Nivolumab in Treating Patients with High-Risk Biochemically Recurrent Prostate Cancer
This phase II trial studies how well nivolumab works in treating patients with prostate cancer that is high-risk to come back after treatment. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body’s immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.
Inclusion Criteria
- Patients must have signed an informed-consent form indicating that the patient understands the purpose of and procedures required for the study and is willing to participate in the study
- Patients must have a history of prostate adenocarcinoma (adenocarcinoma must be the primary histology; secondary components of variant histologies are acceptable) confirmed on biopsy and treated with primary radical prostatectomy (RP) or definitive radiation (RT). Prior salvage RT is acceptable
- Patients must have experienced biochemical recurrence (BCR) with most recent PSA >= 00.5 ng/mL. For patients who received primary radiation therapy (RT), PSA must have risen to >= 2 ng/mL above the nadir (per Radiation Therapy Oncology Group - American Society for Therapeutic Radiology and Oncology [RTOG-ASTRO] consensus criteria) * No evidence of metastases on conventional imaging. (As per Prostate Cancer Working Group [PCWG] 3, lymph nodes >= 1.5 cm are considered pathologic and nodes 1.0 - < 1.5 cm may be considered pathologic but with clinical discretion. Metastases seen on fluciclovine positron emission tomography [PET], sodium fluoride [NaFl], or prostate-specific membrane antigen [PSMA] scans or other advanced imaging but not on conventional imaging are acceptable. Advanced imaging such as fluciclovine PET or PSMA PET with no evidence of metastases may replace conventional imaging for eligibility. NaFl scan would only replace bone scan.)
- PSA doubling time (PSADT) < 10 months * PSADT: calculated as per PCWG3 and the Memorial Sloan Kettering Cancer Center calculator with linear regression model of normal logarithm of PSA and time, based on: ** At least 3 consecutive PSA values with each value >= 0.2 ng/mL ** Interval between first and last PSA values is >= 8 weeks but =< 12 months
- Archival tissue is mandatory, either prostatectomy specimen or (in patients who received primary RT) diagnostic core biopsies. Patients must consent to next-generation sequencing performed on this tissue * If diagnostic core biopsies are only available tissue, at least 3 cores must be involved by tumor
- Eastern Cooperative Oncology Group (ECOG) performance status 0-1
- White blood cell (WBC) =< 2000/uL
- Absolute neutrophil count (ANC) >= 1500/uL
- Platelets (Plt) >= 100 x 10^3/uL
- Hemoglobin (Hgb) > 9.0 g/dL (with or without transfusion)
- Serum creatinine =< 2 x upper limit of normal (ULN)
- Bilirubin =< 1.5 x upper limit of normal (ULN) * Except subjects with Gilbert syndrome, who can have total bilirubin < 3.0 mg/dL
- Aspartate aminotransferase (AST) =< 3 x ULN
- Alanine aminotransferase (ALT) =< 3 x ULN
- Baseline testosterone >= 100 ng/dL
- Recovery from acute toxicity related to prior therapy, including surgery and radiation, or no treatment-related toxicity >= grade 2
- History of prior malignancy or concurrent separate malignancy is not an exclusion criterion so long as the non-prostate malignancy is stable and does not require any treatment
- Able to understand and sign informed consent and adhere to study procedures
- Male patients whose female partners are of reproductive potential must agree to use a contraception during the trial period
Exclusion Criteria
- Current use of antiandrogen therapy (ADT) or plan to initiate ADT during trial period
- Major surgery or radiation therapy within 14 days of starting study treatment
- Subjects with active autoimmune disease. Patients with a history of autoimmune disease that has not required systemic immunosuppressive therapy or does not threaten vital organ function including central nervous system, heart, lungs, kidneys, skin, and gastrointestinal tract will be allowed
- Known history of immune deficiencies or chronic viral infections including human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV) (patients with prior therapy for HBV or HCV is permitted if viral clearance was documented)
- Concurrent medical condition requiring use of systemic corticosteroids with prednisone > 10 mg per day or equivalent. Use of inhaled, nasal, and topical steroids (applied to small body areas) is allowed
- Current use (within past 4 weeks) of other prohibited medications including anti-cancer therapies, hormonal therapies, 5-alpha reductase inhibitors, and alternative medications known to alter PSA (e.g. phytoestrogens and saw palmetto)
- Prior treatment with immune checkpoint inhibitors. (Prior cancer vaccines are allowed.)
- Serious intercurrent medical or psychiatric illness that, in the judgment of the investigator, would interfere with patient’s ability to carry out the treatment program
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT03637543.
PRIMARY OBJECTIVE:
I. To determine the proportion of patients with high-risk biochemically-recurrent (BCR) prostate cancer (PCa) that experiences decline or stabilization in prostate specific antigen (PSA) (without symptomatic/radiographic progression) after 12 weeks of nivolumab.
SECONDARY OBJECTIVES:
I. Determine the maximal change (proportional) and best decline (absolute) in prostate specific antigen (PSA) during nivolumab treatment.
II. Describe the change in PSA doubling time (PSADT) during nivolumab therapy relative to baseline.
III. Determine the time to development of overt metastatic disease after treatment with nivolumab.
IV. Determine the time to initiation of androgen deprivation therapy (ADT) after treatment with nivolumab.
V. Assess the toxicity of nivolumab monotherapy in patients with BCR PCa.
EXPLORATORY OBJECTIVES:
I. Evaluate whether response to nivolumab treatment is enriched among patients with tumor programmed death-ligand 1 (PD-L1) expression on tumor cells and on tumor-infiltrating lymphocytes and antigen-presenting cells (APCs).
II. Identify genomic biomarkers associated with response to nivolumab.
III. Evaluate correlations between alterations in deoxyribonucleic acid (DNA)-damage-repair genes and PD-L1 expression.
IV. Evaluate correlations between tumor-infiltrating lymphocytes and APCs with response to nivolumab.
V. Evaluate subtypes of “exhausted” tumor-infiltrating lymphocytes.
VI. Explore whether peripheral T-cells are present that might recognize tumor neoantigens and whether these correlate with responses to nivolumab.
VII. Assess for genomic alterations in circulating tumor DNA and correlate with mutations identified in primary tumor specimens.
VIII. Assess levels of plasma cytokines prior to initiation and during therapy and determine whether levels or changes in specific cytokines may be predictive biomarkers for response.
IX. Assess peripheral blood mononuclear cell (PBMC) subsets prior to initiation and during therapy and determine basal features or changes during therapy may be predictive biomarkers for response.
OUTLINE:
Patients receive nivolumab intravenously (IV) over 30 minutes on day 1. Cycles repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 100 days and then every 3 months thereafter.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationDana-Farber Harvard Cancer Center
Principal InvestigatorDavid Einstein
- Primary ID18-249
- Secondary IDsNCI-2018-02763
- ClinicalTrials.gov IDNCT03637543