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.
Inclusion Criteria:
- Newly diagnosed histologically confirmed prostate adenocarcinoma within 4 months prior
to study registration with evidence of 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.
- Age ≥18 years
- ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A)
o Participants with ECOG performance status of 2 are only eligible if the performance
status decline is attributed to metastatic prostate cancer
- Serum PSA > 4.0 ng/mL before initiation of ADT
- Serum testosterone > 100 ng/dL before initiation of ADT
o Participants 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.
- Participants 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:
Participants 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 participants 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
- PT, INR and PTT ≤ 1.5 x institutional upper limit of normal. Exception:
Participants 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, defined as:
- At least ten 5-micron formalin-fixed paraffin-embedded (FFPE) slides with
unstained, freshly cut, serial sections from biopsy cores containing at least 20%
tumor involvement with the highest Gleason score(s) for OncoPanel analysis is
required
- At least one 5-micron FFPE slide with unstained, freshly cut, serial sections
from biopsy cores containing at least 50% tumor involvement with the highest
Gleason score(s) for ImmunoProfile analysis is required. If slide with 50% tumor
involvement is unavailable, a 5-micron slide containing at least 30% tumor will
be accepted.
- If archival FFPE tissue is unavailable or insufficient for OncoPanel and
ImmunoProfile analysis, participants must be undergoing a standard of care
prostate biopsy that will provide material meeting the above requirements in
order to be eligible.
- Successful OncoPanel and ImmunoProfile biomarker analysis using baseline prostate
biopsy tissue for allocation into a study cohort during pre-screening
- Participants 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
- Participants 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
- Participants whose tumors do not harbor DDRD and are PD-L1 negative with low CD8+
T cell infiltration will be assigned to Cohort 3
- 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
- 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:
- Participants must not have received prior ADT (LHRH analogue antiandrogen),
chemotherapy, or immunotherapy for prostate cancer. The following exception is
allowed:
- Participants 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
- Antiandrogens (e.g., bicalutamide or flutamide) may be used in addition to LHRH
analogue ≤28 days before initiation of LHRH analogue to cover the testosterone
surge associated with certain LHRH agonists but must be discontinued prior to
study registration
- Second-generation hormonal agents (e.g., abiraterone acetate) are not allowed
- Participants must not have undergone prostatectomy
- 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
- Participants who are receiving any other investigational agents
- Any previous treatment with a PD-1 or PD-L1 inhibitor
- Participants with known brain metastases
- 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:
- 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
- Adequately treated non-melanoma skin cancer or lentigo maligna without evidence
of disease
- 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
- Major surgical procedure as defined by the Site Investigator within 28 days prior to
the first dose of chemoimmunotherapy
- Known history of testing positive for human immunodeficiency virus (HIV) or known
acquired immunodeficiency syndrome.
- History of allogeneic bone marrow or organ transplantation
- 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:
- Vitiligo or alopecia
- Hypothyroidism stable on hormone replacement
- Chronic skin condition that does not require systemic therapy
- Celiac disease controlled by diet alone
- Participants with inactive disease in the last 5 years may be included but only
after consultation with the study physician
- Active infection including tuberculosis, hepatitis B (known positive HBV surface
antigen [HBsAg]), or hepatitis C (HCV)
- Participants with a past or resolved HBV infection (defined as the presence of
hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible
- Participants with positive HCV antibody are eligible if polymerase chain reaction
is negative for HCV RNA
- 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 dexamethasone prior to docetaxel administration
- 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)
