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

  • End date
    Jun 30, 2025
  • participants needed
  • sponsor
    Xiao X. Wei
Updated on 20 April 2022
endocrine therapy
gilbert's syndrome
neutrophil count
hormone therapy
antiandrogen therapy
androgen suppression
bone scan
metastatic prostate cancer
bone metastases
testosterone level
biopsy of prostate
serum testosterone


This research study is studying a combination of hormonal therapy, chemotherapy, and immunotherapy as a possible treatment for metastatic hormone-sensitive prostate cancer. The names of the study drugs involved in this study are:

  • Androgen deprivation therapy (ADT) with a drug of your physician's choice. This may include leuprolide (Lupron), goserelin acetate (Zoladex), or degarelix (Firmagon).
  • Docetaxel
  • Nivolumab


This research study is a Phase 2 clinical trial. Phase 2 clinical trials test the safety and effectiveness of investigational drug(s) to learn whether the drug(s) work in treating a specific disease. "Investigational" means that the drug(s) are being studied.

The U.S. Food and Drug Administration (FDA) has not approved nivolumab for hormone sensitive prostate cancer. However, nivolumab has been approved for other uses, including for advanced melanoma, lung cancer, head and neck cancer, kidney cancer, and bladder cancer.

The U.S. FDA has not approved docetaxel as a treatment option for hormone sensitive prostate cancer. However, docetaxel is approved for advanced hormone resistant prostate cancer and other cancers. There is also evidence from a high quality, phase 3 randomized clinical trial supporting the use of docetaxel in metastatic hormone sensitive prostate cancer patients who have a high burden of metastasis. Docetaxel is an off-label indication for hormone sensitive prostate cancer.

The U.S. FDA has approved androgen deprivation therapy (ADT) agents, including leuprolide (Lupron), goserelin acetate (Zoladex), or degarelix (Firmagon), as a treatment option for hormone sensitive prostate cancer.

The combination of ADT, also called hormonal therapy, with docetaxel chemotherapy and nivolumab immunotherapy is considered investigational. ADT cuts off the supply of testosterone and is the standard of care for hormone sensitive prostate cancer. The addition of docetaxel chemotherapy has been found to prolong life for prostate cancer patients starting hormonal therapy for the first time for metastatic disease, who also have a large volume of cancer.

Another anti-cancer treatment modality is called immunotherapy. The immune system can kill cells that are recognized as different or dangerous, such as infected cells and cancer cells. Nivolumab is an antibody (a type of human protein) that work to stimulate the body's immune system to recognize and fight cancer cells.

Hormonal therapy and chemotherapy may make cancer cells more recognizable to the immune system, and make cancer cells more susceptible to immunotherapy. The goal of this study is to examine the activity and safety of hormonal therapy combined with docetaxel chemotherapy and nivolumab immunotherapy for hormone sensitive prostate cancer. The study is designed to enrich for patients whose tumors may be more most responsive to this treatment strategy. All patients will receive the same treatment of ADT combined with docetaxel chemotherapy and nivolumab immunotherapy.

Condition Hormone Sensitive Prostate Cancer, Prostate Adenocarcinoma, Metastasis Prostate Adenocarcinoma
Treatment docetaxel, Nivolumab, Androgen Deprivation Therapy
Clinical Study IdentifierNCT04126070
SponsorXiao X. Wei
Last Modified on20 April 2022


Yes No Not Sure

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
Subjects with ECOG performance status of 2 are only eligible if the performance status decline is attributed to metastatic prostate cancer
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
Subjects must have adequate organ and marrow function as defined below
Grade ≤ 1 peripheral neuropathy, defined as asymptomatic or paresthesia and/or decreased deep tendon reflexes is allowed
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
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
Availability of adequate baseline prostate biopsy tissue for integral biomarker
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
analysis and correlative studies
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
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 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
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 SponsorInvestigator
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
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
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
Successful OncoPanel and ImmunoProfile biomarker analysis for allocation into a study
Tumors identified as mismatch repair deficient (MMR-d) or microsatellite instability high (MSI-H) will also be included in Cohort 1
cohort during pre-screening
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
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
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
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
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)
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
Willingness to provide leftover metastatic biopsy tissue for correlative studies, if
obtained for clinical purposes
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

Exclusion Criteria

Second-generation hormonal agents (e.g., abiraterone acetate) are not allowed
Prostate radiation is allowed before or after study enrollment and may be delivered concurrently with study chemoimmunotherapy, per provider discretion, assuming adequate prostate biopsy tissue is collected before prostatic radiation
Metastasis-directed radiation is allowed before or after study enrollment and may be delivered concurrently with study chemoimmunotherapy, per provider discretion
Any previous treatment with a PD-1 or PD-L1 inhibitor
History of allergic reactions attributed to compounds of similar chemical or biologic composition to docetaxel (including any drugs formulated with polysorbate 80), nivolumab, or LHRH analogue (e.g., leuprolide, goserelin acetate, degarelix)
History of another primary malignancy, except for
Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
Subjects must not have received prior ADT (LHRH analogue +/- antiandrogen), chemotherapy, or immunotherapy for prostate cancer. The following exception is
Major surgical procedure as defined by the Site Investigator within 28 days prior to the first dose of chemoimmunotherapy
History of allogeneic bone marrow or organ transplantation
The 120-day window commences at the start of either the antiandrogen agent or LHRH analogue, whichever is earlier
Vitiligo or alopecia
Hypothyroidism stable on hormone replacement
Subjects must not have undergone prostatectomy
Chronic skin condition that does not require systemic therapy
Celiac disease controlled by diet alone
Subjects who have initiated ADT prior to study registration and are able to complete biomarker pre-screening, cohort allocation, and start C1D1 study chemoimmunotherapy ≤120 days from initiation of ADT are allowed
Subjects who are receiving any other investigational agents
Antiandrogens (e.g., bicalutamide or flutamide) may be used in addition to LHRH analogue ≤60 days before initiation of LHRH analogue to cover the testosterone surge associated with certain LHRH agonists but must be discontinued prior to study registration
Subjects with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other AEs
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)
Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome. HIV-positive subjects on combination antiretroviral therapy are ineligible because of the potential for nivolumab to be less clinically active in this population. In addition, these subjects are at increased risk of lethal infections when treated with marrow-suppressive chemotherapy
Active or prior documented autoimmune or inflammatory disorders, including= inflammatory bowel disease (e.g., Crohn's disease), systemic lupus erythematosus, Sarcoidosis syndrome, Grave's disease, rheumatoid arthritis, hypophysitis, uveitis, with the following exceptions
Malignancy treated with curative intent and with no known active disease for ≥2 years before the first dose of study treatment and of low potential risk for recurrence
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
Subjects with inactive disease in the last 5 years may be included but only after consultation with the study physician
compliance with study requirements
Subjects with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible
Subjects with positive HCV antibody are eligible if polymerase chain reaction is negative for HCV RNA
Premedication for docetaxel with oral dexamethasone (See Section 5.1)
Inclusion of Minorities
Active infection including tuberculosis, hepatitis B (known positive HBV surface
antigen [HBsAg]), or hepatitis C (HCV)
Concurrent or prior use of immunosuppressive medication within 14 days before the
first dose of study chemoimmunotherapy, with the following exceptions
• Men of all races and ethnic groups are eligible for this trial
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