Clinical Trials /

Pembrolizumab in Metastatic Castration Resistant Prostate Cancer (mCRPC) With or Without DNA Damage Repair Defects

NCT03248570

Description:

This is a multicenter phase 2 open label study of pembrolizumab in patients with metastatic castrate resistant prostate cancer (mCRPC) with or without DNA damage repair defects.

Related Conditions:
  • Prostate Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Pembrolizumab in Metastatic Castration Resistant Prostate Cancer (mCRPC) With or Without DNA Damage Repair Defects
  • Official Title: Phase 2 Open Label Study of Pembrolizumab in Patients With Metastatic Castration Resistant Prostate Cancer (mCRPC) With or Without DNA Damage Repair Defects

Clinical Trial IDs

  • ORG STUDY ID: CC 16557
  • NCT ID: NCT03248570

Conditions

  • Castration Resistant Prostatic Cancer
  • Metastatic Prostate Cancer

Interventions

DrugSynonymsArms
PembrolizumabKEYTRUDA, MK-3475DNA damage repair proficient group
ChemotherapyDNA damage repair proficient group

Purpose

This is a multicenter phase 2 open label study of pembrolizumab in patients with metastatic castrate resistant prostate cancer (mCRPC) with or without DNA damage repair defects.

Detailed Description

      This is a multicenter phase 2 open label study of pembrolizumab in patients with metastatic
      castrate resistant prostate cancer (mCRPC) with or without DNA damage repair defects.

      All subjects will receive pembrolizumab 200mg intravenously (IV) every 3 weeks until disease
      progression or unacceptable toxicity. The primary endpoint of the study is objective response
      rate (ORR) according to immune-mediated response criteria (irRC).
    

Trial Arms

NameTypeDescriptionInterventions
DNA damage repair proficient groupExperimentalTwenty-five subjects with mismatch repair (MMR) intact
  • Pembrolizumab
  • Chemotherapy
DNA damage repair defective groupExperimentalTwenty-five subjects with defective DNA repair
  • Pembrolizumab
  • Chemotherapy

Eligibility Criteria

        Inclusion Criteria:

          1. Histologically documented adenocarcinoma of the prostate.

          2. Metastatic castration resistant prostate cancer with castrate-level testosterone (<50
             ng/dL).

             a. Subjects must maintain a castrate-level testosterone during the study.

          3. Disease progression defined by one or more of the following three criteria:

               1. PSA > 2.0 ng/mL and rising PSA by at least 2 consecutive measurements a minimum
                  of 1-week apart.

               2. Soft tissue progression as defined by RECIST v1.1 criteria

               3. Bone disease progression as defined by Prostate Cancer Clinical Trials Working
                  Group 3 (PCWG3)

          4. Have measurable disease based on RECIST v.1.1 and irRC for response assessment.

             a. Must have at least one lesion that is 10mm in longest diameter for a soft tissue
             lesion or 15mm in short axis for a lymph node.

          5. Have received prior abiraterone and/or enzalutamide.

          6. Be willing and able to provide written informed consent/assent for the trial.

          7. Be ≥ 18 years of age on day of signing informed consent.

          8. Be willing to provide archival tissue from prior biopsy or surgery for prostate
             cancer, if available.

          9. Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG)
             Performance Scale.

         10. Patients must discontinue antiandrogen therapy (i.e. bicalutamide, flutamide,
             nilutamide) at least 4-6 weeks prior to registration with no evidence of PSA decline
             after washout.

               1. Bicalutamide: Washout period at least 6 weeks

               2. Flutamide and nilutamide: Washout period at least 4 weeks

         11. Patients must discontinue therapies for mCRPC, with the exception of
             Gonadotropin-releasing hormone (GnRH) agent, for 5 half-lives or 28 days, whichever is
             shorter.

               1. For patients on abiraterone/prednisone, prednisone should be discontinued for at
                  least 7 days before starting study treatment.

               2. Prior chemotherapy is allowed if no progression of disease on chemotherapy.

               3. Prior treatment with sipuleucel-T, radium-223, or poly adenosine diphosphate
                  (ADP) ribose polymerase (PARP) inhibitor (e.g. olaparib) is allowed.

               4. Tissue biopsy may be performed during washout period.

         12. Demonstrate adequate organ function as defined as follows, all screening labs should
             be performed within 10 days of treatment initiation.

             a. Hematological

             i. Absolute neutrophil count (ANC): ≥ 1,500 /microliters (mcL)

             ii. Platelets: ≥ 100,000 / mcL

             iii. Hemoglobin: ≥ 9 g/dL or ≥ 5.6 mmol/L without transfusion or erythropoietin (EPO)
             dependency (within 7 days of assessment)

             b. Renal

             i. Serum creatinine OR Measured or calculated a creatinine clearance (GFR can also be
             used in place of creatinine or CrCl): ≤ 1.5 X upper limit of normal (ULN) OR ≥ 60
             mL/min for subject with creatinine levels > 1.5 X institutional ULN

             c. Hepatic

             i. Serum total bilirubin: ≤ 1.5 X ULN

             ii. Aspartate Aminotransferase (AST) (SGOT) and Alanine Aminotransferase (ALT) (SGPT):
             ≤ 2.5 X ULN OR ≤ 5 X ULN for subjects with liver metastases

             iii. Albumin: > 2.5 mg/dL

             d. Coagulation

             i. International Normalized Ratio (INR) or Prothrombin Time (PT): ≤ 1.5 X ULN unless
             subject is receiving anticoagulant therapy as long as PT or Partial Thromboplastin
             Time (PTT) is within therapeutic range of intended use of anticoagulants

             ii. Activated Partial Thromboplastin Time (aPTT): ≤ 1.5 X ULN unless subject is
             receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of
             intended use of anticoagulants

         13. Male subjects of childbearing potential must agree to use an adequate method of
             contraception, starting with the first dose of study therapy through 120 days after
             the last dose of study therapy.

        Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception
        for the subject.

        Exclusion Criteria:

          1. Significant liver metastasis or disease-related bone pain requiring scheduled
             narcotics.

          2. Prior taxane-based chemotherapy with progressive disease on chemotherapy.

               1. Prior docetaxel for metastatic hormone sensitive prostate cancer is allowed, if
                  no progression of disease on docetaxel as defined by RECIST v1.1 and PCWG3.

               2. Prior taxane-based chemotherapy (i.e. docetaxel or cabazitaxel with or without
                  platinum agent) for mCRPC is allowed if no progression of disease on chemotherapy
                  as defined by RECIST v1.1 and PCWG3.

          3. Is currently participating and receiving study therapy or has participated in a study
             of an investigational agent and received study therapy or used an investigational
             device within 4 weeks of the first dose of treatment.

          4. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy >10mg/day
             or any other form of immunosuppressive therapy within 7 days prior to the first dose
             of trial treatment.

          5. Has a known history of active Bacillus Tuberculosis (TB).

          6. Hypersensitivity to pembrolizumab or any of its excipients.

          7. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study
             Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events
             due to agents administered more than 4 weeks earlier.

          8. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy
             within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at
             baseline) from adverse events due to a previously administered agent.

               1. Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and
                  may qualify for the study.

               2. Note: If subject received major surgery, they must have recovered adequately from
                  the toxicity and/or complications from the intervention prior to starting
                  therapy.

          9. Has a known additional malignancy that is progressing or requires active treatment.
             Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the
             skin that has undergone potentially curative therapy or in situ cervical cancer.

         10. Has known active central nervous system (CNS) metastases and/or carcinomatous
             meningitis. Subjects with previously treated brain metastases may participate provided
             they are stable (without evidence of progression by imaging for at least four weeks
             prior to the first dose of trial treatment and any neurologic symptoms have returned
             to baseline), have no evidence of new or enlarging brain metastases, and are not using
             steroids for at least 7 days prior to trial treatment. This exception does not include
             carcinomatous meningitis which is excluded regardless of clinical stability.

         11. Has active autoimmune disease that has required systemic treatment in the past 2 years
             (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive
             drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid
             replacement therapy < 10 mg of prednisone/day for adrenal or pituitary insufficiency,
             etc.) is not considered a form of systemic treatment.

         12. Has known history of, or any evidence of active, non-infectious pneumonitis.

         13. Has an active infection requiring systemic therapy.

         14. Has a history or current evidence of any condition, therapy, or laboratory abnormality
             that might confound the results of the trial, interfere with the subject's
             participation for the full duration of the trial, or is not in the best interest of
             the subject to participate, in the opinion of the treating investigator.

         15. Has known psychiatric or substance abuse disorders that would interfere with
             cooperation with the requirements of the trial.

         16. Is expecting to father children within the projected duration of the trial, starting
             with the pre-screening or screening visit through 120 days after the last dose of
             trial treatment.

         17. Has received prior therapy with an anti-programmed cell death protein 1 (PD-1),
             anti-PD-L1, or anti-PD-L2 agent.

         18. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).

         19. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., hepatitis C
             virus [HCV] RNA [qualitative] is detected).

         20. Has received a live vaccine within 30 days of planned start of study therapy. Note:
             Seasonal influenza vaccines for injection are generally inactivated flu vaccines and
             are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live
             attenuated vaccines, and are not allowed.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Male
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective response rate (ORR)
Time Frame:From baseline until complete response, progression on repeat pembrolizumab, or date of death from any cause, whichever comes first, up to 24 months
Safety Issue:
Description:Objective response rate (ORR) in mCRPC subjects with proficient DNA damage repair (Group 1) and defective DNA damage repair (Group 2), using immune-related response criteria (irRC)

Secondary Outcome Measures

Measure:Immune-related progression-free survival (irPFS)
Time Frame:At 20 weeks and 28 weeks
Safety Issue:
Description:Compare rate of immune-related progression-free survival (irPFS) using irRC and RECIST v.1.1.
Measure:Progression-free survival (PFS)
Time Frame:At 20 weeks and 28 weeks
Safety Issue:
Description:Compare rate of progression-free survival (PFS) using irRC and RECIST v.1.1.
Measure:Proportion of subjects achieving any prostate specific antigen (PSA) response
Time Frame:From baseline until complete response, progression on repeat pembrolizumab, or date of death from any cause, whichever comes first, up to 24 months
Safety Issue:
Description:Compare the proportion of subjects achieving any PSA response from baseline in both study groups
Measure:Proportion of subjects achieving any PSA decline ≥ 50%
Time Frame:From baseline until complete response, progression on repeat pembrolizumab, or date of death from any cause, whichever comes first, up to 24 months
Safety Issue:
Description:Proportion of subjects achieving any PSA decline ≥ 50% from baseline in both study groups
Measure:Safety of pembrolizumab
Time Frame:From baseline until 30 days after end of treatment (at complete response, progression on repeat pembrolizumab, or date of death from any cause, whichever comes first, up to 24 months)
Safety Issue:
Description:The safety of pembrolizumab in both study groups by CTCAE v4.0, summarized by maximum toxicity grade for each study group
Measure:Time to progression after taxane-based chemotherapy
Time Frame:From completion of taxane-based chemotherapy to progression, up to 24 months
Safety Issue:
Description:Time to progression after taxane-based chemotherapy in subjects who initially progress on pembrolizumab, undergo taxane-based chemotherapy, followed by repeat pembrolizumab in both study groups.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:University of California, San Francisco

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