Clinical Trials /

Nivolumab in Biochemically Recurrent dMMR Prostate Cancer

NCT04019964

Description:

MMR-deficient cancers of any histologic type appear to be very sensitive to PD-1 blockade with pembrolizumab, and similar data are also beginning to emerge for nivolumab and other immune checkpoint inhibitors. Among the MMR-deficient cancers, the best antitumor responses are often associated with high microsatellite instability (MSI-H status), higher tumor mutational burden (TMB), and higher predicted neoantigen load. Prevalence estimates of MMR deficiency across solid tumor types range from 1% to 20% depending on the type of malignancy. In prostate cancer, 1-3% of unselected cases harbor MMR deficiency and/or microsatellite instability. For men who previously received definitive treatment for prostate cancer and subsequently develop detectable prostate specific antigen (PSA) levels, the clinical state is known as biochemically recurrent prostate cancer. The current standard of care treatment for patients with biochemically recurrent prostate cancer is either surveillance or androgen deprivation therapy (ADT). ADT has not been shown to provide a survival benefit in this setting, and the decision to initiate ADT will depend on patient preference and perceived risks of the disease. A non-hormonal therapy such as nivolumab would provide an alternative to ADT in patients with biomarker selected (i.e. dMMR, MSI-H, high TMB, or CDK12-altered) biochemically recurrent prostate cancer.

Related Conditions:
  • Prostate Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Nivolumab in Biochemically Recurrent dMMR Prostate Cancer
  • Official Title: Nivolumab as a Non-Castrating Therapy for MMR-deficient and CDK12- Altered Prostate Cancer With PSA Recurrence After Local Therapy

Clinical Trial IDs

  • ORG STUDY ID: J1933
  • SECONDARY ID: IRB00205266
  • SECONDARY ID: CA209-76M
  • NCT ID: NCT04019964

Conditions

  • Prostate Cancer
  • Recurrent Prostate Cancer

Interventions

DrugSynonymsArms
NivolumabOpdivoNivolumab in biochemically recurrent prostate cancer

Purpose

MMR-deficient cancers of any histologic type appear to be very sensitive to PD-1 blockade with pembrolizumab, and similar data are also beginning to emerge for nivolumab and other immune checkpoint inhibitors. Among the MMR-deficient cancers, the best antitumor responses are often associated with high microsatellite instability (MSI-H status), higher tumor mutational burden (TMB), and higher predicted neoantigen load. Prevalence estimates of MMR deficiency across solid tumor types range from 1% to 20% depending on the type of malignancy. In prostate cancer, 1-3% of unselected cases harbor MMR deficiency and/or microsatellite instability. For men who previously received definitive treatment for prostate cancer and subsequently develop detectable prostate specific antigen (PSA) levels, the clinical state is known as biochemically recurrent prostate cancer. The current standard of care treatment for patients with biochemically recurrent prostate cancer is either surveillance or androgen deprivation therapy (ADT). ADT has not been shown to provide a survival benefit in this setting, and the decision to initiate ADT will depend on patient preference and perceived risks of the disease. A non-hormonal therapy such as nivolumab would provide an alternative to ADT in patients with biomarker selected (i.e. dMMR, MSI-H, high TMB, or CDK12-altered) biochemically recurrent prostate cancer.

Trial Arms

NameTypeDescriptionInterventions
Nivolumab in biochemically recurrent prostate cancerExperimentalParticipants with previous prostatectomy or radiation therapy who subsequently developed detectable prostate specific antigen (PSA) levels ("biochemically recurrent prostate cancer").
  • Nivolumab

Eligibility Criteria

        Inclusion Criteria:

          -  Willing and able to provide signed informed consent and HIPAA authorization for the
             release of personal health information

          -  Males aged 18 years and above

          -  Prior local therapy with prostatectomy or EBRT/brachytherapy is required

          -  Prior salvage or adjuvant radiation therapy is allowed but not mandated. Radiation
             therapy must have been completed for at least 6 months.

          -  Absolute PSA >=1.0 ng/mL at screening

          -  Must have at least one of the following genetic alterations identified using archival
             tissue (i.e. prostate needle biopsy prior to radiation therapy or prostatectomy
             specimen):

               -  Microsatellite instability (MSI-high) status by clinical grade testing

               -  MMR protein loss (MSH2, MSH6, MLH1, PMS2) by immunohistochemistry

               -  Inactivating mutation of MSH2, MSH6, MLH1 or PSM2 by clinical grade genomic
                  testing

               -  Tumor mutational burden >= 20 mutations/megabase (TMB >=20 muts/Mb) by clinical
                  grade testing

               -  Inactivating mutation (at least monoallelic of CDK12 by clinical grade testing

          -  Serum testosterone >= 150 ng/dL

          -  No radiographic evidence of metastatic disease by CT scan and bone scan, performed
             within the prior 4 weeks.

          -  Karnofsky Performance Status (KPS) >= 70% within 14 days before start of study
             treatment (ECOG <=1)

          -  Participants must have normal organ and bone marrow function measured within 28 days
             prior to administration of study treatment as defined below:

               -  Hemoglobin >= 9.0 g/dL with no blood transfusion in the past 28 days

               -  Absolute neutrophil count (ANC) >= 1.0x10^9 / L

               -  Platelet count >= 100 x 10^9 /L

               -  Total bilirubin within institutional upper limit of normal (ULN) (in patients
                  with Gilbert's syndrome, total bilirubin <1.5x institutional ULN will be
                  acceptable)

               -  Aspartate aminotransferase (AST), Serum Glutamic Oxaloacetic Transaminase (SGOT)
                  / Alanine aminotransferase (ALT), Serum Glutamic Pyruvate Transaminase (SGPT)
                  within institutional ULN

               -  Participants must have creatinine clearance estimated using the Cockcroft-Gault
                  equation of >=40 mL/min:

        Estimated creatinine clearance = [(140 - age (years)) x weight (kg)] / [serum creatinine
        (mg/dL) x 72]

          -  Participants must have a life expectancy of >= 6 months

          -  Male participants and their partners who are sexually active and of childbearing
             potential must agree to the use of two highly effective forms of contraception in
             combination, throughout the period of taking study treatment and for 7 months after
             the last dose of nivolumab to prevent pregnancy in a partner.

          -  No evidence (within 5 years) of prior malignancies (except successfully treated basal
             cell or squamous cell carcinoma of the skin)

        Exclusion Criteria:

          -  Metastatic disease or currently active second malignancy

          -  Prior androgen deprivation therapy (ADT) in the past 6 months. Prior ADT in context of
             neoadjuvant/adjuvant primary; prior ADT for biochemical recurrence is allowed, as long
             as no ADT has been administered in past 6 months and testosterone has recovered (>150
             ng/dL)

          -  Prior oral anti-androgen (e.g. bicalutamide, nilutamide, enzalutamide, apalutamide),
             or androgen synthesis inhibitor (e.g. abiraterone, orteronel) within the past 2 weeks
             is not permitted. 5-alpha reductase inhibitor therapy (e.g. finasteride, dutasteride)
             is allowed, as long as subject has been stable on medication for past 6 months.

          -  Involvement in the planning and/or conduct of the study (applies to both BMS staff
             and/or staff at the study site)

          -  Participation in another clinical study with an investigational product during the
             last 4 weeks/28 days

          -  Patients should be excluded if they have had prior systemic treatment with an
             anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug
             specifically targeting T-cell costimulation or immune checkpoint pathways

          -  Patients should be excluded if they have an active, known or suspected autoimmune
             disease (e.g. inflammatory bowel disease, rheumatoid arthritis, autoimmune hepatitis,
             lupus, celiac disease). Subjects are permitted to enroll if they have vitiligo, type I
             diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring
             hormone replacement, psoriasis not requiring systemic treatment, or conditions not
             expected to recure in the absence of an external trigger.

          -  Patients should be excluded if they have a condition requiring systemic treatment with
             either corticosteroids (>10 mg daily prednisone daily equivalents) or other
             immunosuppressive medications within 14 days of study drug administration. Inhaled or
             topical steroids and adrenal replacement doses >10mg daily prednisone equivalents are
             permitted in the absence of active autoimmune disease

          -  Permitted therapies include topical, ocular, intra-articular, intranasal, and
             inhalational corticosteroids (with minimal systemic absorption). Physiologic
             replacement doses of systemic corticosteroids are permitted, even if > 10 mg/day
             prednisone equivalents. A brief course of corticosteroids for prophylaxis (e.g.
             contrast dye allergy) or for treatment of nonautoimmune conditions (e.g. delayed-type
             hypersensitivity reaction caused by contact allergen) is permitted.

          -  As there is potential for hepatic toxicity with nivolumab, drugs with a predisposition
             to hepatotoxicity should be used with caution in patients treated with
             nivolumab-containing regimen.

          -  Patients should be excluded if they have a positive test for hepatitis B virus surface
             antigen (HBVsAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute
             or chronic infection

          -  Patients should be excluded if they have known history of testing positive for human
             immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).

          -  History of allergy to study drug components

          -  History of severe hypersensitivity reaction to any monoclonal antibody

          -  Any other serious illness or medical condition that would, in the opinion of the
             investigator, make this protocol unreasonably hazardous, including but not limited to:

               -  Any uncontrolled major infection

               -  Cardiac failure NYHA (New York Heart Association) III or IV

               -  Crohn's disease or ulcerative colitis

               -  Bone marrow dysplasia

               -  Known allergy to any of the compounds under investigation

               -  Unmanageable fecal incontinence

          -  Poor medical risk due to a serious, uncontrolled medical disorder, non-malignant
             systemic disease or active, uncontrolled infection. Examples include, but are not
             limited to, uncontrolled ventricular arrhythmia, recent (within 6 months) myocardial
             infarction, uncontrolled major seizure disorder, extensive interstitial bilateral lung
             disease, or any psychiatric disorder that prohibits obtaining informed consent.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Male
Healthy Volunteers:No

Primary Outcome Measures

Measure:Percentage of participants with PSA50 response
Time Frame:up to 6 months post-intervention
Safety Issue:
Description:Percentage of participants who have received at least 1 dose of Nivolumab who experience a confirmed >=50% decline in prostate specific antigen (PSA) from baseline, as defined by Prostate Cancer Working Group 3 (PCWG3) criteria.

Secondary Outcome Measures

Measure:PSA progression-free survival (PSA-PFS)
Time Frame:up to 6 months post-intervention
Safety Issue:
Description:Median time from initiation of therapy until confirmed PSA increase of 25% (PCWG3). Estimated using Kaplan-Meier method.
Measure:Number of participants who achieve undetectable PSA
Time Frame:up to 6 months post-intervention
Safety Issue:
Description:Number of participants who achieve PSA < 0.1 ng/mL lasting at least 12 weeks.
Measure:Metastasis-free survival
Time Frame:up to 6 months post-intervention
Safety Issue:
Description:Median time from first dose of nivolumab until the development of radiographic metastatic disease on CT imaging and/or bone scan, as defined by PCWG3
Measure:Time to initiation of next systemic therapy
Time Frame:up to 6 months post-intervention
Safety Issue:
Description:Median time from first dose of nivolumab until next systemic therapy
Measure:Safety and tolerability of Nivolumab in biochemically recurrent prostate cancer
Time Frame:up to 100 days post-intervention
Safety Issue:
Description:Number of participants experiencing adverse events Grade 3 or higher as defined by CTCAE v5.0

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Trial Keywords

  • Prostate cancer
  • MMR-deficient prostate cancer
  • Biochemically recurrent prostate cancer
  • non-castrating therapy
  • Nivolumab

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