Avelumab Plus 2nd-generation ADT in African American Subjects With mCRPC

Study Overview
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Brief Summary
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This is a nonrandomized, open-label trial of avelumab in subjects with metastatic castration-resistant prostate cancer (mCRPC) experiencing PSA or radiographic progression while receiving 2nd generation ADT (abiraterone / enzalutamide/ apalutamide or darolutamide). Metastases must be radiographically evident by whole body bone scintigraphy or CT/MRI scan. Thirteen African American subjects will be enrolled into the initial cohort. If at least one positive response (PSA decrease by >50% and or radiographic per RECIST 1.1) is found, the study will be expanded to accrue a total of 27 patients. The trial will be conducted in accordance with Good Clinical Practices. Subjects enrolled in the study will receive avelumab 10 mg/kg every 2 weeks (Q2W) and continue their previously started 2nd generation ADT (abiraterone or enzalutamide). Treatment with avelumab will continue until documented confirmed disease progression, unacceptable AEs, intercurrent illness that prevents further administration of treatment, Investigator's decision to withdraw the subject, subject discontinuation from the study, noncompliance with trial treatment or procedure requirements, subject receives 52 administrations of avelumab (approximately 2 years), or administrative reasons requiring the cessation of treatment. After the end of treatment, each subject will be followed for 30 days for AE monitoring (serious AEs will be collected for 90 days after the end of treatment or 30 days after the end of treatment if the subject initiates new anticancer therapy, whichever is earlier). Subjects who discontinue treatment for reasons other than disease progression will remain on study and continue to undergo study-related disease assessments until documented disease progression, initiation of a new non-study prostate cancer treatment, withdrawal of consent, or becoming lost to follow-up. All subjects will enter survival follow up, and will be contacted at their regularly scheduled clinic visit, or by telephone approximately every 6 months, until death or withdrawal of consent or end of study.

Detailed Description
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This is a nonrandomized, open-label trial of avelumab in subjects with metastatic castration-resistant prostate cancer (mCRPC) experiencing PSA or radiographic progression while receiving 2nd generation ADT (abiraterone / enzalutamide/ apalutamide or darolutamide). Metastases must be radiographically evident by whole body bone scintigraphy or CT/MRI scan. Thirteen African American subjects will be enrolled into the initial cohort. If at least one positive response (PSA decrease by >50% and or radiographic per RECIST 1.1) is found, the study will be expanded to accrue a total of 27 patients. The trial will be conducted in accordance with Good Clinical Practices. Subjects enrolled in the study will receive avelumab 10 mg/kg every 2 weeks (Q2W) and continue their previously started 2nd generation ADT (abiraterone or enzalutamide). All subjects will undergo radiographic imaging assessments and PSA assessments to evaluate response to treatment at regular intervals. On study imaging will be assessed every 12 weeks. Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 will be adapted per the consensus guidelines of the Prostate Cancer Clinical Trials Working Group 3 (PCWG3) as described in Appendix A/B to account for the tumor progression patterns seen in bone metastases in prostate cancer. PSA will be obtained every 2 weeks with PSA progression assessed per PCWG3. Adverse events (AEs) will be monitored throughout the trial and graded in severity according to the guidelines outlined in the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Treatment with avelumab will continue until documented confirmed disease progression, unacceptable AEs, intercurrent illness that prevents further administration of treatment, Investigator's decision to withdraw the subject, subject discontinuation from the study, noncompliance with trial treatment or procedure requirements, subject receives 52 administrations of avelumab (approximately 2 years), or administrative reasons requiring the cessation of treatment. After the end of treatment, each subject will be followed for 30 days for AE monitoring (serious AEs will be collected for 90 days after the end of treatment or 30 days after the end of treatment if the subject initiates new anticancer therapy, whichever is earlier). Subjects who discontinue treatment for reasons other than disease progression will remain on study and continue to undergo study-related disease assessments until documented disease progression, initiation of a new non-study prostate cancer treatment, withdrawal of consent, or becoming lost to follow-up. All subjects will enter survival follow up, and will be contacted at their regularly scheduled clinic visit, or by telephone approximately every 6 months, until death or withdrawal of consent or end of study.

Official Title
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PDL-1 Inhibition With Avelumab and Concurrent Second-generation ADT in African Americans With Castrate-resistant Metastatic Prostate Cancer

Conditions
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Metastatic Castration-resistant Prostate Cancer

Intervention / Treatment
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* Drug: Avelumab
* Drug: 2nd generation ADT (abiraterone or enzalutamide)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Must be of African descent; Black or African American: A person having origins in any of the black racial groups of Africa. Terms such as Haitian or Negro can be used in addition to Black or African American. Be willing and able to provide written informed consent for the trial. Be ≥18 years of age on day of signing informed consent. Have histologically or cytologically confirmed adenocarcinoma of the prostate without small cell histology. Diagnosis must be stated in a pathology report. Have evidence of metastatic disease as determined by CT/MRI scans and/or bone metastases by whole body bone scintigraphy. (Use MRI if CT is contraindicated, and for imaging of the brain if clinically indicated). Have documented disease progression within 3 months of screening, as determined by the Investigator, by means of at least one of the following: PSA progression as defined by a minimum of two rising PSA levels with an interval of ≥ 1 week between each assessment where the PSA value at screening should be ≥ 2 ng/mL. Radiographic disease progression in soft tissue or bone with or without PSA progression as determined by Recist 1.1 and/or PCWG3 Have ongoing androgen deprivation with serum testosterone < 50 ng/dL (< 2.0 nM). If the subject is currently being treated with Luteinising Hormone Releasing Hormone (LHRH) agonists or antagonists (for subjects who have not undergone an orchiectomy). This treatment must be continued throughout the study. Be receiving and tolerating either abiraterone acetate, enzalutamide, apalutamide or darolutamide for at least 8 weeks prior to documented disease progression. Note: the 2nd generation ADT that the patient is currently progression on needs to be the first 2nd gen ADT used in the CRPC setting Have a performance status of 0, 1 or 2 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale (Appendix D). Male subjects of reproductive potential must agree practice abstinence from heterosexual activity OR use a highly effective method of contraception, starting at the time of informed consent and continue through 60 days after the last dose of study therapy (see section 6.1.1.) Demonstrate adequate organ function as defined in Table 1, all screening labs should be performed within 10 days of treatment initiation. Exclusion Criteria: Is currently participating and receiving study therapy in a clinical trial, or has participated in a study of an investigational agent (and received study therapy or used an investigation device) within 4 weeks of the first dose of study treatment. No more than one line of a 2nd generation ADT (abiraterone acetate /enzalutamide/ apalutamide/darolutamide) for mCRPC is permitted for study entry. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment. Note: the following are allowed: a. intranasal, inhaled, topical steroids, or local steroid injection (e.g., intraarticular injection); b. systemic corticosteroids at physiological doses < 10mg/day of prednisone or equivalent; c. steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication). Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to the first dose of trial treatment or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to mAbs administered more than 4 weeks earlier. Has had >2 prior systemic chemotherapy agents for mCRPC Note: chemotherapy in the metastatic hormone sensitive prostate cancer (mHSPC) setting is allowed Prior surgery within 4 weeks of initiating study treatment Note: If subjects received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to the first dose of trial treatment. Has any additional malignancy that has required active treatment in the last 3 years. Exceptions include: basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or low-grade Ta or T1 urothelial carcinoma of that bladder that has undergone potentially curative therapy. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Note: Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability. Has an active autoimmune disease that might deteriorate when receiving an immune-stimulatory agent. Patients with diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid diseases not requiring immunosuppressive treatment are eligible. Has had prior organ transplantation including allogenic stem-cell transplantation. Has an active infection requiring systemic therapy. Has active, clinically significant Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). Patients with well controlled HIV will be allowed to be enrolled into the study. Has Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (positive HBV surface antigen or HCV RNA if anti-HCV antibody screening test is positive). Has received a live vaccine within 4 weeks of first dose of avelumab; live vaccines are prohibited throughout course of the trial. Inactivated vaccines are allowed. Has known prior severe hypersensitivity to investigational product or component in its formulations, including known severe hypersensitivity reactions to monoclonal antibodies (NCI CTCAE v4.3 Grade > 3). Has clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke (< 6months prior to enrollment), myocardial infarction (< 6months prior to enrollment), unstable angina, congestive heart failure (> New York Heart Association Classification Class II), or serious cardiac ventricular arrhythmia requiring medication. Persisting toxicity related to prior therapy (NCI CTCAE v. 4.3 Grade > 1); however, alopecia, sensory neuropathy Grade ≤ 2, or other Grade ≤ 2 not constituting a safety risk based on investigator's judgment are acceptable. Other severe acute or chronic medical conditions including colitis, inflammatory bowel disease, immune pneumonitis, pulmonary fibrosis or psychiatric conditions including recent (within the past year) or active suicidal ideation or behavior; or laboratory abnormalities that may increase the risk associated with study participation or study treatment administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Avelumab + 2nd generation ADT<br>Avelumab 10mg/kg every 2 weeks (Q2W) + 2nd generation ADT | Drug: Avelumab<br>* Avelumab 10mg/kg every 2 weeks (Q2W) + 2nd generation ADT<br>* Other names: Bavencio;Drug: 2nd generation ADT (abiraterone or enzalutamide)<br>* 2nd generation ADT (abiraterone or enzalutamide)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PSA Response Greater Than or Equal to 50% | The primary endpoint is a PSA response at 8 weeks or greater from starting study treatment and with a minimum of 3 treatments administered. A PSA response is defined as a ≥50% PSA decline at 8 weeks or greater from the time of starting study treatment. The two-stage minimax design of the study will be utilized to determine whether further investigation of the study drug is warranted. | An interim analysis to assess responders will be performed at 2 years from date of enrolloment of first subject and at end of study. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PSA Progression-free Survival (PFS) | PSA progression-free survival (pPFS) defined as the time from enrollment until PSA progression by PCWG3 or death, whichever occurs earlier. Subjects without pPFS at the time of data cut-off will be censored at the date of last adequate cancer assessment. PSA progression-free survival will be reported using Kaplan-Meier estimates, with 95% CI for median time-to-event. | pPFS will be assessed 12 months after enrollment of last subject. | 
| Radiographic Progression-free Survival (PFS) | Radiographic progression-free survival (rPFS) defined as the time from enrollment until radiographic progression by PCWG3 or death, whichever occurs earlier. Subjects without rPFS at the time of data cut-off will be censored at the date of last known to be alive. Radiographic progression-free survival will be reported using Kaplan-Meier estimates, with 95% CI for median time-to-event. | rPFS will be assessed 12 months after enrollment of last subject. | 
| Overall Survival (OS) | Overall survival (OS) defined as the time from enrollment until death on study. Subjects who are alive at the time of data cut-off will be censored at the date of last known to be alive. OS will be reported using Kaplan-Meier estimates, with 95% CI for median time-to-event. | Overall survival with be assessed at 3 years from time of enrollment of last study subject. | 
| Adverse Events (AEs) Will be Summarized by Nature, Severity, and Frequency Utilizing CTCAE Version 4.03. | Safety will be summarized by nature, severity, and frequency utilizing CTCAE version 4.03. | Safety interim analysis will be performed at 2 years. |