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A Study of CHeckpoint Inhibitors in Men With prOgressive Metastatic Castrate Resistant Prostate Cancer Characterized by a Mismatch Repair Deficiency or Biallelic CDK12 Inactivation

NCT04104893

Description:

The primary objective is to assess the activity and efficacy of pembrolizumab, a checkpoint inhibitor, in Veterans with metastatic castration-resistant prostate cancer (mCRPC) characterized by either mismatch repair deficiency (dMMR) or biallelic inactivation of CDK12 (CDK12-/-). The secondary objectives involve determining the frequency with which dMMR and CDK12-/- occur in this patient population, as well as the effects of pembrolizumab on various clinical endpoints (time to PSA progression, maximal PSA response, time to initiation of alternative anti-neoplastic therapy, time to radiographic progression, overall survival, and safety and tolerability). Lastly, the study will compare the pre-treatment and at-progression metastatic tumor biopsies to investigate the molecular correlates of resistance and sensitivity to pembrolizumab via RNA-sequencing, exome-sequencing, selected protein analyses, and multiplexed immunofluorescence.

Related Conditions:
  • Prostate Adenocarcinoma
  • Prostate Small Cell Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Single-arm, Open-label, Phase II Study of CHeckpoint Inhibitors in Men With prOgressive Metastatic Castrate Resistant Prostate Cancer Characterized by a Mismatch Repair Deficiency or Biallelic CDK12 Inactivation
  • Official Title: A Phase 2 Study of a Checkpoint Inhibitor in Men With Progressive Metastatic Castrate Resistant Prostate Cancer Characterized by a Mismatch Repair Deficiency or Biallelic CDK12 Inactivation

Clinical Trial IDs

  • ORG STUDY ID: CSDR-003-18F
  • NCT ID: NCT04104893

Conditions

  • Metastatic Castration Resistant Prostate Cancer

Interventions

DrugSynonymsArms
PembrolizumabKeytrudaSingle Arm

Purpose

The primary objective is to assess the activity and efficacy of pembrolizumab, a checkpoint inhibitor, in Veterans with metastatic castration-resistant prostate cancer (mCRPC) characterized by either mismatch repair deficiency (dMMR) or biallelic inactivation of CDK12 (CDK12-/-). The secondary objectives involve determining the frequency with which dMMR and CDK12-/- occur in this patient population, as well as the effects of pembrolizumab on various clinical endpoints (time to PSA progression, maximal PSA response, time to initiation of alternative anti-neoplastic therapy, time to radiographic progression, overall survival, and safety and tolerability). Lastly, the study will compare the pre-treatment and at-progression metastatic tumor biopsies to investigate the molecular correlates of resistance and sensitivity to pembrolizumab via RNA-sequencing, exome-sequencing, selected protein analyses, and multiplexed immunofluorescence.

Detailed Description

      Research Plan:

      This is a single-arm, open-label phase II study that examines the response rate of
      pembrolizumab in metastatic castration-resistant prostate cancer (mCRPC) patients who have
      either a mismatch repair deficiency (dMMR) or a biallelic inactivation of CDK12 (CDK12-/-).
      The study will enroll mCRPC patients who have the selected genetic mutation and at least one
      metastatic lesion that is amendable to biopsy. All patients must have progressed on at least
      one prior line of mCRPC therapy, such as abiraterone acetate or enzalutamide. Eligible
      patients will undergo at least 12 weeks (4 cycles) of pembrolizumab (200 mg IV).

      Methodology:

      Patients with either a mismatch repair deficiency or biallelic inactivation of CDK12 in their
      tumor are eligible for this study. If the patient has progressed on at least one prior
      therapy for mCRPC, including abiraterone acetate or enzalutamide, he is eligible to begin
      genetic screening. Patients with these mutations will be identified primarily through
      standard of care genetic testing with either archival tissue or blood. Specimens will be sent
      to VA approved vendors for genetic testing to determine if the patient has the necessary
      mutations to receive the study drug (pembrolizumab). If eligible, the patient will sign the
      Main Treatment ICF and proceed with the screening procedures. Once enrolled the patient will
      undergo a biopsy of a metastatic lesion (baseline biopsy) to identify molecular correlates.
      If the patient does not have any archival tissue or blood to be used to identify genetic
      mutations, the biopsy of a metastatic lesion will be used to both identify genetic mutations
      and to identify molecular correlates.

      When the patient has met all the eligibility criteria, he will receive pembrolizumab.
      Pembrolizumab will be administered at a starting dose of 200 mg intravenously every 3 weeks
      until disease progression or unacceptable toxicity. During the treatment, patients will
      either simultaneously receive a GnRH analogue or undergo a bilateral orchiectomy prior to
      treatment to maintain a castrate level of testosterone ( 50 ng/dl). At progression, patients
      will undergo a second biopsy of the same metastatic lesion of the baseline biopsy. The
      baseline (pre-treatment) and at-progression biopsies will be used for correlative analyses to
      determine the efficacy of pembrolizumab.

      Note: after the testing process is complete, Oncoplex will return any remaining sample back
      to the Department of Pathology at the West LA VA Medical Center. These specimens will be
      stored in Dr. Matthew Rettig's biorepository on site for analysis and future research.

      Results:

      Since this is a new study, the results have not yet been obtained. The primary endpoint of
      this study is to measure the objective response rate, radiographic progression free survival
      at 6 months, and decline in PSA of 50% or more 12 weeks of therapy.

      Clinical Significance:

      There are 230,000 new incidences of prostate cancer and 30,000 deaths from prostate cancer
      per year in the US. It is the second most common cause of death in American men. Importantly,
      prostate cancer is diagnosed in more than 12,000 US Veterans each year, representing nearly
      one third of all cancer diagnoses in Veterans.

      Metastatic prostate cancer is incurable, and its treatment is palliative. However, many
      Veterans with metastatic castration-resistant prostate cancer (mCRPC) progress despite
      experiencing some clinical benefit from hormonal therapy and chemotherapy. As a result, novel
      therapies that provide a robust clinical benefit and have a good safety profile are needed
      for these patients.

      Immunotherapies, such as checkpoint inhibitor, for mCRPC patients that have either a mismatch
      repair deficiency (dMMR) or a biallelic inactivation of CDK12 (CDK12-/-) is an attractive
      therapy, especially since therapies involving checkpoint inhibitors have exhibited
      significant improvements in patients with advanced melanoma, non-small cell lung cancer,
      renal cell carcinoma, and many other cancers. The results of this study will establish the
      ideal subset of mCRPC patients who will benefit from the study drug. Importantly, the
      correlative studies will provide critical insight into the mechanisms of primary and acquired
      resistance that occur despite selection of patients with CDK12-/- or dMMR. This result can
      inform further selection of patients for checkpoint inhibition, as well as identify other
      potential therapies that can be co-administered with pembrolizumab to prevent or overcome
      resistance to checkpoint inhibitors.
    

Trial Arms

NameTypeDescriptionInterventions
Single ArmExperimentalThis is a single-arm, open-label study of the checkpoint inhibitor, pembrolizumab, in Veterans with mCRPC who have progressed on at least 1 prior novel androgen receptor (AR) signaling inhibitor, inclusive of abiraterone acetate, enzalutamide, apalutamide, and darolutamide. In addition to progressive mCRPC, a patient must have a somatic tumor mutation characterized by dMMR or CDK12-/- detected by next generation sequencing (NGS). Patients enrolled in this study will be treated with pembrolizumab at the FDA approved dosage of 200 mg intravenously every 3 weeks (21 days) until disease progression or unacceptable toxicity. During study, patients will maintain a castrate level of testosterone, = 50 ng/dL by ongoing treatment with a GnRH analogue or prior bilateral orchiectomy. Prior to initiating treatment with pembrolizumab, patients will undergo a baseline biopsy of a metastatic lesion. An additional biopsy of a metastatic lesion at the time of progression will be encouraged as well.
  • Pembrolizumab

Eligibility Criteria

        Inclusion Criteria:

          -  Subject must be 18 years of age or older at the time the Informed Consent is signed.

          -  The subject (or legally acceptable representative if applicable) must provide written
             informed consent for the trial.

          -  Pathologic diagnosis of prostate cancer of adenocarcinoma or small cell histology.

          -  Metastatic disease as documented by technetium-99m (99mTc) bone scan or metastatic
             lesions by computed tomography (CT) or magnetic resonance imaging (MRI) scans
             (visceral or lymph node disease). CT-portion of FDG-PET/CT or scan may be used for
             eligibility. NaF PET-CT is an alternative to 99mTc bone scan. If lymph node metastasis
             is the only evidence of metastatic disease, it must be 1.5 cm in short axis and above
             the level of the iliac bifurcation. Imaging studies for the purpose of determining
             eligibility must be completed within 60 days of Day 1.

          -  Progressive castration resistant prostate cancer as defined by serum testosterone < 50
             ng/mL and one of the following:

          -  -PSA progression confirmed per Prostate Cancer Clinical Trials Working Group (PCWG3),

             -- Radiographic progression of soft tissues according to Response Evaluation Criteria
             in Solid Tumors, version 1.1 (iRECIST 1.1) modified based on PCWG3, or radiographic
             progression of bone according to PCWG3.

          -  Prior use of a novel AR signaling inhibitor for 4 weeks, including abiraterone acetate
             plus prednisone/prednisolone, enzalutamide, apalutamide, and/or darolutamide.

        NOTE: These AR signaling inhibitors may have been used for mCSPC, M0CRPC, and/or mCRPC.

        7. Ongoing surgical or medical castration, with testosterone levels of <50 ng/dL. If the
        subject is being treated with GnRH analogs (subject who has not undergone bilateral
        orchiectomy), this therapy must have been initiated at least 30 weeks prior to initiation
        of pembrolizumab and must be continued throughout the study.

          -  ECOG PS grade of 0-2.

          -  Metastatic lesion that is amenable to biopsy and performed within 180 days of Day 1.

          -  dMMR or CDK12-/- as determined by somatic tumor DNA NGS.

               -  Either monoallelic or biallelic inactivation of CDK12 on NGS is considered
                  sufficient for eligibility purposes.

               -  MMR genes include: MLH1, MSH2, MLH3, PMS1, MSH6, and PMS2.

               -  dMMR is established by MSI-H on NGS. However, for "weak" MMR genes, inclusive of
                  PMS2 and MSH6, monoallelic inactivation will be allowed for eligibility purposes
                  if and only if there is at least MSI-low or hypermutation that is concomitantly
                  present.

               -  If there is biallelic inactivation of "strong" MMR genes (MLH1 and MSH2), then
                  patients must manifest MSI-H. However, if the tumor DNA utilized for MSI analysis
                  was obtained > 6 months prior to NGS, then the NGS should be repeated to
                  determine if MSI-H has developed. Monoallelic inactivation of "strong" MMR genes
                  will be allowed if MSI-H is present; in this scenario, it is presumed that
                  biallelic inactivation is present but the second inactivating event was not
                  detected due to technical issues such as low sensitivity for copy loss.

          -  Adequate organ function:

               -  Hemoglobin (hgb) > 9.0 g/dL,

               -  Absolute neutrophil count (ANC) > 1500/ �L,

               -  Platelets > 100,000/ �L,

               -  Total bilirubin 1.5 �ULN OR direct bilirubin ULN for participants with total
                  bilirubin levels >1.5 � ULN

               -  ALT and AST 2.5 � ULN ( 5 � ULN for participants with liver metastases)
                  (Child-Pugh class A and B allowed; Child-Pugh class C is excluded).

               -  Creatinine < (2.0 mg/dL) during screening evaluation (>2.0 is allowed if EGFR >30
                  mL/min/1.73 m2).

          -  Subject must agree to use contraception during the treatment period plus an additional
             120 days after the last dose of study treatment and must refrain from donating sperm
             during this period.

        Exclusion Criteria:

          -  Brain metastases.

          -  Prior treatment with an anti-PD1, anti-PDL1, or anti PD L2 agent or with an agent
             directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX 40,
             CD137).

          -  Anti-neoplastic therapies for prostate cancer must be completed > 2 weeks prior to Day
             1 (initiation of pembrolizumab); chemotherapy must be completed > 4 weeks prior to Day
             1.

          -  Has received prior systemic anti-cancer therapy including investigational agents
             within 4 weeks [could consider shorter interval for kinase inhibitors or other short
             half-life drugs] prior to [randomization /allocation].

        Note: Participants must have recovered from all AEs due to previous therapies to Grade 1 or
        baseline. Participants with Grade 2 neuropathy may be eligible.

          -  Herbal and non-herbal products that may decrease PSA levels other than medical
             castration and megestrol (up to 40 mg/day is allowed) for hot flashes.

          -  Has received prior radiotherapy within 2 weeks of start of study treatment.
             Participants must have recovered from all radiation-related toxicities, not require
             corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted
             for palliative radiation ( 2 weeks of radiotherapy) to non-CNS disease.

          -  Is currently participating in or has participated in a study of an investigational
             agent or has used an investigational device within 4 weeks prior to the first dose of
             study treatment.

        Note: Participants who have entered the follow-up phase of an investigational study may
        participate as long as it has been 4 weeks after the last dose of the previous
        investigational agent.

          -  If a subject has undergone major surgery, they must have recovered adequately from the
             toxicities or complications from the intervention within 4 weeks prior to starting
             therapy.

          -  History of non-prostate active malignancy requiring treatment in the 24 months prior
             to Day 1 except for non-muscle invasive urothelial cancer and non-melanoma skin
             cancer.

          -  Active infection or conditions requiring treatment with antibiotics.

          -  Immunosuppressive doses of systemic medications, such as corticosteroids (doses > 10
             mg/day prednisone or equivalent), within 2 weeks of Day 1.

          -  Has a history of (non-infectious) pneumonitis that required steroids or has current
             pneumonitis.

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

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

          -  Active autoimmune disease or a documented history of autoimmune disease that requires
             immunosuppressive medications within the last two years (e.g., chronic steroids,
             methotrexate, tacrolimus, etc.).

          -  Active or chronic hepatitis B or hepatitis C disease as determined by hepatitis B
             surface antigen (HBsAg), hepatitis B core antibody, or hepatitis C antibody (anti-HCV)
             positivity at screening. If positive, further testing of quantitative levels to rule
             out active infection is required.

          -  History of positive test for human immunodeficiency virus (HIV). NOTE: Hepatitis B and
             C and HIV testing is NOT required during screening.

          -  Vaccinated with a live vaccine within 30 days of enrollment.

          -  Has severe hypersensitivity ( Grade 3) to pembrolizumab and/or any of its excipients.

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

          -  Subject is planning to conceive or father children within the projected duration of
             the study, starting with the screening visit through 120 days after the last dose of
             trial treatment.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Male
Healthy Volunteers:No

Primary Outcome Measures

Measure:PSA Decline
Time Frame:12 weeks of therapy
Safety Issue:
Description:Decline in PSA of 50% or more (PSA50) 12 weeks of therapy (ng/mL)

Secondary Outcome Measures

Measure:Time to Progression of Disease
Time Frame:Date of enrollment to the date of the last patient in plus one year after
Safety Issue:
Description:Time to PSA progression Time to initiation of alternative anti-neoplastic therapy, Time to radiographic progression
Measure:Overall Survival
Time Frame:From enrollment until death assessed up to 36 months
Safety Issue:
Description:The overall survival rate measured as time from enrollment until death.
Measure:Maximum PSA Response
Time Frame:Date of Enrollement to the date of the last patient in plus one year after
Safety Issue:
Description:Maximal PSA response (ng/mL)
Measure:Safety and Tolerability
Time Frame:Date of first patient in to the date of the last patient in plus one year after
Safety Issue:
Description:See what the safety and tolerability of Pembrolizumab on patients with prostate cancer is by assessing adverse and serious adverse events that each patient experiences.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:VA Office of Research and Development

Trial Keywords

  • Metastatic Prostate Cancer
  • Pembrolizumab
  • Checkpoint Inhibitor
  • Mismatch Repair Deficiency
  • CDK12

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