Biomarker-Driven Therapy With Nivolumab and Ipilimumab in Treating Patients With Metastatic Hormone-Resistant Prostate Cancer Expressing AR-V7

Study Overview
=================
Brief Summary
-----------------
This phase II trial studies how well nivolumab and ipilimumab work in treating patients with hormone-resistant prostate cancer that has spread to other places in the body and express androgen receptor-variant-7 (AR-V7). Tumor cells expressing AR-V7 has been shown to be resistant to hormone therapy and some chemotherapy in patients with prostate cancer. Biomarker-driven therapy, such as nivolumab and ipilimumab, may work by blocking key biomarkers or proteins that help tumor cells to escape the immune system surveillance and this may help the immune system to kill tumor cells that express AR-V7.

Official Title
-----------------
Biomarker-Driven Phase-2 Study of Combined Immune Checkpoint Blockade for AR-V7-Expressing Metastatic Castration-Resistant Prostate Cancer (STARVE-PC)

Conditions
-----------------
Prostate Cancer, Recurrent Prostate Carcinoma, Stage IV Prostate Adenocarcinoma

Intervention / Treatment
-----------------
* Biological: Ipilimumab
* Biological: Nivolumab
* Drug: Enzalutamide


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histologically or cytologically confirmed adenocarcinoma of the prostate Metastatic disease as defined by two or more bone metastases confirmed by bone scintigraphy or radiographic soft tissue metastasis Detectable circulating tumor cells (CTCs) with detectable AR-V7 splice-variant by reverse transcriptase (RT)-polymerase chain reaction (PCR) For second cohort (amendment 1): The most recent therapy must be enzalutamide and enzalutamide will be continued for study duration despite progressive disease. The minimum required dose of Enzalutamide at enrolment should be no less than 80 mg once daily. Known castration-resistant disease, defined according to Prostate Cancer Working Group 2 (PCWG2) criteria as: Castrate serum testosterone level: =< 50 ng/dL (=< 1.7 nmol/L) Subjects who have failed initial hormonal therapy, either by orchiectomy or by using a gonadotropin-releasing hormone (GnRH) agonist in combination with an anti-androgen, must first progress through antiandrogen withdrawal prior to being eligible; the minimum timeframe to document failure of anti-androgen withdrawal will be four weeks Serum PSA progression defined as two consecutive increases in PSA over a previous reference value within 6 months of first study treatment, each measurement at least one week apart; serum PSA at screening >= 2 ng/mL OR Documented bone lesions by the appearance of two or more new lesions by bone scintigraphy OR Bidimensionally-measureable soft tissue metastatic lesion assessed by computed tomography (CT) or magnetic resonance imaging (MRI) Karnofsky performance status (KPS): >= 70% within 14 days before start of study treatment (Eastern Cooperative Oncology Group [ECOG] =< 1) Life expectancy: at least 6 months White blood count (WBC) >= 2000/uL Neutrophils >= 1500/uL Platelets >= 100 x10^3/uL Hemoglobin > 9.0 g/dL Serum creatinine =< 1.5 x upper limit of normal (ULN) or creatinine clearance (CrCl) >= 40 mL/min (if using the Cockcroft-Gault formula) Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 3 x ULN Total bilirubin =< 1.5 x ULN (except subjects with Gilbert syndrome, who can have total bilirubin < 3.0 mg/dL) Men who are sexually active with women of childbearing potential (WOCBP) must use any contraceptive method with a failure rate of less than 1% per year; men receiving nivolumab and who are sexually active with WOCBP will be instructed to adhere to contraception for a period of 31 weeks after the last dose of investigational product WOCBP is defined as any female who has experienced menarche and has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or who is not postmenopausal; menopause is defined clinically as 12 months of amenorrhea in a woman over 45 in the absence of other biological or physiological causes; in addition, women under the age of 55 must have a documented serum follicle stimulating hormone (FSH) level less than 40 mIU/mL No evidence (within 5 years) of prior malignancies (except successfully treated basal cell or squamous cell carcinoma of the skin) The subject is willing and able to comply with the protocol, and agrees to return to the hospital for follow-up visits and examination The subject has been fully informed about the study and has signed the informed consent form and, where appropriate, Health Insurance Portability and Accountability Act (HIPAA) authorization for release of personal health information NOTE: HIPAA authorization may be included in the informed consent or obtained separately Exclusion Criteria: Has received an investigational therapeutic drug within the last 4 weeks prior to start of study treatment, or is scheduled to receive one during the treatment period Has received external radiotherapy within the last 4 weeks prior to start of study treatment Previous therapy with antiandrogens within 4 weeks Patients should be excluded if they have had prior systemic treatment with an anti-programmed cell death protein 1 (PD-1), anti-PD-L1, anti-programmed cell death 1 ligand 2 (PD-L2), anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody, or any other antibody or drug specifically targeting T-cell costimulation or immune checkpoint pathways Symptomatic metastatic disease with signs of rapid progression per investigator's clinical judgment Concurrent use of other anticancer agents or treatments, with the following exceptions: Ongoing treatment with luteinizing hormone-releasing hormone (LHRH) agonists or antagonists, denosumab (Prolia) or bisphosphonate (eg, zoledronic acid) is allowed; ongoing treatment should be kept at a stable schedule; however, if medically required, a change of dose, compound, or both is allowed Any treatment modalities involving major surgery within 4 weeks prior to the start of study treatment Symptomatic nodal disease, i.e. scrotal, penile or leg edema (>= Common Terminology Criteria for Adverse Events [CTCAE] grade 3) Patients are excluded if they have active brain metastases or leptomeningeal metastases; subjects with brain metastases are eligible if metastases have been treated and there is no magnetic resonance imaging (MRI) evidence of progression for at least 4 weeks after treatment is complete and within 28 days prior to the first dose of nivolumab administration; there must also be no requirement for immunosuppressive doses of systemic corticosteroids (> 10 mg/day prednisone equivalents) for at least 2 weeks prior to study drug administration Patients should be excluded if they have an active, known or suspected autoimmune disease (e.g. inflammatory bowel disease, rheumatoid arthritis, autoimmune hepatitis, lupus, celiac disease); subjects are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger Patients should be excluded if they have a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration; inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease Permitted therapies include topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic absorption); physiologic replacement doses of systemic corticosteroids are permitted, even if > 10 mg/day prednisone equivalents; a brief course of corticosteroids for prophylaxis (eg, contrast dye allergy) or for treatment of nonautoimmune conditions (e.g. delayed-type hypersensitivity reaction caused by contact allergen) is permitted Drugs with a predisposition to hepatoxicity should be used with caution in patients treated with nivolumab-containing regimen Patients should be excluded if they have a positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection Patients should be excluded if they have known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS) Allergies and adverse drug reaction History of allergy to study drug components History of severe hypersensitivity reaction to any monoclonal antibody Other primary tumor (other than castration-resistant prostate cancer [CRPC]) including hematological malignancy present within the last 5 years (except non-melanoma skin cancer or low-grade superficial bladder cancer) Has imminent or established spinal cord compression based on clinical findings and/or MRI Any other serious illness or medical condition that would, in the opinion of the investigator, make this protocol unreasonably hazardous, including, but not limited to: Any uncontrolled infection Cardiac failure NYHA (New York Heart Association) III or IV Crohn's disease or ulcerative colitis Bone marrow dysplasia Known allergy to any of the compounds under investigation Unmanageable fecal incontinence

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nivolumab and ipilimumab<br>Patients receive nivolumab IV over 60 minutes and ipilimumab IV over 90 minutes every 3 weeks for 12 weeks. Patients then receive nivolumab IV over 60 minutes every 2 weeks for 36 weeks in the absence of disease progression or unacceptable toxicity. | Biological: Ipilimumab<br>* Given 1 mg/kg IV<br>* Other names: Yervoy;Biological: Nivolumab<br>* Given 3 mg/kg IV<br>* Other names: Opdivo;|
| Experimental: Enzalutamide plus Nivolumab and Ipilimumab<br>Patients will continue on standard of care enzalutamide, with the addition of nivolumab IV over 60 minutes and ipilimumab IV over 90 minutes every 3 weeks for 12 weeks. Patients then receive nivolumab IV over 60 minutes every 2 weeks for 36 weeks in the absence of disease progression or unacceptable toxicity. | Biological: Ipilimumab<br>* Given 1 mg/kg IV<br>* Other names: Yervoy;Biological: Nivolumab<br>* Given 3 mg/kg IV<br>* Other names: Opdivo;Drug: Enzalutamide<br>* given orally per standard of care<br>* Other names: Xtandi;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Change in PSA Response | Number of participants with greater than 50% decline in PSA from start of treatment, sustained for >= 4 weeks, as defined by Prostate Cancer Working Group 2 (PCWG2) criteria. | up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Durable Progression Free Survival (PFS) | Number of participants with PFS >= 24 weeks. PFS is described as number of weeks from start of treatment until first evidence of clinical radiographic progression, or death. | up to 3 years | 
| Number of Participants Experiencing Adverse Events | Number of participants experiencing Grade 3-4 adverse events, Grade 3-4 immune-related AEs (irAEs), as defined by National Cancer Institute (NIH) CTCAE version 4.0 | up to 3 years | 
| Objective Response Rate (ORR) | Number of participants with complete response (CR) or partial response (PR) in measurable soft tissue lesions, as defined by RECIST version 1.1 | up to 3 years | 
| Overall Survival | Number of months alive after start of treatment. | up to 3 years | 
| Progression Free Survival (PFS) | Number of months from start of treatment until first evidence of progression, as defined by based on RECIST version 1.1 and PCWG2 | up to 3 years | 
| Number of Participants With Change in AR-V7 Expression | Change in AR-V7 expression is defined as converting from AR-V7-positive to AR-V7-negative during treatment. | up to 3 years | 
| PSA-PFS | Number of months until >= 25% or >=2 ng/mL increase in PSA, as defined per PCWG2 criteria | up to 3 years | 
| Response Duration in Patients With Objective Response | Number of months from first evidence of response until progression. | up to 12 months | 
| Number of Participants With Change in AR-V7 Expression as Expressed by AR-V7 to Full Length AR Ratio Converting From AR-V7-positive to -Negative With Changes in AR-V7 Expression | Change in AR-V7 is described as converting from AR-V7-positive to -negative, expressed as a ratio of AR-V7 to full-length AR (AR-FL) | up to 3 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Hormone-Resistant Prostate Cancer, Prostate Carcinoma Metastatic in the Bone