Nivolumab + Docetaxel + ADT in mHSPC Patients With DDRD or Inflamed Tumors

Inclusion Criteria

• •Newly diagnosed histologically confirmed prostate adenocarcinoma within 6 months prior to study registration with evidence of high-volume distant metastasis on conventional imaging
• •Distant metastasis is defined by non-regional lymph node(s) metastasis (M1a), bone metastasis (M1b), and/or other site(s) of metastatic disease (M1c).
• •Conventional imaging consists of CT, MRI or radionuclide bone scan
• •High volume of disease is defined by presence of four or more bone lesions with at least one beyond the vertebral bodies or pelvis or any site of visceral metastasis.
• •Age ≥18 years
• •ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A)
• •Serum PSA \> 4.0 ng/mL before initiation of ADT
• •Serum testosterone \> 100 ng/dL before initiation of ADT
• •Subjects whose testosterone level is unknown before initiation of ADT may be allowed after discussion with Sponsor-Investigator.
• •Grade ≤ 1 peripheral neuropathy, defined as asymptomatic or paresthesia and/or decreased deep tendon reflexes is allowed.
• •Subjects must have adequate organ and marrow function as defined below:
• •* Absolute neutrophil count ≥1,500 /mcL
• •* Platelets ≥100,000 /mcL
• •* Total bilirubin ≤1.5 × institutional upper limit of normal. Exception: Subjects with confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology) may be allowed after consultation with treating physician
• •* AST(SGOT) and ALT(SGPT) ≤2.5 × institutional upper limit of normal. Exception: ≤5 x institutional upper limit of normal in subjects with liver metastasis
• •* Creatinine (Cr) and creatinine clearance (CrCl) Cr \<1.6 mg/dL or CrCl ≥30 mL/min; CrCl should be calculated using the Cockcroft-Gault formula: CrCl (mL/min) = (140-Age) x Body weight (Kg)/72 x Serum creatinine (mg/dL)
• •* PT, INR and PTT ≤ 1.5 x institutional upper limit of normal. Exception: Subjects who are on a stable regimen of therapeutic anticoagulation for an appropriate clinical indication may be enrolled
• •Availability of adequate baseline prostate biopsy tissue for integral biomarker analysis and correlative studies:
• •* Sources of tumor tissue allowed are (1) prostate biopsy, (2) transurethral resection of the prostate tissue (TURP) , (3) trans urethral resection of bladder tumor tissue (TURBT) with contiguous spread of prostate cancer to the bladder, and (4) metastatic biopsy tissue excluding bone and lymph node metastases (e.g. lung or liver biopsies are acceptable).
• •* For OncoPanel, submit at least one (1) H\&E slide and ten (10) 5-micron thick serially sectioned unstained formalin-fixed paraffin-embedded (FFPE) slides. Biopsy should contain at least 20% tumor involvement with the highest Gleason score(s). If requested tissue is unavailable, a lower number of 4-micron or 5- micron slides and/or slides containing lower tumor involvement may be accepted after discussion with the Sponsor-Investigator.
• •* For ImmunoProfile, submit at least one (1) H\&E slide and one (1) 5-micron thick serially sectioned unstained, freshly cut, FFPE slide. Biopsy should contain at least 50% tumor involvement with the highest Gleason score(s). If requested tissue is unavailable, a 5-micron slide containing lower tumor involvement may be accepted after discussion with the study Sponsor-Investigator.
• •* Submission of one (1) H\&E slide and at least one (1) FFPE tissue core block with at least 3mm2 tumor area with the highest Gleason score is an acceptable alternative to unstained FFPE slides.
• •* Subjects who have insufficient baseline prostate biopsy tissue for OncoPanel analysis but have baseline metastatic biopsy tissue available may have OncoPanel analysis performed using metastatic biopsy tissue. Successful OncoPanel testing (but not ImmunoProfile) of metastatic biopsy tissue is acceptable from any source including lymph node or bone, after discussion with the study Sponsor- Investigator.
• •* For Exploratory Correlative Studies, at least 1 tissue core block (preferred) or one (1) H\&E slide and twelve (12) 5-micron thick FFPE slides with unstained, freshly cut, serial sections from biopsy cores containing at least 20% tumor involvement with the highest Gleason score(s) will be requested, if available.
• •* Tissue should be submitted with redacted pathology report.
• •Successful OncoPanel and ImmunoProfile biomarker analysis for allocation into a study cohort during pre-screening
• •* Subjects whose tumors harbor somatic or germline homozygous deletions and/or deleterious mutations in a DDR gene using OncoPanel will be assigned to Cohort 1, regardless of ImmunoProfile results
• •* DDR genes include and are not limited to BRCA2, ATM, CHEK2, BRCA1, PALB2, RAD51D, ATR, NBN, PMS2, GEN1, MLH1, MSH2, MSH6, RAD51C, MRE11A, BRIP1, FAM175A, and CDK12
• •* Deleterious mutations are defined as loss of function, splice site, nonsense, or frameshift mutations, and determination will be made between DFCI molecular pathology and study Sponsor-Investigator
• •* Tumors identified as mismatch repair deficient (MMR-d) or microsatellite instability high (MSI-H) will also be included in Cohort 1
• •* Patients with germline DDRD or MMR-d/MSI-H (Lynch Syndrome) or tumors with DDRD or MMR-d/MSI-H identified in another CLIAcertified laboratory (e.g., Foundation Medicine) using prostate or metastatic tissue may be assigned to Cohort 1 after discussion with the Sponsor-Investigator. If archival tissue is available, it will be requested for OncoPanel testing; however, results will not influence eligibility.
• •* Subjects whose tumors are PD-L1 positive and/or CD8+ T cell inflamed using ImmunoProfile without the presence of DDRD will be assigned to Cohort 2
• •* PD-L1 positivity will be defined as Combined Positive Score (CPS) ≥ 1, which is the number of PD-L1 staining cells (e.g., tumor cells, immune cells) divided by the total number of tumor cells, multiplied by 100
• •* CD8+ T cell inflammation will be defined as CD8+ T cell density ≥ 200, which is the number of CD8+ cells divided by the surface area of a region of interest (mm2)
• •* Subjects whose tumors do not harbor DDRD and are PD-L1 negative with low CD8+ T cell infiltration will be assigned to Cohort 3
• •* Subjects whose prescreening is unsuccessful for cohort allocation or whose biomarker status matches that of a filled cohort will not be eligible
• •* Subjects who underwent successful ImmunoProfile pre-screening but failed OncoPanel pre-screening may be allocated to Cohort 2 or Cohort 3 based on ImmunoProfile results and assuming DDRD negativity, at the discretion of the Sponsor-Investigator.
• •* Before one of the study cohorts enrolls 15 of 20 subjects (Cohort 3 is anticipated to complete accrual first), subjects may undergo main study screening when ImmunoProfile and OncoPanel analyses are ongoing, and may proceed to study treatment if they meet all eligibility criteria with the exception that OncoPanel analysis is ongoing. These patients will be allocated into their respective cohort after OncoPanel results return.
• •Willingness to provide leftover metastatic biopsy tissue for correlative studies, if obtained for clinical purposes
• •Based on its mechanism of action and data from animal studies, nivolumab can cause fetal harm. For this reason non-sterilized men who are sexually active with a female partner of childbearing potential treated or enrolled on this protocol must agree to use adequate contraception prior to the study, for the duration of study participation, and for 7 months after last dose of nivolumab administration
• •* Adequate contraception includes male condom plus spermicide
• •* Not engaging in sexual activity is an acceptable practice; however, occasional abstinence, the rhythm method, and the withdrawal method are not acceptable methods of contraception
• •* Subjects in this study should refrain from sperm donation
• •Ability to understand and the willingness to sign a written informed consent document, or have a legally authorized representative sign on the subject's behalf
• •Concurrent or prior use of immunosuppressive medication within 14 days before the first dose of study chemoimmunotherapy, with the following exceptions:
• •* Premedication for docetaxel with oral dexamethasone (See Section 5.1)
• •* Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intraarticular injection)
• •* Systemic corticosteroids at physiologic doses not exceeding 10mg/day of prednisone or its equivalent
• •* Steroids as premedication for hypersensitivity reactions (e.g., premedication for iodinated contrast allergy before CT scan)
• •Inclusion of Minorities
• •Men of all races and ethnic groups are eligible for this trial.