripheral neuropathy > 2 11. History of hypersensitivity to ribociclib or compounds of similar chemical or biologic composition to ribociclib including to peanut and soy or other drugs formulated with polysorbate 80; or enzalutamide. All herbal, alternative and food supplements (i.e., PC-Spes, Saw Palmetto, St John Wort, etc.). They must be discontinued prior to enrollment. Patients may continue on a daily Multi-Vitamin, calcium and Vitamin D. 12. Planned surgery or radiation therapy during protocol treatment, 13. Hormonal-acting agents (including DES, aldosterone, and spironolactone but not including GnRH agonists or antagonists) are forbidden during the trial and must be stopped prior to enrollment. No washout period will be required for any of these agents. 14. Initiation of bisphosphonate/denosumab therapy during protocol treatment. Patients on stable doses of bisphosphonates or denosumab which have been started no less than 4 weeks prior to enrollment may continue on this medication. NOTE: Initiation of bisphosphonate/denosumab therapy will be allowed for the treatment of osteoporosis or prevention of skeletal-related events (SRE) during protocol treatment. 15. Patient has a concurrent malignancy or malignancy within 3 years of enrollment, with the exception of adequately treated, basal or squamous cell carcinoma, non-melanomatous skin cancer or curatively resected cervical cancer. 16. Patient has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the study drugs (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection). 17. Patient has a known history of HIV infection (testing not mandatory). 18. Patient has any other concurrent severe and/or uncontrolled medical condition that would, in the investigator's judgment, cause unacceptable safety risks, contraindicate patient participation in the clinical study or compromise compliance with the protocol (e.g., chronic pancreatitis, chronic active hepatitis, active untreated or uncontrolled fungal, bacterial or viral infections, etc.). 19. Patient has clinically significant, uncontrolled heart disease and/or recent events including any of the following:
• History of acute coronary syndromes (including myocardial infarction, unstable angina, coronary artery bypass grafting, coronary angioplasty, or stenting) or symptomatic pericarditis within 12 months prior to enrollment
• History of documented congestive heart failure (New York Heart Association functional classification III-IV)
• Documented cardiomyopathy
• Patient has a Left Ventricular Ejection Fraction (LVEF) < 50% as determined by Multiple Gated acquisition (MUGA) scan or echocardiogram (ECHO) at screening
• History of any cardiac arrhythmias, eg., ventricular, supraventricular, nodal arrhythmias, or conduction abnormality within 12 months prior to enrollment.
• Family history of QTc prolongation or of unexplainable sudden death at <50 years of age.
• On screening 12 lead ECG, any of the following cardiac parameters: bradycardia (heart rate < 50 at rest), tachycardia (heart rate > 90 at rest), PR interval > 220 msec, QRS interval >109 msec, or QTcF >450 msec. Congenital long QT syndrome or family history of long QT syndrome.
• Systolic blood pressure (SBP) >160 mmHg or <90 mmHg.
• Bradycardia (heart rate < 50 at rest), by ECG or pulse, at screening 20. On screening, inability to determine the QTcF interval on the ECG (i.e.: unreadable or not interpretable) or QTcF >450 msec (using Fridericia's correction). All as determined by screening ECG (mean of triplicate ECGs) 21. Patient is currently receiving any of the following medications and cannot be discontinued 7 days prior to enrollment:
• Known strong inducers or inhibitors of CYP3A4/5, including grapefruit, grapefruit hybrids, pummelos, star-fruit, and Seville oranges.
• That have a narrow therapeutic window and are predominantly metabolized through CYP3A4/5.
• That have a known risk to prolong the QT interval or induce Torsades de Pointes.
• Herbal preparations/medications, dietary supplements 22. Patient is currently receiving or has received systemic corticosteroids within <2 weeks prior to enrollment, or who have not fully recovered from side effects of such treatment.
• The following uses of corticosteroids are permitted: single doses, topical applications (e.g., for rash), inhaled sprays (e.g., for obstructive airways diseases), eye drops or local injections (e.g., intra-articular) 23. Patient is currently receiving warfarin or other coumarin-derived anticoagulant for treatment, prophylaxis or otherwise. Therapy with heparin, low molecular weight heparin (LMWH) or fondaparinux is allowed. 24. Patient who has participated in a prior investigational study within 30 days prior to enrollment or within 5 half-lives of the investigational product, whichever is longer. 25. Patient who has received radiotherapy ≤ 4 weeks or limited field radiation for palliation ≤ 2 weeks prior to enrollment, and who has not recovered to Grade 1 or better from related side effects of such therapy (exceptions include alopecia) and/or in whom ≥ 30% of the bone marrow was irradiated. 26. Patients with central nervous system (CNS) involvement unless they meet ALL of the following criteria:
• At least 4 weeks from prior therapy completion (including radiation and/or surgery) to enrollment
• Clinically stable CNS tumor at the time of screening and not receiving steroids and/or enzyme-inducing anti-epileptic medications for brain metastases 27. Patient has had major surgery within 14 days prior to enrollment or has not recovered from major side effects (tumor biopsy is not considered as major surgery). 28. Patient has not recovered from all toxicities related to prior anticancer therapies to NCI-CTCAE version 4.03 Grade <1 (Exception to this criterion: patients with any grade of alopecia are allowed to enter the study). 29. Patient with a Child-Pugh score B or C. 30. Patient has a history of non-compliance to medical regimen or inability to grant consent. 31. Sexually active males unless they use a condom during intercourse while taking the drug and for 30 days after stopping treatment and should not father a child in this period. A condom is required to be used by vasectomized men in order to prevent delivery of the drug via seminal fluid.

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Condition: Prostate Cancer

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT03706365

Sponsor: Eli Lilly and Company

Phase: Phase 2/Phase 3

Eligibility:

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

Inclusion Criteria:

• Histologically confirmed adenocarcinoma of the prostate.
• Metastatic prostate cancer documented by positive bone scan and/or measurable soft tissue metastatic lesions by CT or magnetic resonance imaging (MRI).
• Progressive disease at study entry demonstrated during continuous androgen-deprivation therapy (ADT)/post orchiectomy defined as one or more of the following:
• PSA progression
• Radiographic progression per Response Evaluation Criteria in Solid Tumors (RECIST)1.1 for soft tissue and/or per Prostate Cancer Working Group 3 (PCWG3) for bone, with or without PSA progression
• Have adequate organ function.
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1.

Exclusion Criteria:

• Prior therapy with cytochrome P450 (CYP)17 inhibitors.
• Prior treatment with abemaciclib or any cyclin-dependent kinase (CDK) 4 & 6 inhibitors.
• Prior cytotoxic chemotherapy for metastatic castration resistant prostate cancer (participants treated with docetaxel in the metastatic hormone-sensitive prostate cancer [mHSPC] are eligible). Prior radiopharmaceuticals for prostate cancer, or prior enzalutamide, apalutamide, darolutamide or sipuleucel-T. Participants who had prior radiation or surgery to all target lesions.
• Currently enrolled in a clinical study involving an investigational product.
• Gastrointestinal disorder affecting the absorption or ability to swallow large pills.
• Clinically significant heart disease, active or chronic liver disease, moderate/severe hepatic impairment (Child-Pugh Class B and C).

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Condition: Recurrent Prostate Cancer

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT03067051

Sponsor: SpectraCure AB

Phase: Phase 1/Phase 2

Eligibility:

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

Inclusion Criteria:

1. Males > 18 years who have gone through external or internal, high dose rate (brachy) radiation therapy for localized prostate cancer with histopathologically verified local recurrence.
2. Prostate volume less than 50 cm3 defined by transrectal ultrasound
3. Subject not eligible for surgery or curative radiotherapy
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
5. Expected survival ≥ 8 months
6. Sufficient bone marrow reserve as indicated by; granulocyte count ≥ 1500/mm3, platelet count ≥ 100,000/mm3
7. Adequate renal function as defined by creatinine ≤ 1.5 mg /dl
8. Adequate hepatic function, based on a total bilirubin ≤ 1.5 mg/dl, serum glutamate-oxaloacetate transaminase (SGOT) ≤ 3 times the upper limit of normal, and alanine transaminase (ALT) ≤ 3 times the upper limit of normal
9. Signed Informed Consent Phase 1 Exclusion Criteria:
10. Patients with locally advanced (AJCC 7th edition T3/T4) or metastatic disease
11. Patients who have been treated with seed implantation brachytherapy
12. Gleason score ≥ 8 at initial diagnosis
13. Less than 1 week since surgery (excluding minimal procedures, e.g. vascular access device insertion)
14. Concomitant infection
15. Subjects with other severe concurrent disease that in the judgement of the investigator would make the subject inappropriate for entry into this study
16. Mental incapacity or psychiatric illness that would interfere with the subject's ability to understand and give informed consent or to complete follow-up visits according to the judgement of the investigator
17. Contraindication for photosensitizer
18. Porphyria or other diseases exacerbated by light
19. Known hypersensitivity to verteporfin for injection (VFI) or to any of the excipients
20. Known allergies to porphyrins
21. Tumours known to be eroding into a major blood vessel in or adjacent to the illumination site
22. On-going therapy with a photosensitizing agent
23. Enrolment in another therapeutic clinical study within 3 months prior to randomization and throughout the study.
24. Subjects with a history of CTCAE v4 grade 3 or greater or persistent (>1 separate episode or symptoms lasting more than 3 months after initiation of medical intervention) grade 2 proctitis attributed to radiation. Phase 2 Inclusion Criteria:
25. Subjects > 18 years who have gone through external or internal, high dose-rate (brachy) radiation therapy for localized prostate cancer with histopathologically verified local recurrence.
26. Treatment target volume less than 50 cm
27. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or
28. Expected survival ≥ 12 months.
29. Sufficient bone marrow reserve as indicated by; granulocyte count ≥ 1500/mm3, platelet count ≥ 100,000/mm
30. Adequate renal function as defined by creatinine ≤ 1.5 mg /dl.
31. Adequate hepatic function, based on a total bilirubin ≤ 1.5 mg/dl, serum glutamate- oxaloacetate transaminase (SGOT) ≤ 3 times the upper limit of normal, and alanine transaminase (ALT) ≤ 3 times the upper limit of normal.
32. Signed Informed Consent. Phase 2

Exclusion Criteria:

1. Patients with locally advanced (AJCC 7th edition T3/T4) or metastatic disease
2. Patients who have been treated with seed implantation brachytherapy
3. Gleason score ≥ 8 at initial diagnosis
4. Less than 1 week since surgery (excluding minimal procedures, e.g. vascular access device insertion)
5. Concomitant infection
6. Subjects with other severe concurrent disease that in the judgement of the investigator would make the subject inappropriate for entry into this study
7. Mental incapacity or psychiatric illness that would interfere with the subject's ability to understand and give informed consent or to complete follow-up visits according to the judgement of the investigator
8. Contraindication for photosensitizer
9. Porphyria or other diseases exacerbated by light
10. Known hypersensitivity to verteporfin for injection (VFI) or to any of the excipients
11. Known allergies to porphyrins
12. Tumours known to be eroding into a major blood vessel in or adjacent to the illumination site
13. On-going therapy with a photosensitizing agent
14. Enrolment in another therapeutic clinical study within 3 months prior to randomization and throughout the study.
15. Subjects with a history of CTCAE v4 grade 3 or greater or persistent (>1 separate episode or symptoms lasting more than 3 months after initiation of medical intervention) grade 2 proctitis attributed to radiation. Phase 2 Inclusion Criteria:
16. Subjects > 18 years who have gone through external or internal, high dose-rate (brachy) radiation therapy for localized prostate cancer with histopathologically verified local recurrence.
17. Treatment target volume less than 50 cm
18. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or
19. Expected survival ≥ 12 months.
20. Sufficient bone marrow reserve as indicated by; granulocyte count ≥ 1500/mm3, platelet count ≥ 100,000/mm
21. Adequate renal function as defined by creatinine ≤ 1.5 mg /dl.
22. Adequate hepatic function, based on a total bilirubin ≤ 1.5 mg/dl, serum glutamate- oxaloacetate transaminase (SGOT) ≤ 3 times the upper limit of normal, and alanine transaminase (ALT) ≤ 3 times the upper limit of normal.
23. Signed Informed Consent. Phase 2 Exclusion Criteria:
24. Subjects with locally advanced (AJCC 7th edition T3/T4), regional pelvic lymph node metastasis, or metastatic disease defined by PSMA PET.
25. Subjects who have been treated with seed implantation brachytherapy.
26. Less than 1 week since surgery (excluding minimal procedures, e.g. vascular access device insertion).
27. Concomitant infection.
28. Subjects with other severe concurrent disease that in the judgement of the investigator would make the subject inappropriate for entry into this study.
29. Mental incapacity or psychiatric illness that would interfere with the subject's ability to understand and give informed consent or to complete follow-up visits according to the judgement of the investigator.
30. Contraindication for photosensitizer.
31. Porphyria or other diseases exacerbated by light.
32. Known hypersensitivity to verteporfin for injection (VFI) or to any of the excipients.
33. Known allergies to porphyrins.
34. Tumours known to be eroding into a major blood vessel in or adjacent to the illumination site.
35. On-going therapy with a photosensitizing agent.
36. Enrolment in another therapeutic clinical study within 3 months prior to randomization and throughout the study.
37. Subjects with a history of CTCAE v4 grade 3 or greater or persistent (>1 separate episode or symptoms lasting more than 3 months after initiation of medical intervention) grade 2 proctitis attributed to radiation.
38. Contraindication for MRI/Gadolinium contrast such as: implants, severe renal impairment (glomerular filtration rate [GFR] <30 mL/min/1.73m2, or previous contrast reactions.
39. On-going or planned hormone therapy.

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Condition: Prostate Cancer

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT03436654

Sponsor: Memorial Sloan Kettering Cancer Center

Phase: Phase 2

Eligibility:

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

Inclusion Criteria:

• Willing and able to provide written informed consent and Authorization for Use and Release of Health and Research Study Information (HIPAA authorization) NOTE: HIPAA authorization may be either included in the informed consent or obtained separately
• Male aged 18 years and above
• Serum testosterone of ≥150 ng/dL (For Cohorts A and B1, testosterone level requirement is exempted if they are already on ADT prior to treatment start. For Cohort B2, subjects will be considered eligible if their testosterone is currently ≥150 ng/dl).
• Histologically confirmed adenocarcinoma of the prostate, who meet the following criteria: Cohort A
• Clinically localized disease with histologically confirmed adenocarcinoma of the prostate with either ≥3 positive cores or 2 positive cores if >1cm in length with at least 50% tumor content WITH
• With Gleason score 8-10 OR
• Gleason 4+3 with one of the following features:
• PSA ≥ 20 mg/mL within 2 months prior to diagnostic biopsy
• MRI suspicious for radiographic ≥T3 disease (if urologist deems tumor is resectable at baseline); defined as >75% probability of extracapsular extension or seminal vesicle invasion in the opinion of the reading radiologist. OR
• Gleason 3+4 or 4+3 and Oncotype DX Genomic Prostate Score of >40
• With or without clinical N1 (size >1.5cm in the short axis) (Gleason score requirement can be omitted if node positive) OR Cohort B1
• Newly diagnosed low-volume metastatic disease with either.
• Bone metastases as documented by CT, MRI or radionuclide bone scan amenable to treatment with a maximum of 3 radiation isocenters* These lesions must have a structural correlate on CT or MRI to allow for adequate radiation targeting *(note:subjects with PET scans that show osseous metastases that would not be amenable to 3-isocenter radiation treatment are still eligible if conventional imaging shows osseous disease that can be treated with 3 radiation isocenters) And/or
• Retroperitoneal nodes up to the level of the renal hilum with/without pelvic nodal metastasis >1.5cm in the short axis OR Cohort B2 (Cohort B2 expansion)
• Biochemically persistent/recurrent disease (defined as PSA >0.2) after RP ± extended pelvic nodal dissection identified on PSMAb PET scans
• PSMA PET evidence of M1a/M1b disease that could be covered in up to 3 radiation plans (note that the isocenter for planned prostate bed/pelvic nodal irradiation does not count towards the 3 isocenter limit)
• No radiographic evidence of local or regional recurrence on imaging in subjects with prior salvage radiation to these areas.
• Prior salvage radiotherapy is permitted. Prior metastasis-directed radiation is not permitted.
• Castration sensitive disease
• Multiple lesions within one isocenter may be permitted upon review by the sponsor's radiation oncologist
• ECOG performance status of ≤ 1
• Adequate bone marrow, hepatic and renal function, as evidenced within 28 days prior to treatment start by:
• ANC ≥ 1500/µl
• Hemoglobin ≥ 9g/dL
• Platelet count ≥ 100,000/µl
• Serum Creatinine GFR ≥30 mL/min
• Porassium within institutional normal range
• Total Bilirubin ≤ 1.5 x ULN (Note: In subjects with Gilbert's syndrome, if total bilirubin is >1.5 x ULN, measure direct and indirect bilirubin and if direct bilirubin is ≤ 1.5 x ULN, subject may be eligible)
• Albumin ≥ 3.0 g/dL
• SGOT (AST) ≤ 2.5 x ULN
• SGPT (ALT) ≤ 2.5 x ULN
• Subjects must have a clinical T stage documented by the treating urologist/medical oncologist within 90 days prior to treatment start using the 7th edition AJCC staging system, recorded as the urologist's/medical oncologist's best clinical assessment of extent of local disease by digital rectal examination and/or available imaging studies such as transrectral ultrasound, CT scan, and/or MRI. Applicable to Cohort A and B1.
• The primary tumor must be considered unresectable by RP based on initial imaging with gross negative margins as determined by a urologist and documented as such. (applicable to Cohorts A and B1 only)
• Recovery of reversible effects of prior surgery (i.e., incisional pain, wound drainage) to Grade ≤1, and at least 4 weeks from prior surgery to treatment start. (biopsy excluded)
• Able to swallow the study drug(s) whole as a tablet
• Willing to take abiraterone acetate on an empty stomach; no food should be consumed at least one hour before and for at least two hours after the dose of abiraterone acetate is taken (Note: apalutamide does not have to be taken on an empty stomach.)
• Agrees to use a condom (even men with vasectomies) and another effective method of birth control if he is having sex with a woman of childbearing potential or agrees to use a condom if he is having sex with a woman who is pregnant while on study drug and for 3 months following the last dose of study drug. Must also agree not to donate sperm during the study and for 3 months after receiving the last dose of study drug.
• For Cohorts B1 and B2 only, biopsy confirmation of metastases (strongly encouraged; if safe and feasible at treating center)

Exclusion Criteria:

• Prior treatment for prostate cancer including prior surgery (excluding TURP and subjects with rising PSA after RP), pelvic lymph node dissection, radiation therapy unless the subject is eligible for Cohort B2.
• Prior cytotoxic chemotherapy or biologic therapy for prostate cancer
• Up to 2 months of prior ADT with GnRH antagonist/agonist at time of treatment start. Bicalutamide given for ≤ 12 months at the time of registration as flare prevention is allowed. For Cohort B2, prior ADT and/or first generation anti-androgen treatment in the (neo)adjuvant and/or salvage setting in conjunction with radiation or surgery is allowed provided last effective dose of ADT and/or first generation anti-androgen is > 12 months prior to the on treatment date and total duration of prior therapy is 12 months or lesser, and their testosterone is currently >150ng/dL.
• Prior exposure to ketoconazole (systemic), abiraterone acetate, enzalutamide or other agents targeting the AR signaling pathway
• Concomitant therapy with any other experimental drug
• Known brain, liver, lung or other visceral metastasis (except for retroperitoneal and / or pelvic nodal metastases as per inclusion criteria)
• Prior prostate cancer metastasis-directed therapies
• Currently active second malignancy or past history of malignancies diagnosed within the last 2 years that require active therapy and/or in remission with life expectancy of < 5 years, with the exception of resected non-melanoma skin cancers, non-muscle invasive bladder cancer, state I head and neck cancer, or stage I colorectal cancer
• Significant medical condition other than cancer, that would prevent consistent and compliant participation in the study that would, in the opinion of the investigator, make this protocol unreasonably hazardous including but not limited to:
• Any medical condition requiring a higher dose of corticosteroid than 10mg prednisone/prednisolone once daily
• Active infection requiring systemic therapy
• History of gastrointestinal disordered (medical disorders or extensive surgery) that may interfere with the absorption of the study agents
• Uncontrolled hypertension (systolic BP ≥ 160 mmHg or diastolic BP ≥ 95 mmHg); subjects with a history of hypertension are allowed provided blood pressure is controlled by anti-hypertensive treatment (systolic BP < 160 mmHg or diastolic BP <95 mmHg)
• Active or symptomatic viral hepatitis of chronic liver disease
• Acute or chronic hepatitis B or hepatitis C infection. (Hepatitis B and C testing are not mandatory)
• Presence of hepatitis B surface antibody is acceptable Human immunodeficiency virus (HIV)-positive subjects with 1 or more of the following: Not receiving highly active anti-retroviral therapy. A change in anti-retroviral therapy within 6 months of the start of screening (except if, after consultation with the principal investigator (PI) / sponsor, a change is made to avoid a potential drug-drug interaction with the study drug). Receiving anti-retroviral therapy that may interfere with the study drug(s) (consult the PI / sponsor for review of medication prior to enrollment). CD4 count < 350 cell/mm^3 at screening. An acquired immunodeficiency syndrome-defining opportunistic infection within 6 months of the start of screening.
• History of pituitary or adrenal dysfunction
• History of hypogonadism
• 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 III or IV heart disease or cardiac ejection fraction measurement of <50% at baseline, or clinically significant ventricular arrhythmias within 6 months prior to treatment start.
• History of seizure or any condition that may predispose to seizure (including, but not limited to prior stroke, transient ischemic attack or loss of consciousness
• Uncontrolled diabetes mellitus
• History of inflammatory bowel disease
• Baseline moderate and severe hepatic impairment (Child Pugh Class B & C)
• Use of any prohibited concomitant medications within 14 days prior to treatment start, or use of prohibited concomitant medication listed in section 7.9.1 within the outlined windows NOTE: Medications known to lower the seizure threshold must be discontinued or substituted at least 4 weeks prior to treatment start
• Pre-existing condition that warrants long-term corticosteroid use in excess of 10 mg prednisone/prednisolone daily
• Known allergies, hypersensitivity or intolerance to apalutamide, abiraterone acetate, prednisone, or GBRH agonist or GNRH antagonist
• Administration of an investigational therapeutic within 30 days of treatment start
• Patients that cannot tolerate MRI
• Any condition which, in the opinion of the investigator, would preclude participation in this trial

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Condition: Metastatic Castration Resistant Prostate Cancer (mCRPC)

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT03874884

Sponsor: Peter MacCallum Cancer Centre, Australia

Phase: Phase 1

Eligibility:

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

Inclusion Criteria:

• Patients must meet all of the following criteria for study entry: 1. Patient must be ≥ 18 years of age and must have provided written informed consent. 2. Histologically confirmed adenocarcinoma of the prostate without neuroendocrine or small cell differentiation. 3. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 1 (see Appendix 1). 4. Patients must have had at least one prior line of taxane (docetaxel) chemotherapy either in the hormone sensitive or castrate resistant setting unless the patient is deemed medically unsuitable for chemotherapy. If a patient has had docetaxel chemotherapy twice, this will be considered one line. 5. Patients must have progressed on a second generation AR targeted agent (e.g. enzalutamide, abiraterone and/or apalutamide). Determination of disease progression on second generation AR targeted agent will be made by the local investigator. 6. Patients must have progressive disease for study entry. This is defined by PCWG3 as any one of the following:
• PSA progression: minimum of two rising PSA values from a baseline measurement with an interval of ≥ 1 week between each measurement. The PSA value at screening should be ≥ 10ng/ml.
• Soft tissue or visceral disease progression as per RECIST 1.1 criteria (see Appendix 2)
• Bone progression: ≥ 2 new lesions on bone scan (Appendix 2) 7. At least 3 weeks since the completion of surgery or radiotherapy prior to registration. Any clinically relevant sequelae from the surgery or radiotherapy must have improved to grade 1 prior to registration. 8. Prior surgical orchiectomy or chemical castration maintained on luteinizing hormone-releasing hormone (LHRH) analogue (agonist or antagonist). Patients without prior surgical castration must be currently taking and willing to continue luteinizing hormone-releasing hormone (LHRH) analogue (agonist or antagonist) therapy throughout the duration of study treatment. 9. Serum testosterone levels ≤ 50ng/dL (≤ 1.75nmol/L) within 28 days before registration. 10. Imaging evidence of metastatic disease documented with either bone scan or CT scan (Appendix 2). 11. Prior prostate cancer vaccine therapy, radiation therapy, systemic therapies, diethylstilboestrol (DES) or other estrogens, bicalutamide, flutamide or nilutamide are allowed up to 28 days prior to trial registration. Note: bicalutamide, flutamide or nilutamide must be discontinued within 4 weeks of registration. 12. Significant PSMA avidity on 68Ga/18F-PSMA PET/CT, defined as a minimum uptake of SUVmax 15 at a site of disease, and SUVmax > 10 at other sites of disease ≥10mm (unless subject to factors explaining a lower uptake, e.g. respiratory motion, reconstruction artefact). 13. Patients must have a life expectancy ≥ 24 weeks. 14. Patients must use a condom during treatment and for 3 months after the last dose of olaparib when having sexual intercourse with a pregnant woman or with a woman of childbearing potential. Female partners of male patients should also use a highly effective form of contraception (see section 11.7.4 for acceptable methods). 15. Patients must be willing and able to comply with the protocol for the duration of the study including undergoing treatment, scheduled assessments including completing Patient Reported Outcomes (PRO) instruments. 16. Patients must have adequate bone marrow, hepatic and renal function documented within 28 days prior to registration, defined as:
• Haemoglobin ≥ 100 g/L independent of transfusions (no red blood cell transfusion in last 8 weeks)
• Absolute neutrophil count ≥ 1.5x109/L
• Platelets ≥ 150 x109/L
• Total bilirubin ≤ 1.5 x upper limit of normal (ULN) except for patients with known Gilbert's syndrome where this applies for the unconjugated bilirubin.
• Aspartate transaminase (AST) (SGOT) and alanine transaminase (ALT) (SGPT) ≤ 2.5 x ULN if there is no evidence of liver metastasis or ≤ 5 x ULN in the presence of liver metastases.
• Albumin ≥ 30 g/L
• Adequate renal function: patients must have creatinine clearance estimated of ≥ 51 mL/min using the Cockcroft-Gault equation or based on a 24 hour urine test to appendix 5). 17. Patients who are deemed by PSMA imaging to have readily accessible disease will be required to consent to 3 serial tumour biopsies
• at screening, post combination treatment (at any time between weeks 2-4) and in the event of disease progression.

Exclusion Criteria:

• Patients must not meet any of the following criteria for study entry: 1. Site(s) of disease that are FDG positive with low PSMA expression defined by PSMA SUVmax < 10. 2. Extensive marrow disease defined by a "Super Scan" on bone scintigraphy or diffuse marrow infiltration on PSMA PET. 3. Previous history or presence of brain metastases or leptomeningeal metastases. A scan to confirm the absence of brain metastases is not required if there is no clinical history of this. 4. Surgery or radiotherapy within < 3 weeks of registration (except for palliative reasons). Patients must have recovered from any effects of any major surgery. 5. Patients with symptomatic or impending cord compression unless appropriately treated beforehand and clinically stable for ≥ 4 weeks. 6. Any prior exposure to 177Lu-PSMA, cabazitaxel, platinums, PARP inhibitors, mitoxantrone or cyclophosphamide. 7. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, extensive interstitial bilateral lung disease on High Resolution Computed Tomography (HRCT) scan or psychiatric illness/social situations that is likely to impede participation and /or compliance in the study. 8. Persistent toxicities [Common Terminology Criteria for Adverse Event (CTCAE) ≥ grade 2] caused by previous cancer therapy, excluding alopecia. 9. Other malignancies within the previous 2-years other than basal cell or squamous cell carcinomas of skin or other cancers that are unlikely to recur within 24 months. 10. Previous history of interstitial lung disease or non-infectious pneumonitis. 11. Patients with a history or clinical features suggestive of myelodysplastic syndrome / acute myeloid leukaemia. 12. Patients unable to swallow orally administered medications or with gastrointestinal disorders likely to interfere with the absorption of the study medication. 13. Resting ECG indicating uncontrolled, potentially reversible cardiac conditions, as judged by the investigator (e.g., unstable ischemia, uncontrolled symptomatic arrhythmia, congestive heart failure, QTcF prolongation > 500 ms, electrolyte disturbances, etc.), or patients with congenital long QT syndrome. 14. Known hypersensitivity to olaparib or any of the excipients of olaparib. 15. Immunocompromised patients, e.g., patients who are known to be serologically positive for human immunodeficiency virus (HIV1/2). Only need to check this if there is a clinical history. HIV-infected (HIV1/2 antibody-positive) patients may participate if they meet all the following eligibility requirements:
• They must be on an anti-retroviral regimen with evidence of at least two undetectable viral loads within the past 6 months on this same regimen; the most recent undetectable viral load must be within the past 12 weeks.
• They must have a CD4 count ≥ 250 cells/µL over the past 6 months on this same anti-retroviral regimen and must not have had a CD4 count < 200 cells/µl over the past 2 years, unless it was deemed related to the cancer and/or chemotherapy-induced bone marrow suppression.
• For patients who have received chemotherapy in the past 6 months, a CD4 count < 250 cells/µl during chemotherapy is permitted as long as viral loads were undetectable during this same chemotherapy.
• They must have an undetectable viral load and a CD4 count ≥ 250 cells/µL within 7 days of enrolment.
• They must not be currently receiving prophylactic therapy for an opportunistic infection and must not have had an opportunistic infection within the past 6 months. 16. Patients with known active hepatitis (i.e. Hepatitis B or C). Only need to check this if there is a clinical history.
• Active hepatitis B virus (HBV) is defined by a known positive HBV surface antigen (HBsAg) result. Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody and absence of HBsAg) are eligible.
• Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA. 17. Concomitant use of known strong CYP3A inhibitors (e.g. itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (e.g. ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout period prior to starting olaparib is 2 weeks. 18. Concomitant use of known strong (e.g. phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort) or moderate CYP3A inducers (eg. bosentan, efavirenz, modafinil). The required washout period prior to starting olaparib is 5 weeks for phenobarbital and enzalutamide and 3 weeks for other agents. 19. Previous allogenic bone marrow transplant or double umbilical cord blood transplantation (dUCBT). 20. Participation in another clinical study with an investigational product or another systemic therapy administered in the last 3 weeks.

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