Clinical Trials

Condition: Cancer Of Prostate, Prostate Neoplasms

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT04633252

Sponsor: National Cancer Institute (NCI)

Phase: Phase 1/Phase 2

Eligibility:

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

Inclusion Criteria:

• Participants must have documented histopathological confirmation of prostate cancer. 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.
• Participants must have metastatic disease, defined as at least one lesion on TC99 bone scan or at least one lesion that is measurable per, per RECIST 1.1.
• mCSPC participants:
• Participants must be within 134 days of starting ADT.
• If participants are on ADT and responding, this may impact the findings on scans. Pre- treatment scans could be used to confirm that participants have metastatic high-volume disease in such cases.
• For Cohorts 1 and 2, Dose escalation and Safety Run-in, only: mCSPC may have high or low volume disease.
• For Cohort 3, Dose Expansion: mCSPC participants must have high volume disease (as defined by visceral lesion or 4 or greater bone lesions, at least one of which is beyond the spine and pelvis).
• mCRPC participants:
• Must need ADT as part of their cancer therapy (unless previous orchiectomy)
• Must have been previously treated with modern anti-androgens such as abiraterone, enzalutamide, apalutamide, or darolutamide.
• Must have not had progression while on docetaxel if given for mCSPC or within 3 months of completing docetaxel for mCSPC.
• Progression defined as either rising PSA greater than 2.0 ng/ml or radiographic evidence of progression seen on CT scan or TC-99 bone scan.
• Toxicities related to prior therapy, including surgery and/ or radiation, must have resolved to <= grade 1.
• Men age >=18 years. Because no dosing or adverse event data are currently available on the use of M9241 in combination with docetaxel in participants <18 years of age, children are excluded from this study.
• ECOG performance status 0-2.
• Participants must have adequate organ and marrow function as defined below:
• Absolute neutrophil count >=1,500/mcL, without CSF support
• Platelets >=100,000/mcL
• Hemoglobin >9 g/dL
• PT <= 1.5 x ULN
• aPTT <= 1.5 x ULN
• Total bilirubin <= upper limit of normal (ULN), OR in participants with Gilbert s syndrome, a total bilirubin <= 3.0
• Serum albumin >=2.8 g/dL
• AST(SGOT)/ALT(SGPT) <=1.5 X institutional upper limit of normal -- Hepatic function based on Child-Pugh Class: Participants with hepatic impairment must have Child-Pugh Class A or better
• Serum Creatinine OR Creatinine Clearance <= 1.5 X institutional upper limits of normal OR >=50 mL/min/1.73 m^2 calculated by eGFR in the clinical lab for participants with serum creatinine levels > 1.5 ULN
• The effects of M9241 in combination with docetaxel and abiraterone on the developing human fetus are unknown. For this reason and because docetaxel agents as well as other immuno-therapeutic agents used in this trial are known to be teratogenic, sexually active subjects and their female partners must agree to use medically accepted barrier methods of contraception (e.g., male or female condom)after enrollment on study , during the study treatment and for 4 months after the last dose of abiraterone, docetaxel or M921, even if oral contraceptives are also used. Should a woman become pregnant or suspect she is pregnant while her partner is participating in this study, she should inform her treating physician immediately and her partner should inform the study doctor immediately.
• Ability of subject to understand and the willingness to sign a written informed consent document. Subject should be willing to travel to the NIH for follow-up visits.
• Participants with prior immune checkpoint therapy are eligible to enroll upon PI discretion.

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.
• Other immunodeficiency diseases that in the opinion of the investigator could compromise the participants or limit treatment efficacy
• Serious intercurrent medical illness that, in the judgment of the investigator, would interfere with a participant s ability to carry out the treatment program.
• Current use of other medications for urinary symptoms including 5-alpha reductase inhibitors (finasteride and dutasteride) and alternative medications known to alter PSA (e.g. phytoestrogens and saw palmetto).
• Concurrent use of CYP3A4 inducers or sensitive CYP2D6 substrates within 14 days or 5 half-lives, whichever is shorter.
• Receipt of any investigational agent within 28 days (or 60 days for an antibody drug conjugates) before the first planned dose of study drugs.
• Participants who are positive for Hepatitis B surface antigen and/or Anti-Hepatitis C antibody
• Uncontrolled hypertension (SBP>170/ DBP>105)
• Has received or will receive a live vaccine within 30 days prior to the first administration of study intervention. Seasonal flu vaccines that do not contain a live virus are permitted. Locally approved COVID vaccines are permitted.
• Participants who have had prior docetaxel for mCRPC
• mCSPC participants will be excluded if they did not start abiraterone within 6 weeks of ADT and/or had any docetaxel
• Participants who have had progression within 3 months of completing docetaxel for mCSPC
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to M9241 investigational agents used in the study
• The subject has had evidence within 3 years of the start of study treatment of another active malignancy which required systemic treatment (except for nonmelanoma skin cancers or carcinoma in situ of the bladder).
• The subject has active brain metastases or epidural disease.
• Participants with greater than or equal to grade 2 peripheral neuropathy (defined by CTCAE 5.0) at baseline.

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Condition: Castration-Sensitive Prostate Carcinoma, Metastatic Prostate Adenocarcinoma, Stage IVB Prostate Cancer AJCC v8

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT05733351

Sponsor: Emory University

Phase: Phase 1

Eligibility:

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

Inclusion Criteria:

• Age >= 18 years
• Histologically confirmed adenocarcinoma of the prostate with metastatic disease
• Castration-sensitive status: either not have been treated with androgen deprivation therapy (ADT) (hormone therapy) or not on ADT at the time of progression
• Participants can have received up to 3 months of ADT with luteinizing hormone-releasing hormone (LHRH) agonists or antagonists or orchiectomy with or without concurrent first-generation antiandrogens prior to enrollment, with no radiographic evidence of disease progression or rising prostate-specific antigen (PSA) prior to enrollment
• Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
• Life expectancy > 12 weeks as determined by the investigator
• Hemoglobin >= 9.0 g/dl (within 28 days of cycle 1 day 1) (no transfusions allowed within 7 days of Cycle 1 Day 1 to meet entry criteria)
• White blood cell (WBC) >= 2000/uL (within 28 days of cycle 1 day 1) (after at least 7 days without growth factor support or transfusion)
• Absolute neutrophil count (ANC) >= 1,500/mcL (within 28 days of cycle 1 day 1) (after at least 7 days without growth factor support or transfusion)
• Platelets >= 100,000/mcL (within 28 days of cycle 1 day 1) (no transfusions allowed within 7 days of cycle 1 day 1 to meet entry criteria)
• Prothrombin time (PT)/ partial thromboplastin time (PTT) =< 1.5 x upper limit of normal (ULN) (within 28 days of cycle 1 day 1)
• Total bilirubin =< 1.5 institutional upper limit of normal (ULN) (within 28 days of cycle 1 day 1)
• Aspartate aminotransferase (AST) / alanine aminotransferase (ALT) =< 3 institutional upper limit of normal (ULN) (within 28 days of cycle 1 day 1)
• Serum creatinine =< 2 mg/dL (or glomerular filtration rate >= 40 mL/min) (within 28 days of cycle 1 day 1)
• Willingness to provide pre- and post-treatment fresh tumor biopsies, if safe and medically feasible
• Male subjects must be surgically sterile or must agree to use adequate method of contraception from the time of consent until at least 120 days after the last dose of Xmab27017
• Willingness and ability of the subject to comply with scheduled visits, drug administration plan, protocol specified laboratory tests, other study procedures, and study restrictions
• Completion of all previous surgery, radiotherapy, chemotherapy, immunotherapy, or investigational therapy for the treatment of cancer >= 2 weeks before the start of study therapy. (No radiotherapy to Xmab27017 injection site within 4 weeks)
• Evidence of a personally signed informed consent indicating that the subject is aware of the neoplastic nature of the disease and has been informed of the procedures to be followed, the experimental nature of the therapy, alternatives, potential risks and discomforts, potential benefits, and other pertinent aspects of study participation

Exclusion Criteria:

• Patients who have had chemotherapy or radiotherapy within 4 weeks prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier (i.e., have residual toxicities > grade 1)
• Patients who are receiving any other investigational agents or an investigational device within 21 days before administration of first dose of study drugs
• Prior treatment with any CTLA4, PD1, or PDL1, or directed immunotherapy
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to (investigational new drug [IND] agent[s]) or other agents used in study
• Have known active central nervous system metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are radiologically stable, ie, are without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), are clinically stable, and are without requirement of steroid treatment for at least 14 days prior to first dose of study treatment
• Active known or suspected autoimmune disease (except that subjects are permitted to enroll if they have vitiligo; type 1 diabetes mellitus or residual hypothyroidism due to an autoimmune condition that is treatable with hormone replacement therapy only; psoriasis, atopic dermatitis, or another autoimmune skin condition that is managed without systemic therapy; or arthritis that is managed without systemic therapy beyond oral acetaminophen and nonsteroidal anti-inflammatory drugs)
• Has any condition requiring systemic treatment with corticosteroids, prednisone equivalents, or other immunosuppressive medications within 14 days prior to first dose of study drug (except that inhaled or topical corticosteroids or brief courses of corticosteroids given for prophylaxis of contrast dye allergic response are permitted.)
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• Receipt of an organ allograft
• Known history of left ventricular ejection fraction =< 40%
• Receipt of a live-virus vaccine within 30 days prior to first dose of study drug (seasonal flu vaccines that do not contain live virus are permitted. COVID-19 vaccines are permitted)
• Known human immunodeficiency virus (HIV) positive subject with CD4+ T-cell (CD4+) counts < 350 cells/uL, or an HIV viral load greater than 400 copies/mL, or a history of an AIDS (acquired immunodeficiency syndrome)-defining opportunistic infection within the past 12 months, or who has not been on established antiretroviral therapy (ART) for at least 4 weeks prior to initiation of study drug dosing. (Effective ART is defined as a drug, dosage, and schedule associated with reduction and control of the viral load.)
• Known positive test for hepatitis C ribonucleic acid (RNA) (a subject who is hepatitis C virus [HCV] antibody positive but HCV RNA negative due to documented, curative prior antiviral treatment or natural resolution is eligible).
• Known positive test for hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb; a subject whose HBsAg is negative and HBcAb is positive may be enrolled if a hepatitis B virus [HBV] deoxyribonucleic acid (DNA) test is negative, and the subject is retested for HBsAg and HBV DNA every 2 months)

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Condition: Prostatic Neoplasm

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT05162573

Sponsor: The Netherlands Cancer Institute

Phase: Phase 1

Eligibility:

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

Inclusion Criteria:

• Histologically proven prostate cancer;
• cT2-4, partly determined by MRI;
• N1, determined by LND/SNP and/or PSMA PET/CT;
• iM0, determined by PSMA PET/CT;
• Accepted for curative intent treatment with EBRT of the prostate and regional nodes + 3y ADT;
• Visually PSMA-positive primary tumor and nodes, largest lesion ≥ average liver uptake;
• WHO performance score 0-1;
• Age > 18 years;
• For patients who have partners of childbearing potential: Willingness to use a method of birth control with adequate barrier protection during the study and for 6 months after the study drug administration; and
• Signed written informed consen

Exclusion Criteria:

• Inability to comply to study procedures;
• Inability to adhere to radiation safety measures in hospital or at home;
• Inability to undergo the required biodistribution scans;
• Prior or current malignant disease with potential impact on treatment outcome or survival;
• Prior treatment with EBRT;
• Prior treatment with ADT, already initiated >1 month before the start of EBRT;
• Prior treatment with radionuclide therapies, 177Lu-PSMA-617 or other;
• Reduced bone marrow reserve (Hb<6 mmol/L, Leukocytes<2.5 10E9/L, or Platelets<100 10E9/L not older than 1 month before start of EBRT);
• Reduced renal function (GFR < 60 not older than 1 month before start of EBRT);
• Reduced salivary gland function (history of prior salivary gland disease); or
• Miction problems requiring pre-treatment with ADT.

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Condition: Prostate Cancer

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT04946370

Sponsor: Weill Medical College of Cornell University

Phase: Phase 1/Phase 2

Eligibility:

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

Inclusion Criteria:

• Male participants who are at least 18 years of age on the day of signing informed consent with histologically confirmed diagnosis of prostate adenocarcinoma.
• A male participant must agree to use a contraception during the treatment period and for at least 4 months after the last dose of study treatment and refrain from donating sperm during this period.
• Documented progressive metastatic CRPC based on Prostate Cancer Working Group 3 (PCWG3) criteria, which includes at least one of the following criteria: PSA progression, Objective radiographic progression in soft tissue, New bone lesions
• ECOG performance status of 0-1
• Have serum testosterone < 50 ng/dL. Subjects must continue primary androgen deprivation with an LHRH/GnRH analogue (agonist/antagonist) if they have not undergone orchiectomy.
• Have previously been treated with at least one of the following in any disease state: Androgen receptor signaling inhibitor (such as enzalutamide), CYP 17 inhibitor (such as abiraterone acetate). These drugs may have been initiated in the metastatic hormone sensitive or non-metastatic (M0) CRPC setting provided they meet criteria for progressive mCRPC at study entry.
• Age > 18 years
• Patients must have normal organ and marrow function as defined: Absolute neutrophil count >2,000 cells/mm3, Hemoglobin ≥9 g/dL, Platelet count >150 x 10^3/mcL, Serum creatinine <1.5 x upper limit of normal (ULN) or calculated creatinine clearance ≥ 50 mL/min/1.73 m2 by Cockcroft-Gault, Serum total bilirubin <1.5 x ULN (unless due to Gilbert's syndrome in which case direct bilirubin must be normal), Serum AST and ALT <3 x ULN in absence of liver metastases; < 5x ULN if due to liver metastases (in both circumstances bilirubin must meet entry criteria), Serum internalized normalized ratio (INR) OR prothrombin time (PT) AND activated partial thromboplastin time (aPTT) must be <1.5 x ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants.
• Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

• Prior receipt of chemotherapy for castration-resistant prostate cancer. Prior receipt of docetaxel chemotherapy in the hormone sensitive setting or for localized disease is acceptable provided at least 6 months has passed since the last dose.
• Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX 40, CD137).
• Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment and is allowed.
• Prior bone-seeking beta-emitting radioisotopes (e.g. Sm-153, Sr-89) or investigational PSMA-targeted therapy; prior radium-223 is allowed provided last dose administered >12 weeks prior to C1D1 on this study
• Has a history of a second malignancy, unless treatment with curative intent has been completed with no evidence of malignancy for 2 years. Patients with treated localized non-melanoma skin care, non-muscle invasive urothelial carcinoma, or carcinoma in-situ of other site are not excluded.
• Known history of myelodysplastic syndrome
• Has a known history of Human Immunodeficiency Virus (HIV) infection
• Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection.
• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug.
• Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study intervention.
• Has received prior systemic anti-cancer therapy including investigational agents within 4 weeks or <5 half-lives prior to enrollment.
• Has known active CNS metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable, i.e. without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study intervention.
• Diagnosis of deep vein thrombosis and/or pulmonary embolus within 1 month of C1D1
• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject's participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator
• Has received radiotherapy within 4 weeks of start of study treatment. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease.
• Patients on stable dose of bisphosphonates or denosumab, which have been started no less than 4 weeks prior to treatment start, may continue on this medication, however patients are not allowed to initiate bisphosphonate/Denosumab therapy during the DLT-assessment period of the study. These drugs may be added after week 12.
• Unless azoospermia is present (whether due to surgery or underlying medical condition), having partners of childbearing potential and not willing to use a method of birth control deemed acceptable by the principal investigator and chairperson during the study and for 4 months after last study drug administration.
• Is expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of trial treatment
• Has received a live vaccine or live-attenuated vaccine within 30 days prior to the first dose of study drug. Administration of killed vaccines are allowed.
• Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
• Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
• Has an active infection requiring systemic therapy at the time of treatment initiation
• Has a known history of active TB (Bacillus Tuberculosis)
• Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
• Has had an allogenic tissue/solid organ transplant

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Condition: Metastatic Castration-resistant Prostate Cancer, mCRPC

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT05340374

Sponsor: Peter MacCallum Cancer Centre, Australia

Phase: Phase 1/Phase 2

Eligibility:

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

Inclusion Criteria:

1. Male patients aged 18 years or older at the time of informed consent.
2. Patient has provided written informed consent.
3. Histologically confirmed adenocarcinoma of the prostate without neuroendocrine or small cell differentiation.
4. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 1
5. Patients must have had prior treatment with docetaxel.
6. Patients must have progressed on a second-generation androgen receptor (AR)-targeted agent (e.g., enzalutamide, abiraterone, or apalutamide) in the castrate-resistant setting.
7. Patients must have progressive disease. The Prostate Cancer Clinical Trials Working Group 3 (PCWG3) defines this as any one of the following:
8. PSA progression: minimum of two rising PSA values from a baseline measurement with an interval of ≥ 1 week between each measurement
9. Soft tissue or visceral disease progression as per Response Evaluation Criteria in Solid Tumours version 1.1 (RECIST 1.1) criteria
10. Bone progression: ≥ 2 new lesions on bone scan
11. At least three weeks since the completion of surgery prior to registration.
12. Prior surgical orchiectomy or chemical castration maintained on luteinizing hormone-releasing hormone (LHRH) analogue (agonist or antagonist).
13. Serum testosterone levels ≤ 1.75nmol/L within 28 days prior to registration.
14. Imaging evidence of metastatic disease documented with either whole body bone scan (WBBS) or computed tomography (CT) scan performed within 28 days prior to registration.
15. Significant prostate-specific membrane antigen (PSMA) avidity on PSMA PET/CT, defined as a minimum uptake of SUVmax 15 at a site of disease.
16. Patients must have a life expectancy ≥ 12 weeks.
17. Assessed by a medical oncologist as suitable for treatment with cabazitaxel and 177Lu-PSMA-6
18. Patients must have adequate bone marrow, hepatic and renal function documented within 28 days prior to registration, defined as:
19. Haemoglobin ≥ 90 g/L independent of transfusions (no red blood cell transfusion in last 28 days prior to registration)
20. Absolute neutrophil count (ANC) ≥ 1.5x10^9/L
21. Platelets ≥ 150 x10^9/L
22. 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 component
23. Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.5 x ULN if there is no evidence of liver metastasis or ≤ 5 x ULN in the presence of liver metastases
24. Albumin ≥ 25 g/L
25. Adequate renal function: patients must have a creatinine clearance estimated of ≥ 40 mL/min using the Cockcroft-Gault equation
26. Sexually active patients are willing to use medically acceptable forms of barrier contraception.
27. Willing and able to comply with all study requirements, including all treatments and the timing and nature of all required assessments.

Exclusion Criteria:

1. Superscan on WBBS or diffuse marrow disease on PSMA PET.
2. Site(s) of measurable disease that are FDG-positive with low PSMA expression (SUVmax <10).
3. Prior treatment with cabazitaxel or 177Lu-PSMA-6
4. Contraindications to the use of corticosteroid treatment.
5. 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.
6. Presence of untreated brain metastases or leptomeningeal metastases.
7. Patients with symptomatic or impending cord compression unless appropriately treated beforehand and clinically stable for ≥ four weeks.
8. Concurrent illness, including severe infection that may jeopardise the ability of the patient to undergo the procedures outlined in this protocol with reasonable safety.
9. Persistent toxicities (CTCAE v5.0 >/= Grade 2) caused by previous cancer therapy, excluding alopecia.
10. Known HIV or hepatitis B or C infection.
11. Radiotherapy or systemic anti-cancer therapies administered within 14 days prior to registration, excluding androgen deprivation therapy (ADT).

View trial on ClinicalTrials.gov

Condition: Metastatic Castration-resistant Prostate Cancer, mCRPC, Prostate Cancer

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT05383079

Sponsor: Peter MacCallum Cancer Centre, Australia

Phase: Phase 1/Phase 2

Eligibility:

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

Inclusion Criteria:

• Patient must be ≥ 18 years of age and must have provided written informed consent.
• Histologically or cytologically confirmed adenocarcinoma of the prostate, OR unequivocal diagnosis of metastatic prostate cancer. (i.e. involving bone or pelvic lymph nodes or para-aortic lymph nodes) with an elevated serum PSA.
• Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2
• Patients must have progressed on ≥ 1 second-generation AR-targeted agent (e.g., enzalutamide, abiraterone, apalutamide, or darolutamide).
• Patients must have progressive disease for study entry. PCWG3 defines this 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.
• Soft tissue progression as per RECIST 1.1 criteria
• Bone progression: ≥ 2 new lesions on bone scan
• Symptomatic progression eg. Bone pain
• At least three weeks since receiving anti-cancer treatment (other than ADT), the completion of surgery or radiotherapy prior to registration.
• Prior surgical orchiectomy or chemical castration maintained on luteinizing hormone-releasing hormone (LHRH) analogue (agonist or antagonist).
• Serum testosterone levels ≤ 1.75nmol/L (≤ 50ng/dL) within 28 days before registration.
• Significant PSMA avidity on PSMA PET/CT, defined as a minimum uptake of SUVmax 20 at a site of disease, and SUVmax >10 at sites of measurable disease >10mm (unless subject to factors explaining a lower uptake, e.g. respiratory motion, reconstruction artefact).
• ≥ 2 bone metastases must be present on bone scintigraphy which have not been previously treated with radiotherapy.
• No contraindication to treatment with a bone antiresorptive agent such as denosumab or zoledronic acid.
• Patients must have adequate bone marrow, hepatic and renal function documented within 28 days prior to registration, defined as:
• Haemoglobin ≥ 90 g/L independent of transfusions (no red blood cell transfusion in last four weeks)
• Absolute neutrophil count ≥ 1.5x10^9/L
• Platelets ≥ 150 x10^9/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 component.
• Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.5 x ULN if there is no evidence of liver metastasis or ≤ 5 x ULN in the presence of liver metastases
• Albumin ≥ 25 g/L
• Adequate renal function: patients must have a creatinine clearance estimated of ≥ 40 mL/min using the Cockcroft Gault equation
• Sexually active patients are willing to use medically acceptable forms of barrier contraception.
• Willing to undergo biopsies, if disease is considered accessible and biopsy is feasible.
• Willing and able to comply with all study requirements, including all treatments and the timing and nature of all required assessments.

Exclusion Criteria:

• Patients who meet any of the following criteria will be excluded from study entry:
• Superscan on Bone scan (WBBS) or diffuse marrow involvement on PSMA PET/CT
• Prior treatment with 223Ra or 177Lu-PSMA.
• Has received more than one previous line of chemotherapy for the treatment of metastatic prostate cancer.
• Sites of discordant FDG-positive disease defined by minimal PSMA-expression and no uptake on WBBS (for bone metastases).
• 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.
• Symptomatic brain metastases or leptomeningeal metastases.
• Patients with symptomatic or impending cord compression unless appropriately treated beforehand and clinically stable for ≥ four weeks.
• Concurrent illness, including severe infection that may jeopardise the ability of the patient to undergo the procedures outlined in this protocol with reasonable safety.

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Condition: Non Muscle Invasive Bladder Cancer, Urologic Cancer, Bladder Cancer, Urothelial Carcinoma

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT06111235

Sponsor: CG Oncology, Inc.

Phase: Phase 3

Eligibility:

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

Inclusion Criteria:

• Pathologically confirmed IR-NMIBC, per American Urologic Association/Society of Urologic Oncology/National Comprehensive Cancer Network guidelines, within 90 days of participant randomization: 1. Recurrent LG Ta within 12 months of prior LG or HG (HG Ta ≤ 3 cm) tumor 2. Solitary LG Ta >3 cm tumor 3. Multifocal LG Ta tumors 4. Primary and solitary HG Ta ≤3 cm tumor 5. LG T1 tumor
• All visible disease removed by TURBT within 12 weeks of study randomization
• Acceptable baseline organ function

Exclusion Criteria:

• High-risk NMIBC (e.g., HG T1, Recurrent or multifocal HG Ta>3cm tumor(s), CIS)
• Low-Risk NMIBC (e.g., solitary LG Ta ≤3 cm tumor)
• Disease in the prostatic urethra at any time or in the upper genitourinary tract within 24 months of randomization
• Muscle-invasive bladder cancer, locally advanced or metastatic bladder cancer
• Prior treatment with any human adenovirus serotype 5 based therapy (e.g., Ad-interferon or Adstiladrin)

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Condition: Non-muscle Invasive Bladder Cancer, NMIBC, Carcinoma in Situ of Bladder, Bladder Cancer, Urothelial Carcinoma Bladder, Urothelial Carcinoma Recurrent

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT05375903

Sponsor: UroGen Pharma Ltd.

Phase: Phase 1

Eligibility:

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

Inclusion Criteria:

• 1. Able to give informed consent. 2. Arm A: Have confirmed recurrent NMIBC with HG Ta and/or T1 disease and/or CIS or recurrent IR LG Ta and/or T1 disease. Arm B: Have confirmed recurrent NMIBC with HG Ta and/or T1 disease and/or CIS. Arm C: Have confirmed recurrent NMIBC with HG Ta and/or T1 disease and/or CIS. 3. Patients with HG Ta and/or T1 disease and/or CIS must meet one of the following criteria: • Have Bacillus Calmette-Guérin (BCG)-unresponsive disease, defined as 1) persistent or recurrent CIS alone or with recurrent Ta/T1 disease within 12 months of completion of adequate BCG therapy, or 2) recurrent HG Ta/T1 disease within 6 months of completion of adequate BCG therapy, or 3) HG T1 disease at the first evaluation following a BCG induction course. Notes: Adequate BCG therapy is defined as at least 5 of 6 doses of an initial induction course plus 1) at least 2 of 3 doses of maintenance therapy or 2) at least 2 of 6 doses of a second induction course. Patients with BCG-unresponsive disease also must be unwilling or unfit to undergo radical cystectomy.
• Have otherwise failed adequate BCG therapy (eg, recurrence > 6 months [papillary] or > 12 months [CIS] after last BCG exposure).
• Are BCG intolerant, defined as the inability to tolerate at least one full induction course of BCG.
• Have HG Ta disease with tumors ≤ 3 cm and failed at least one previous course of therapy (eg, adjuvant intravesical chemotherapy). 4. Have all papillary tumors visible by white light resected, and obvious areas of CIS fulgurated during Screening or within 6 weeks before Screening. Note: Blue light cystoscopy is not permitted. 5. Eastern Cooperative Oncology Group (ECOG) status ≤ 2. 6. Absence of concomitant upper tract urothelial carcinoma (UTUC) or urothelial carcinoma (UC) within the prostatic urethra. Freedom from upper tract disease (if clinically indicated) as indicated by no evidence of upper tract tumor by either intravenous pyelogram, retrograde pyelogram, computerized tomography (CT) urogram with or without contrast, or magnetic resonance imaging (MRI) urogram with or without contrast performed within 6 months of enrollment. 7. Patients with prostate cancer on active surveillance at very low, low, or intermediate risk for progression, defined as Gleason Grade Group 1 or 2, Gleason score ≤ 7, with prostate-specific antigen < 20 ng/dL, and cT1-cT2b (NCCN, 2023) are permitted to be in the study at the discretion of the investigator (see exclusion criterion 8). 8. Female patients of childbearing potential must use maximally effective birth control during the period of therapy, must be willing to use contraception for 1 month following the last administration of study drug and must have a negative urine or serum pregnancy test upon entry into this study. Otherwise, female patients must be postmenopausal (no menstrual period for a minimum of 12 months) or surgically sterile. "Maximally effective birth control" means that the patient, if sexually active, should be using a combination of 2 methods of birth control that are approved and recognized to be effective by health authorities. 9. Male patients must be surgically sterile or willing to use 2 highly effective forms of birth control upon enrollment, during the course of the study, and for 1 month following the last study drug instillation. 10. Has adequate organ and bone marrow function within 14 days of treatment initiation as determined by routine laboratory tests outlined below:
• Leukocytes ≥ 3,000/μL;
• Absolute neutrophil count (ANC) ≥ 1,500/μL;
• Platelets ≥ 100,000/μL;
• Hemoglobin ≥ 9.0 g/dL;
• Total bilirubin ≤ 1.5 × upper limit of normal (ULN);
• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ 2.5 × ULN;
• Alkaline phosphatase (ALP) ≤ 2.5 × ULN;
• Estimated creatinine clearance ≥ 30 mL/min calculated using the Cockcroft-Gault equation. 11. Has a life expectancy > 12 months.

Exclusion Criteria:

1. Current or previous evidence of muscle invasive, locally advanced nonresectable, or metastatic urothelial carcinoma (ie, T2, T3, T4 and/or stage IV).
2. Current systemic therapy for bladder cancer.
3. Prior therapy with an anti-cytotoxic T lymphocyte antigen 4 (CTLA-4), anti-programmed cell death 1 (PD-1), anti-PD-ligand 1 (L1) agent, or with an agent directed to another co-inhibitory T-cell receptor.
4. Active infection requiring systemic therapy including urinary tract infection (once satisfactorily treated, patients can enter the study).
5. Active systemic autoimmune disease that required systemic treatment in the past 2 years. Short courses of steroids (≤ 14 days) for medical reasons without anticancer intent (eg, atopic dermatitis, psoriasis, infection, allergic reaction) are permitted if the last dose was ≥ 4 weeks before the first dose of study treatment.
6. Women who are pregnant or nursing.
7. Any medical psychological, familial, sociological, or geographical condition that, in the opinion of the Investigator, would preclude participation in the study.
8. History of malignancy of other organ system within the past 5 years, except previously treated UTUC, basal cell carcinoma or squamous cell carcinoma of the skin, and/or prostate cancer under active surveillance (see inclusion criterion 8).
9. Patients who cannot tolerate intravesical dosing or intravesical surgical manipulation.
10. Intravesical therapy within 4 weeks before starting study treatment.
11. Has participated in a study of an investigational agent and received study therapy or received investigational device within 4 weeks before the first dose of study treatment.
12. Has received an immune modulator therapy within 5 half-lives of starting study treatment.
13. Has received a vaccine within 2 weeks before starting study treatment.
14. Has a known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients.

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Condition: Biochemically Recurrent Prostate Cancer

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT05526248

Sponsor: Bayer

Phase: Phase 2

Eligibility:

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

Inclusion Criteria:

• Male of ≥ 18 years of age.
• Patients must have histologically or cytologically confirmed adenocarcinoma of the prostate.
• Prior treatment with primary radical prostatectomy or definitive RT for localized prostate cancer
• Patients must have PSA ≥0.2 ng/mL after ART or SRT post-RP or after RP in participants who are unfit for ART or SRT, OR PSA ≥2 ng/mL above the nadir after primary RT only. (RP, radical prostatectomy; ART, adjuvant radiotherapy; SRT, salvage radiotherapy; RT primary radiotherapy)
• The presence of < 5 asymptomatic metastatic lesions on conventional or PSMA-PET based imaging methods permitted. Lesions that need treatment with any opioid based analgetic are considered symptomatic
• PSADT ≤ 20 months calculated per PCWG3 + RECIST 1.1 per Scher et al. (Scher et al. 2016) and MSKCC nomogram.
• Eastern Cooperative Oncology Group ECOG (PS) of 0
• 1.
• Serum testosterone >150 ng/dl.
• Patients must have adequate organ function within 4 weeks before the first dose of study intervention.
• More than 30 days (or 5 half-lives) (whichever is longer) since prior participation in another clinical trial with an investigational medicinal product.

Exclusion Criteria:

• Prior treatment with ADT of up to 6 months for localized disease is permitted but not if during the prior 6 months before first dose of study intervention. Plan to initiate ADT during the trial period is not allowed.
• Radiation therapy or major surgery within 4 weeks of screening.
• Systemic glucocorticoids within 3 months prior to the first dose or study intervention was expected to require systemic glucocorticoids during the study period
• Had any of the following within 6 months before randomization: stroke, myocardial infarction, severe/unstable angina pectoris, coronary/peripheral artery bypass graft, congestive heart failure (New York Heart Association Class III or IV)
• Uncontrolled hypertension
• A gastrointestinal disorder or procedure which is expected to interfere significantly with absorption of study intervention.
• Prior history of a clinically significant malignancy with the exception of basal cell, squamous cell carcinoma of the skin, and superficial bladder cancer.
• Prior treatment with:
• Second-generation androgen receptor (AR) inhibitors such as enzalutamide, apalutamide, darolutamide other investigational AR inhibitors
• or Cytochrome P17 enzyme inhibitor such as abiraterone acetate as antineoplastic treatment for prostate cancer
• Prior history of gynecomastia
• Use of herbal products that may have had hormonal anti-prostate cancer activity or were known to decrease PSA levels (e.g., saw palmetto) within 4 weeks before the first dose of study intervention

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Condition: Prostate Cancer

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT05075577

Sponsor: ESSA Pharmaceuticals

Phase: Phase 1/Phase 2

Eligibility:

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

Inclusion Criteria:

• Males ≥18 years.
• Histologically, pathologically, or cytologically confirmed prostate adenocarcinoma.
• Evidence of castration-resistant prostate cancer (CRPC).
• Presence of metastatic disease at study entry documented by 1 or more bone lesions on bone scan or by soft tissue disease observed by CT/MRI.
• Naïve to second generation anti-androgens.
• Evidence of progressive disease defined as 1 or more Prostate Cancer Working Group 3 (PCWG3) criteria.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Ongoing ADT with luteinizing hormone-releasing hormone (LHRH) agonist/antagonist therapy or history of bilateral orchiectomy, with castrate level testosterone.
• Serum testosterone ≤1.73 nmol/L (50 ng/dL).
• Subjects receiving bisphosphonates or other approved bone-targeting therapy (e.g., denosumab) must be on a stable dose for at least 28 days prior to the start of study treatment.
• Demonstrate adequate organ function.

Exclusion Criteria:

• Biologic anti-cancer therapy within 28 days prior to the start of study treatment.
• Use of hormonal agents with anti-tumor activity against prostate cancer within 28 days prior to the start of study treatment.
• Use of herbal products or alternative therapies that may decrease PSA levels or that may have hormonal anti-prostate cancer activity within 28 days prior to the start of study treatment or plans to initiate during the study.
• Intervention with any chemotherapy, investigational agents, or other anti-cancer drugs within 28 days of the first dose of study treatment.
• Use of radium-223 dichloride or other radioligand/radiopharmaceutical within 28 days prior to the start of study treatment.
• Received limited-field palliative bone radiotherapy >5 fractions and/or any radiotherapy within 2 weeks prior to the start of study treatment.
• Received a blood transfusion within 28 days of hematologic screening labs.
• Known intra-cerebral disease or brain metastasis unless adequately treated and stable for the last 28 days before signing of informed consent.
• Spinal cord compression.
• Diagnosis of another clinically significant malignancy within the previous 3 years other than curatively treated non-melanomatous skin cancer or superficial urothelial carcinoma and other in situ or non-invasive malignancies.
• Gastrointestinal issues affecting absorption.
• Significant cardiovascular disease.
• Known history of seizure or conditions that may pre-dispose them to seizure, including brain injury with loss of consciousness, transient ischemic attack within the past 12 months, cerebral vascular accident, brain metastases, and brain arteriovenous malformation.
• Concurrent disease or any clinically significant abnormality.
• Known or suspected hypersensitivity to any components of the formulation used for EPI-7386 or enzalutamide.
• Use of strong inhibitors of CYP2C8.
• Use of strong inducers of CYP3A.
• Use of narrow therapeutic index sensitive CYP2C8 or sensitive substrates for CYP3A and CYP2B6.
• Use of granulocyte colony stimulating factor within 7 days prior to screening laboratories.
• Not a candidate for enzalutamide treatment.
• Patients with rare hereditary problems of fructose intolerance.

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Condition: Prostate Cancer

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT04421222

Sponsor: ESSA Pharmaceuticals

Phase: Phase 1

Eligibility:

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

Inclusion Criteria:

• Male 18 years of age or older.
• Histologically, pathologically, or cytologically confirmed prostate cancer without small cell features.
• Evidence of castration-resistant prostate cancer (CRPC).
• Presence of metastatic disease at study entry documented by 1 or more bone lesions on bone scan or by soft tissue disease observed by CT/MRI.
• Limited further treatment options available known to confer clinical benefit in this disease setting from the perspective of the treating physician. Specifically, patients must have progressed on at least 2, but not more than 3, prior approved systemic therapies for mCRPC which include at least one, but not more than 2, second generation anti-androgen drug.
• Patients may have received prior docetaxel for mCSPC or mCRPC but must not have had disease progression during, or within 6 months of completing chemotherapy. Only one line of prior chemotherapy is allowed.
• Evidence of progressive disease defined as 1 or more Prostate Cancer Working Group 3 (PCWG3) criteria.
• The patient must have recovered from toxicities related to any prior treatments.
• Castrate at screening.
• Patients receiving bisphosphonates or other approved bone-targeting therapy must be on a stable dose for at least 4 weeks prior to the start of study drug.
• Demonstrate adequate organ function.
• Eastern Cooperative Oncology Group (ECOG) performance status score of 0 to 1. Part A/Phase 1b (Dose Expansion) Inclusion Criteria: The inclusion criteria for this cohort are the same as for Phase 1a with the exception of: limit of prior therapies to 2 and prior chemotherapy is not allowed for this cohort of patients. Part B/Cohort 1 (EPI-7386 in combination with AAP) Inclusion Criteria:
• Patients are eligible to enroll in this cohort if they meet the clinical criteria for receiving AAP as standard of care treatment as per label (i.e., high-risk mHSPC or mCRPC).
• All other inclusion criteria listed for Part A/Phase 1a apply except for those that do not apply to mHSPC or mCRPC patients (i.e. evidence of CRPC and limited treatment options for mCRPC). Part B/Cohort 2 (Window of Opportunity with clinical endpoints followed by combination with Apalutamide)
• Male 18 years of age or older.
• Histologically, pathologically, or cytologically confirmed prostate cancer without small cell features.
• Evidence of castration-resistant prostate cancer (CRPC).
• Patients who received a first generation anti-androgen as part of an initial combined androgen blockade therapy or as second-line hormonal therapy must show continuing disease (PSA) progression off the anti-androgen for at least 4 weeks prior to enrollment.
• At least 4 weeks must have elapsed from the use of 5-α reductase inhibitors, estrogens, and any other anti-cancer therapy prior to enrollment.
• At least 4 weeks must have elapsed from major surgery or radiation therapy prior to enrollment.
• The patient must have recovered from toxicities related to any prior treatments.
• Castrate at screening.
• Demonstrate adequate organ function.
• Eastern Cooperative Oncology Group (ECOG) performance status score of 0 to 1. Part A Phase 1a and Phase 1b Exclusion Criteria:
• Biologic anti-cancer therapy or a cytotoxic chemotherapy within 4 weeks prior to the start of study drug.
• Use of hormonal agents with anti-tumor activity against prostate cancer within 4 weeks prior to the start of study drug.
• Any lutamides or abiraterone within 14 days or 5 half-lives, whichever is longer prior to start of study drug.
• Use of radium-223 dichloride or other radioligand/radiopharmaceutical within 28 days prior to the start of study drug.
• Received limited-field palliative bone radiotherapy >5 fractions and/or any radiotherapy within 2 weeks prior to the start of study drug.
• Received a blood transfusion within 28 days of screening.
• Received prior chemotherapy (for Part 1b Cohort A only).
• Known intra-cerebral disease or brain metastasis unless adequately treated and stable for the last 4 weeks before enrollment.
• Spinal cord compression.
• Diagnosis of another invasive malignancy within the previous 3 years other than curatively treated non-melanomatous skin cancer or superficial urothelial carcinoma.
• Gastrointestinal disorder affecting absorption.
• Significant cardiovascular disease.
• Concurrent disease or any clinically significant abnormality.
• Use of strong inducers of CYP3A within 14 days of the first dose of study drug. Part A Phase 1b (Dose Expansion) Exclusion Criteria: The exclusion criteria for this cohort are the same as the criteria from Phase 1a with the addition of the following: • Any prior treatment with chemotherapy. Part B Cohort 1 (EPI-7386 in combination with AAP) Exclusion Criteria: The

Exclusion Criteria:

• Biologic anti-cancer therapy or a cytotoxic chemotherapy within 4 weeks prior to the start of study drug.
• Use of hormonal agents with anti-tumor activity against prostate cancer within 4 weeks prior to the start of study drug.
• Any lutamides or abiraterone within 14 days or 5 half-lives, whichever is longer prior to start of study drug.
• Use of radium-223 dichloride or other radioligand/radiopharmaceutical within 28 days prior to the start of study drug.
• Received limited-field palliative bone radiotherapy >5 fractions and/or any radiotherapy within 2 weeks prior to the start of study drug.
• Received a blood transfusion within 28 days of screening.
• Received prior chemotherapy (for Part 1b Cohort A only).
• Known intra-cerebral disease or brain metastasis unless adequately treated and stable for the last 4 weeks before enrollment.
• Spinal cord compression.
• Diagnosis of another invasive malignancy within the previous 3 years other than curatively treated non-melanomatous skin cancer or superficial urothelial carcinoma.
• Gastrointestinal disorder affecting absorption.
• Significant cardiovascular disease.
• Concurrent disease or any clinically significant abnormality.
• Use of strong inducers of CYP3A within 14 days of the first dose of study drug. Part A Phase 1b (Dose Expansion) Exclusion Criteria: The exclusion criteria for this cohort are the same as the criteria from Phase 1a with the addition of the following: • Any prior treatment with chemotherapy. Part B Cohort 1 (EPI-7386 in combination with AAP) Exclusion Criteria: The exclusion criteria for this cohort are the same as the criteria from Phase 1a with the addition of the following:
• Use of concomitant CYP2D6 substrates with narrow therapeutic index.
• Known allergies, hypersensitivity, or intolerance to the excipients of AA (refer to AA Investigator's Brochure [IB] or package inserts as appropriate). Part B Cohort 2 (Window of Opportunity with clinical endpoints followed by combination with Apalutamide)
• Presence of distant metastases, including visceral, nodal and bones involvement. Exception: pelvic lymph nodes < 2 cm in short axis (N1) located below the iliac bifurcation are allowed.
• Symptomatic loco-regional disease requiring medical intervention, such as moderate or severe urinary obstruction or hydronephrosis due to primary tumor.
• Prior treatment with second generation anti-androgens.
• Prior treatment with CYP17 inhibitors.
• Prior treatment with radiopharmaceutical agents, immunotherapy, or any other investigational agent for nmCRPC.
• Prior chemotherapy.
• History or evidence of: prior malignancy (other than adequately treated basal cell or squamous cell skin cancer, superficial bladder cancer, or any other cancer in situ currently in complete remission) within 3 years prior to enrollment; severe/unstable angina, myocardial infarction, symptomatic congestive heart failure, arterial or venous thromboembolic events; uncontrolled hypertension.
• Gastrointestinal disorder affecting absorption.
• Use of strong inducers of CYP3A within 14 days of the first dose of study drug.

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Condition: Prostatic Neoplasms, Castration-Resistant

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT04597411

Sponsor: Endocyte

Phase: Phase 1

Eligibility:

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

Inclusion Criteria:

• Patients must have the ability to understand and sign an approved ICF.
• Patients must have the ability to understand and comply with all protocol requirements.
• Patients must be >=18 years of age.
• Patients must have an ECOG performance status of 0 to 2.
• Patients must have had histological, pathological, and/or cytological confirmation of prostate cancer.
• Patients must have a positive 68Ga-PSMA-11 PET/CT scan performed within 28 days of study entry as described in Imaging Manual).
• Patients must have recovered or stabilized to =< Grade 2 or baseline from all clinically significant toxicities related to prior prostate cancer therapy.
• Determination of disease progression on treatment prior to enrollment. Progressive disease for study entry is defined as any one or more of the following: 1. PSA progression: minimum of two rising PSA values from a baseline measurement with an interval of >= 1 week between each measurement. 2.0 ng/mL is the minimal starting value if PSA rise is only indication of progression. 2. Soft tissue or visceral disease progression as per RECIST 1.1 criteria: increase >= 20% in the sum of the diameter (SOD) (short axis for nodal lesions and long axis for non-nodal lesions) of all target lesions based on the smallest SOD since treatment started or the appearance of one or more new lesions. 3. Bone progression: >= 2 new lesions on bone scan.
• Patients must have adequate organ function (bone morrow reserve, hepatic function and renal function).
• Known HIV-positive patients who are healthy and have a low risk of AIDS-related outcomes are eligible. HIV testing is required.
• For patients who have partners of childbearing potential, patient must use a method of birth control with adequate barrier protection, deemed acceptable by the principle investigator during the study and for 6 months after last study drug administration.
• Group A Subjects: Patients must have prior orchiectomy and/or ongoing androgen-deprivation therapy, a castrate level of serum testosterone (< 50 ng/dL or < 1.7 nmol/L) and must have received prior cytotoxic chemotherapy and a novel androgen axis drug (e.g., abiraterone or enzalutamide). Patients must also be naïve to prior 177Lu-PSMA radioligand therapy (177Lu-PSMA-617 or 177Lu-PSMA I&T)
• Group B Subjects (South-Africa only): Patients must have ongoing androgen deprivation therapy (ADT) and either prior orchiectomy or be medically castrate using LHRH agonists/antagonists in order to achieve adequate suppression of serum testosterone (< 50 ng/dL) but must not have received prior cytotoxic chemotherapy or novel androgen axis drugs (e.g., abiraterone or enzalutamide). These patients are naïve to 177Lu-PSMA radioligand therapy (177Lu-PSMA-617 or 177Lu-PSMA I&T).
• Group C Subjects: Patients must have ongoing androgen deprivation therapy (ADT) and either prior orchiectomy or be medically castrate using LHRH agonists/antagonists in order to achieve adequate suppression of serum testosterone (< 50 ng/dL). Patients must have been treated with prior 177Lu-PSMA radioligand therapy (177Lu-PSMA-617 or 177Lu-PSMA I&T) for at least one cycle administered greater than 6 weeks from study enrollment, and been evaluated for biochemical and radiological response to therapy. Prior exposure to ARPI and/or chemotherapy is not required.

Exclusion Criteria:

• Previous treatment with Strontium-89, Samarium-153, Rhenium-186, Rhenium-188, Radium-223 or hemi-body irradiation.
• Any investigational agents within 28 days of study enrollment.
• Known hypersensitivity to the components of the study therapy or its analogues.
• Other concurrent cytotoxic chemotherapy, targeted therapy, biologic agents, immunotherapy, radioligand therapy, or investigational therapy.
• Transfusion for the sole purpose of eligibility into the study.
• Patients with a history of CNS metastases must have received therapy (surgery, radiotherapy, gamma knife) and be neurologically stable, asymptomatic, and not receiving corticosteroids for the purposes of maintaining neurologic integrity. Patients with epidural disease, canal disease and prior cord involvement are eligible if those areas have been treated, are stable, and not neurologically impaired.
• Symptomatic cord compression, or clinical or radiologic findings indicative of impending cord compression.
• Concurrent serious (as determined by the Principal Investigator) medical conditions, including, but not limited to, uncontrolled infection, active hepatitis B or C, or other significant co-morbid conditions that in the opinion of the investigator would impair study participation or cooperation.
• Diagnosed with other malignancies that are expected to alter life expectancy or may interfere with disease assessment. Patients with a prior history of malignancy who have been disease free for more than 3 years are eligible.
• Participants with an active documented COVID-19 infection (any grade of disease severity) at the time of informed consent may be included only when completely recovered (in accordance with local guidance).

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Condition: Metastatic Castration-resistant Prostate Cancer (mCRPC)

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT05983198

Sponsor: Novartis Pharmaceuticals

Phase: Phase 1/Phase 2

Eligibility:

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

Key Inclusion Criteria:

• Evidence of PSMA-positive disease by 68Ga-PSMA-R2 PET/CT and eligible as determined by central reading
• Documented progressive mCRPC
• Adequate organ function (bone marrow reserve, hepatic, renal)
• Prior orchiectomy and/or ongoing ARPI and taxane-based chemotherapy and should have received prior 177Lu-PSMA-RLT (Group1 dose escalation & expansion) or never received 177Lu-PSMA-RLT (Group 2 dose escalation & expansion).

Key Exclusion Criteria:

• Any other investigational agents within 28 days of the anticipated C1D1 of 225Ac-PSMA-R2 therapy
• Any systemic anti-cancer therapy within 28 days of the anticipated C1D1 of 225Ac-PSMA-R2 therapy
• Uncontrolled pain or incompatibility that may result in participant's lack of ability to comply with imaging procedures
• History of CNS metastases and symptomatic cord compression, or clinical or radiologic findings indicative of impending cord compression
• Uncontrolled cardiovascular history
• Diagnosis of other malignancies expected to alter life expectancy or may interfere with disease assessment Other protocol-defined inclusion/

Exclusion Criteria:

1. may apply.

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Condition: Prostate Cancer

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT05803941

Sponsor: Novartis Pharmaceuticals

Phase: Phase 4

Eligibility:

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

Inclusion Criteria:

1. Signed informed consent must be obtained prior to participation in the study
2. Must have received at least one dose of AAA617 within an interventional, Phase I-IV Novartis sponsored clinical trial in prostate cancer and have fulfilled the trial's requirements that allows them to participate in this study.
3. Willingness of sexually active participant to use a condom during intercourse for up to 14 weeks from the last dose of AAA617 treatment administered on the parent study.

Exclusion Criteria:

1. Inability to complete the needed investigational examinations due to any reason.

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Condition: Carcinoma, Non-Small-Cell Lung, Cutaneous Melanoma, Carcinoma, Renal Cell, Carcinoma, Ovarian Epithelial, Nasopharyngeal Carcinoma, Carcinoma, Thymic, Anal Cancer, Mesothelioma, Esophagogastric Cancer, High Microsatellite Instability Colorectal Carcinoma, Squamous Cell Carcinoma of Head and Neck, Triple Negative Breast Neoplasms

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT05544929

Sponsor: Novartis Pharmaceuticals

Phase: Phase 1

Eligibility:

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

Inclusion Criteria:

• Non-small cell lung cancer with historic PD-L1 ≥ 1%, as determined locally using a clinically accepted assay. Patients must have experienced benefit from previous anti-PD(L)1-containing therapy for at least 4 months based on investigator-assessed disease stability or response prior to developing documented disease progression. Patients must have also received prior platinum-based chemotherapy, either in combination or in sequence with anti-PD-(L)1, unless patient was ineligible to receive such treatment.
• Renal cell carcinoma, clear cell histology, previously treated with anti-PD(L)1-containing therapy and a VEGF targeted therapy as monotherapy or in combination. Patients should have documented disease progression following anti-PD(L)1-containing therapy.
• Cutaneous melanoma, previously treated with anti-PD(L)1-containing therapy. Patients should have documented disease progression following anti-PD(L)1-containing therapy. Patients with BRAF V600-mutant melanoma must have also received prior therapy with a BRAF V600 inhibitor, with or without a MEK inhibitor.
• Ovarian cancer, high-grade serous histology, naïve to anti-PD(L)1 therapy, must have received one prior systemic therapy in platinum-resistant setting.
• Nasopharyngeal carcinoma, non-keratinizing locally advanced recurrent or metastatic. Depending on the study arm, patients may be naïve to anti-PD(L)1 therapy, or previously treated with platinum-based chemotherapy with or without anti-PD-(L)1.
• Locally advanced unresectable or metastatic triple negative breast cancer, ovarian cancer (high-grade serous histology), anal cancer (squamous), MSI-H CRC, esophagogastric cancer, mesothelioma, and HNSCC.
• Locally advanced unresectable or metastatic anal cancer (squamous), thymic carcinoma, MSI-H CRC, esophagogastric cancer, mesothelioma, and HNSCC, all naïve to anti-PD(L)1 therapy and for whom anti PD(L)1 therapy is not available.
• Triple negative breast cancer with historic PD-L1 CPS ≥ 1%, must have received at least one line of chemotherapy. Exclusion Criteria:
• Impaired cardiac function or clinically significant cardiac disease.
• Use of agents known to prolong the QT interval unless they can be permanently discontinued for the duration of study.
• History of severe hypersensitivity reactions to any ingredient of study drug(s) and other mAbs and/or their excipients.
• Active, known or suspected autoimmune disease. Patients with vitiligo, type I diabetes, residual hypothyroidism only requiring hormone replacement, psoriasis not requiring systemic treatment or conditions not expected to recur may be considered. Patients previously exposed to anti-PD-1/PD-L1 treatment who are adequately treated for skin rash or with replacement therapy for endocrinopathies should not be excluded.
• Any evidence of interstitial lung disease (ILD) or pneumonitis, or a prior history of ILD or non-infectious pneumonitis requiring high-dose glucocorticoids.
• Patients who discontinued prior anti-PD-(L)1 therapy due to an anti-PD-(L)1-related toxicity (applicable to the KFA115 in combination with pembrolizumab treatment arms).
• Patients with symptomatic peripheral neuropathy limiting instrumental activities of daily living. Other protocol-defined inclusion/

Exclusion Criteria:

• Impaired cardiac function or clinically significant cardiac disease.
• Use of agents known to prolong the QT interval unless they can be permanently discontinued for the duration of study.
• History of severe hypersensitivity reactions to any ingredient of study drug(s) and other mAbs and/or their excipients.
• Active, known or suspected autoimmune disease. Patients with vitiligo, type I diabetes, residual hypothyroidism only requiring hormone replacement, psoriasis not requiring systemic treatment or conditions not expected to recur may be considered. Patients previously exposed to anti-PD-1/PD-L1 treatment who are adequately treated for skin rash or with replacement therapy for endocrinopathies should not be excluded.
• Any evidence of interstitial lung disease (ILD) or pneumonitis, or a prior history of ILD or non-infectious pneumonitis requiring high-dose glucocorticoids.
• Patients who discontinued prior anti-PD-(L)1 therapy due to an anti-PD-(L)1-related toxicity (applicable to the KFA115 in combination with pembrolizumab treatment arms).
• Patients with symptomatic peripheral neuropathy limiting instrumental activities of daily living. Other protocol-defined inclusion/exclusion criteria may apply

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Condition: Carcinoma, Non-Small-Cell Lung, Carcinoma, Renal Cell, Esophageal Squamous Cell Carcinoma, Squamous Cell Carcinoma of Head and Neck

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT05462873

Sponsor: Novartis Pharmaceuticals

Phase: Phase 1

Eligibility:

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

Inclusion Criteria:

• Signed informed consent must be obtained prior to participation in the study.
• Adult men and women ≥ 18 years of age.
• Histologically confirmed and documented advanced malignancies (locally advanced malignancies, non-curable by surgery or radiotherapy and metastatic disease). Disease must be measurable, including presence of at least one measurable lesion, as determined by RECIST v1.1.
• In the opinion of the treating investigator, patients must have received, but are not benefitting from standard therapies, be intolerant or ineligible to receive such therapy, or have no standard therapy option for the respective disease types (diseases listed below), as well as any other therapies deemed to be standard by local/institutional standard.
• Non-small cell lung cancer
• Esophageal squamous cell carcinoma
• Renal cell carcinoma
• HPV-associated head and neck squamous cell carcinoma
• Must have a site of disease amenable to biopsy and be a candidate for tumor biopsy according to the treating institution's guidelines. The patient must be willing to undergo a new tumor biopsy at screening and during treatment. Exclusion Criteria:
• Active previously documented or suspected autoimmune disease. Patients with vitiligo, type I diabetes, residual hypothyroidism only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur should not be excluded. Patients previously exposed to anti-PD-1/PD-L1 treatment who are adequately treated for skin rash or with replacement therapy for endocrinopathies should not be excluded.
• Patients with a history of or current interstitial lung disease or pneumonitis ≥ Grade 2.
• Patients who discontinued prior anti-PD-1 therapy due to an anti-PD-1-related toxicity
• Clinically significant cardiac disease or risk factors at screening
• Insufficient bone marrow function at screening:
• Infections:
• Known history of testing positive for Human Immunodeficiency Virus infection.
• Active Hepatitis B and / or Hepatitis C.
• Active, documented COVID-19 infection
• Known history of tuberculosis
• Any serious uncontrolled infection (acute or chronic).
• Systemic chronic steroid therapy (>10 mg/day prednisone or equivalent) or any immunosuppressive therapy, other than replacement-dose steroids in the setting of adrenal insufficiency, within 7 days of the first dose of study treatment. Topical, inhaled, and ophthalmic steroids are allowed. Other protocol-defined inclusion/

Exclusion Criteria:

• Active previously documented or suspected autoimmune disease. Patients with vitiligo, type I diabetes, residual hypothyroidism only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur should not be excluded. Patients previously exposed to anti-PD-1/PD-L1 treatment who are adequately treated for skin rash or with replacement therapy for endocrinopathies should not be excluded.
• Patients with a history of or current interstitial lung disease or pneumonitis ≥ Grade 2.
• Patients who discontinued prior anti-PD-1 therapy due to an anti-PD-1-related toxicity
• Clinically significant cardiac disease or risk factors at screening
• Insufficient bone marrow function at screening:
• Infections:
• Known history of testing positive for Human Immunodeficiency Virus infection.
• Active Hepatitis B and / or Hepatitis C.
• Active, documented COVID-19 infection
• Known history of tuberculosis
• Any serious uncontrolled infection (acute or chronic).
• Systemic chronic steroid therapy (>10 mg/day prednisone or equivalent) or any immunosuppressive therapy, other than replacement-dose steroids in the setting of adrenal insufficiency, within 7 days of the first dose of study treatment. Topical, inhaled, and ophthalmic steroids are allowed. Other protocol-defined inclusion/exclusion criteria may apply.

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Condition: Advanced Solid Tumor, Clear Cell Renal Cell Carcinoma, Hepatocellular Carcinoma, Non-small Cell Lung Cancer

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT04374877

Sponsor: Coherus Biosciences, Inc.

Phase: Phase 1

Eligibility:

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

Inclusion Criteria:

• ≥ 18 years of age
• Locally advanced or metastatic (Stage IV) solid tumor that has progressed during or after standard therapy, and for whom no available therapies are appropriate (based on investigator judgment)
• Patients in Part B with advanced or metastatic ccRCC, HCC, or NSCLC must have at least 1 measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
• Patients with HCC in Part B must have at least 1 measurable target lesion according to modified RECIST (mRECIST)
• Patients with HCC must have unresectable disease, Barcelona Clinic Liver Cancer (BCLC1) Stage B (not eligible for transcatheter arterial chemoembolization [TACE]) or Stage C
• For patients in Part B with ccRCC, demonstrated progressive disease (PD) during or after the most recent treatment regimen. Prior treatment history must include progression during or after treatment with regimen(s) that have included a vascular endothelial growth factor (VEGF)-targeted agent and an immune checkpoint inhibitor. Patients who did not progress on but discontinued the VEGF-targeted agent for toxicity or intolerability are permitted.
• For patients in Part B with HCC, demonstrated PD during or after the most recent treatment regimen. Prior treatment history must include progression during or after treatment with a VEGF-targeted agent. Patients who did not progress on but discontinued the VEGF-targeted agent for toxicity or intolerability are permitted.
• For Part B patients in the tumor biopsy subsets only, must have tumor tissue that is accessible for pretreatment and on-treatment tumor biopsy in the opinion of the Investigator and be willing to undergo pretreatment and on-treatment biopsies per protocol
• Serum creatinine clearance ≥ 30 mL/min per Cockcroft-Gault formula or serum creatinine ≤ 2.0 x the upper limit of normal (ULN)
• Total bilirubin ≤ 1.5 x ULN (≤ 3 x ULN if elevated because of Gilbert's syndrome and ≤ 2 x ULN for patients with HCC or patients with known liver metastases)
• Aspartate aminotransferase (AST/SGOT) and alanine aminotransferase/serum glutamic pyruvic transaminase (ALT/SGPT) < 2.5 x ULN (< 5 x ULN if liver metastasis or for patients with HCC)
• For patients with HCC, Child-Pugh class A or B7 with a serum albumin ≥ 2.8 g/dL (≥ 28 g/L)
• Adequate hematologic function, defined as absolute neutrophil count (ANC) ≥ 1.0 x 109/L, hemoglobin ≥ 9.0 g/dL, and platelet count ≥ 100 x 109/L. For patients with HCC, platelet count ≥ 75 x 109/L without transfusion
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1
• Patients with NSCLC must have histologically confirmed locally advanced and/or metastatic Stage IV NSCLC
• Patients with NSCLC must have demonstrated progressive disease during or after the most recent treatment regimen Part C Abbreviated Inclusion Criteria:
• ≥ 18 years of age
• Advanced RCC of any histology or advanced HCC previously treated with at least one systemic anticancer therapy OR histologically or cytologically confirmed metastatic or unresectable adenocarcinoma or squamous cell NSCLC
• Patients with HCC must have unresectable disease, Barcelona Clinic Liver Cancer (BCLC) Stage B (not eligible for transcatheter arterial chemoembolization) or Stage C
• At least 1 measurable lesion per RECIST 1.1
• Patients with HCC must have at least 1 measurable target lesion according to modified RECIST (mRECIST)
• ECOG performance status of 0-1
• ANC ≥1500/µL (1.5 x 109/L)
• Platelets ≥100 000/µL (≥ 100 x 109/L)
• Hemoglobin for participants with RCC: ≥9.0 g/dL; for participants with HCC: ≥8.5 g/dL
• Creatinine OR measured or calculated creatinine clearance (GFR can also be used in place of creatinine or CrCl) ≤1.5 × ULN OR ≥30 mL/min for participant with creatinine levels >1.5 × institutional ULN
• Total bilirubin ≤1.5 × ULN OR direct bilirubin ≤ULN for participants with total bilirubin levels >1.5 × ULN
• AST (SGOT) and ALT (SGPT) ≤2.5 × ULN (≤5 × ULN for participants with liver metastases)
• International normalized ratio (INR) OR prothrombin time (PT) Activated partial thromboplastin time (aPTT) ≤1.5 × ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants
• For patients with HCC, Child-Pugh Class A or B7 with a serum albumin ≥ 2.8 g/dL (≥ 28 g/L)
• Willingness of male and female patients who are not surgically sterile or postmenopausal to use medically acceptable methods of birth control for the duration of the study drug period (or beginning 14 days before the initiation of pembrolizumab for oral contraception), including 75 days after the last dose of CHS-388 or 120 days after the last dose of pembrolizumab; male patients must refrain from donating sperm during this period. Sexually active men, and women using oral contraceptive pills, should also use barrier contraception with spermicide. Azoospermic male patients and WCBP who are continuously not heterosexually active are exempt from contraceptive requirements. However, female patients must still undergo pregnancy testing as described in this section. Part C Abbreviated Inclusion Criteria Specific to Patients with RCC or HCC from Part A or Part B:
• Progressed on CHS-388 by RECIST 1.1
• Did not experience prior Grade ≥ 3 toxicity related to CHS-388
• Willingness to undergo pretreatment core or excisional biopsy if deemed safe and tumor is accessible, in the opinion of the Investigator
• Has received no systemic anticancer therapies between CHS-388 doses Part C Abbreviated Inclusion Criteria specific to NSCLC Patients:
• No more than 3 prior lines of systemic therapy for unresectable or metastatic disease with prior radiologic progression on or following platinum-based chemotherapy and prior anti-PD-(L)1 therapy whether given alone or in combination Part A and Part B Abbreviated Exclusion Criteria:
• Previously received an anti-IL-27 antibody or anti-IL-27 targeted therapy
• For patients in Part B with renal cell carcinoma (RCC), non-clear cell RCC histology
• For patients with HCC, known fibrolamellar or mixed hepatocellular cholangiocarcinoma
• History of Grade 4 allergic or anaphylactic reaction to any monoclonal antibody therapy or any excipient in the study drugs
• Major surgery within 4 weeks prior to Screening
• Unstable or severe uncontrolled medical condition (eg, unstable cardiac function, unstable pulmonary condition including pneumonitis and/or interstitial lung disease, uncontrolled diabetes) or any important medical illness or abnormal laboratory finding that would, in the Investigator's judgment, increase the risk to the patient associated with his or her participation in the study Part C Abbreviated Exclusion Criteria:
• Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study drug
• Previously received an anti-IL 27 antibody or anti-IL 27 targeted therapy (exception to patients who received CHS-388 in Part A or Part B)
• No prior systemic therapy for unresectable or metastatic disease
• Received > 4 prior systemic regimens for unresectable or metastatic disease (prior PD-(L)1 inhibitors are allowed if the patient did not discontinue therapy due to ≥ Grade 3 drug-related toxicity)
• For patients with HCC, fibrolamellar histology or mixed hepatocellular cholangiocarcinoma
• For patients with HCC, moderate or severe ascites
• For patients with HCC, inability to undergo disease evaluation with triphasic computed tomography or magnetic resonance imaging because of contrast allergy or other contraindication
• For patients with HCC, imaging findings consistent with ≥ 50% liver occupation by HCC tumors
• History of Grade 4 allergic or anaphylactic reaction to any monoclonal antibody therapy or any excipient in the study drugs
• Surgeries that required general anesthesia must be completed at least 2 weeks before first study drug administration
• Prior autologous stem cell transplant ≤ 3 months before the first dose
• Prior allogeneic hematopoietic cell transplant within 6 months of the first dose or with a history of or current clinical Graft-Versus-Host Disease
• Has had an allogenic tissue/solid organ transplant
• Other unstable or severe uncontrolled medical condition (eg, unstable cardiac function, unstable pulmonary condition, uncontrolled diabetes) or any important medical illness or abnormal laboratory finding that would, in the Investigator's judgment, increase the risk to the patient associated with his or her participation in the study Part D Abbreviated Inclusion Criteria
• ≥ 18 years of age
• Histologically or cytologically confirmed metastatic or unresectable adenocarcinoma or squamous cell NSCLC
• No more than 3 prior lines of systemic therapy for unresectable or metastatic disease with prior radiologic progression on or following platinum-based chemotherapy and prior anti-PD-(L)1 therapy whether given alone or in combination
• At least 1 measurable lesion per RECIST 1.1
• ECOG performance status of 0-1
• ANC ≥1500/µL (1.5 x 109/L)
• Platelets ≥100 000/µL (≥ 100 x 109/L)
• Hemoglobin for participants with RCC: ≥9.0 g/dL
• Creatinine OR measured or calculated creatinine clearance (GFR can also be used in place of creatinine or CrCl) ≤1.5 × ULN OR ≥30 mL/min for participant with creatinine levels >1.5 × institutional ULN
• Total bilirubin ≤1.5 × ULN OR direct bilirubin ≤ULN for participants with total bilirubin levels >1.5 × ULN
• AST (SGOT) and ALT (SGPT) ≤2.5 × ULN (≤5 × ULN for participants with liver metastases)
• International normalized ratio (INR) OR prothrombin time (PT) Activated partial thromboplastin time (aPTT) ≤1.5 × ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants
• Willingness of male and female patients who are not surgically sterile or postmenopausal to use medically acceptable methods of birth control for the duration of the study drug period (or beginning 14 days before the initiation of pembrolizumab for oral contraception), including 75 days after the last dose of CHS-388 or 180 days after the last dose of toripalimab; male patients must refrain from donating sperm during this period. Sexually active men, and women using oral contraceptive pills, should also use barrier contraception with spermicide. Azoospermic male patients and WCBP who are continuously not heterosexually active are exempt from contraceptive requirements. However, female patients must still undergo pregnancy testing as described in this section. Part D Abbreviated

Exclusion Criteria:

• Previously received an anti-IL-27 antibody or anti-IL-27 targeted therapy
• For patients in Part B with renal cell carcinoma (RCC), non-clear cell RCC histology
• For patients with HCC, known fibrolamellar or mixed hepatocellular cholangiocarcinoma
• History of Grade 4 allergic or anaphylactic reaction to any monoclonal antibody therapy or any excipient in the study drugs
• Major surgery within 4 weeks prior to Screening
• Unstable or severe uncontrolled medical condition (eg, unstable cardiac function, unstable pulmonary condition including pneumonitis and/or interstitial lung disease, uncontrolled diabetes) or any important medical illness or abnormal laboratory finding that would, in the Investigator's judgment, increase the risk to the patient associated with his or her participation in the study Part C Abbreviated Exclusion Criteria:
• Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study drug
• Previously received an anti-IL 27 antibody or anti-IL 27 targeted therapy (exception to patients who received CHS-388 in Part A or Part B)
• No prior systemic therapy for unresectable or metastatic disease
• Received > 4 prior systemic regimens for unresectable or metastatic disease (prior PD-(L)1 inhibitors are allowed if the patient did not discontinue therapy due to ≥ Grade 3 drug-related toxicity)
• For patients with HCC, fibrolamellar histology or mixed hepatocellular cholangiocarcinoma
• For patients with HCC, moderate or severe ascites
• For patients with HCC, inability to undergo disease evaluation with triphasic computed tomography or magnetic resonance imaging because of contrast allergy or other contraindication
• For patients with HCC, imaging findings consistent with ≥ 50% liver occupation by HCC tumors
• History of Grade 4 allergic or anaphylactic reaction to any monoclonal antibody therapy or any excipient in the study drugs
• Surgeries that required general anesthesia must be completed at least 2 weeks before first study drug administration
• Prior autologous stem cell transplant ≤ 3 months before the first dose
• Prior allogeneic hematopoietic cell transplant within 6 months of the first dose or with a history of or current clinical Graft-Versus-Host Disease
• Has had an allogenic tissue/solid organ transplant
• Other unstable or severe uncontrolled medical condition (eg, unstable cardiac function, unstable pulmonary condition, uncontrolled diabetes) or any important medical illness or abnormal laboratory finding that would, in the Investigator's judgment, increase the risk to the patient associated with his or her participation in the study Part D Abbreviated Inclusion Criteria
• ≥ 18 years of age
• Histologically or cytologically confirmed metastatic or unresectable adenocarcinoma or squamous cell NSCLC
• No more than 3 prior lines of systemic therapy for unresectable or metastatic disease with prior radiologic progression on or following platinum-based chemotherapy and prior anti-PD-(L)1 therapy whether given alone or in combination
• At least 1 measurable lesion per RECIST 1.1
• ECOG performance status of 0-1
• ANC ≥1500/µL (1.5 x 109/L)
• Platelets ≥100 000/µL (≥ 100 x 109/L)
• Hemoglobin for participants with RCC: ≥9.0 g/dL
• Creatinine OR measured or calculated creatinine clearance (GFR can also be used in place of creatinine or CrCl) ≤1.5 × ULN OR ≥30 mL/min for participant with creatinine levels >1.5 × institutional ULN
• Total bilirubin ≤1.5 × ULN OR direct bilirubin ≤ULN for participants with total bilirubin levels >1.5 × ULN
• AST (SGOT) and ALT (SGPT) ≤2.5 × ULN (≤5 × ULN for participants with liver metastases)
• International normalized ratio (INR) OR prothrombin time (PT) Activated partial thromboplastin time (aPTT) ≤1.5 × ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants
• Willingness of male and female patients who are not surgically sterile or postmenopausal to use medically acceptable methods of birth control for the duration of the study drug period (or beginning 14 days before the initiation of pembrolizumab for oral contraception), including 75 days after the last dose of CHS-388 or 180 days after the last dose of toripalimab; male patients must refrain from donating sperm during this period. Sexually active men, and women using oral contraceptive pills, should also use barrier contraception with spermicide. Azoospermic male patients and WCBP who are continuously not heterosexually active are exempt from contraceptive requirements. However, female patients must still undergo pregnancy testing as described in this section. Part D Abbreviated Exclusion Criteria:
• Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study drug
• Previously received an anti-IL 27 antibody or anti-IL 27 targeted therapy (exception to patients who received CHS-388 in Part A or Part B)
• No prior systemic therapy for unresectable or metastatic disease
• Received > 4 prior systemic regimens for unresectable or metastatic disease (prior PD-(L)1 inhibitors are allowed if the patient did not discontinue therapy due to ≥ Grade 3 drug-related toxicity)
• Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX 40, CD137), and was discontinued from that treatment due to a ≥ Grade 3 irAE. because of contrast allergy or other contraindication
• History of Grade 4 allergic or anaphylactic reaction to any monoclonal antibody therapy or any excipient in the study drugs
• Surgeries that required general anesthesia must be completed at least 2 weeks before first study drug administration
• Prior autologous stem cell transplant ≤ 3 months before the first dose
• Prior allogeneic hematopoietic cell transplant within 6 months of the first dose or with a history of or current clinical Graft-Versus-Host Disease
• Has had an allogenic tissue/solid organ transplant
• Other unstable or severe uncontrolled medical condition (eg, unstable cardiac function, unstable pulmonary condition, uncontrolled diabetes) or any important medical illness or abnormal laboratory finding that would, in the Investigator's judgment, increase the risk to the patient associated with his or her participation in the study

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Condition: Cancer

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT04464226

Sponsor: Bayer

Phase: Phase 3

Eligibility:

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

Inclusion Criteria:

• Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
• Participants enrolled in any Bayer-sponsored darolutamide feeder study at the time of study closure or primary completion, who are currently receiving darolutamide and are experiencing clinical benefit from treatment.
• Participants who have not met any treatment discontinuation criteria in the feeder study protocol.
• Willingness to continue practicing acceptable methods of birth control during the study.

Exclusion Criteria:

• Participant is unable to comply with the requirements of the study.
• Negative benefit/ risk ratio as determined by the investigator.
• Meet any criteria for treatment discontinuation of the feeder study the participant is coming from.

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Condition: Advanced Solid Tumors

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT05614102

Sponsor: Bayer

Phase: Phase 1

Eligibility:

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

Inclusion Criteria:

• Have measurable disease per Response evaluation criteria in solid tumors version 1.1 (RECIST 1.1) as assessed by the local site investigator.
• Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
• Participants with histologically confirmed diagnosis of a solid tumor (specifications for the different parts of the study below) will be enrolled onto this study: • Dose escalation: All solid cancers, except primary central nervous system cancers
• The following tumor types will be recruited to the monotherapy expansion cohorts:
• Non-small cell lung cancer (NSCLC)
• Gastric/Gastroesophageal Junction (GEJ) adenocarcinoma
• The following tumor types will be recruited to the BAY 2965501 and pembrolizumab combination expansion cohorts:
• NSCLC: participants with tumors that are TPS score ≥50% PDL-1 high (based on local historical testing) and are eligible for standard of care anti-PD(L)-1 monotherapy in the first line incurable treatment setting.
• NSCLC
• Gastric/GEJ adenocarcinoma

Exclusion Criteria:

• Previous therapy with a DGK inhibitor is prohibited for monotherapy cohorts (participants previously treated with BAY 2965501 or BAY 2862789 must have progressed on that DGK inhibitor (and not discontinued for toxicity) to be eligible for combination).
• Has received a prior therapeutic regimen containing an anti-PD-1, anti-PD-L1, or anti PD-L2 agent or an agent directed to another co-stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX 40, CD137) and was discontinued from that treatment due to a Grade 3 or higher infusion-related adverse event (irAE).
• Participants with new brain metastases on screening brain MRI/CT. Previously treated brain metastases that are progressive at screening compared to a brain MRI/CT at least 6 weeks earlier are also excluded. Participants with known previously treated brain metastases, which are radiologically stable compared to a CT/MRI scan at least 6 weeks earlier, clinically stable and without the requirement of steroid treatment for at least 14 days prior to the first dose of study treatment may be eligible.
• Primary central nervous system malignancy or presence of leptomeningeal disease (i.e., positive cerebrospinal fluid cytology or unequivocal radiological or clinical evidence of leptomeningeal involvement).
• Participants with gastrointestinal conditions that may compromise oral absorption such as short bowel syndrome or active tumor-related bowel obstruction with ongoing symptoms compromising absorption over last 6 months.

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