Clinical Trials /

Carboplatin or Olaparib for BRcA Deficient Prostate Cancer

NCT04038502

Description:

This is an unblinded, randomized clinical study comparing the efficacy of DNA damaging chemotherapy using carboplatin, to standard of care therapy for patients who have metastatic castrate resistant prostate cancer. This trial will use olaparib or carboplatin as initial therapy with crossover to the alternate or second-line drug after first progression for patients with tumors containing BRCA1, BRCA2 or PALB2 inactivating DNA mutations. Participants are randomized (1:1) and receive either carboplatin (AUC 5, IV) every 21 days, first or olaparib taken orally (300 mg), twice daily in 28 day cycles, until intolerance, complete response, or progression by Prostate Cancer Working Group 3 (PCWG3) criteria. Participants then crossover from the first-line therapy to the second-line therapy with the opposite study medication and receive treatment to intolerance or progression (whichever is first). Enrolled participants will be allowed to crossover to second line therapy if they continue to meet initial eligibility criteria, and at least three weeks have elapsed since last administration of either carboplatin or olaparib. Throughout the study, safety and tolerability will be assessed. Progression will be evaluated with bone scan, CT of the abdomen/pelvis, or MRI and PSA as per PCWG3 criteria.

Related Conditions:
  • Prostate Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Carboplatin or Olaparib for BRcA Deficient Prostate Cancer
  • Official Title: An Open-label, Multicenter Phase II Study to Compare the Efficacy of Carboplatin as First-line Followed by Second-line Olaparib Versus Olaparib as First-line Followed by Second-line Carboplatin in the Treatment of Patients With Castration Resistant Prostate Cancer Containing Homologous Recombination Deficiency

Clinical Trial IDs

  • ORG STUDY ID: ONCA-009-18F
  • SECONDARY ID: CX-18-006
  • SECONDARY ID: 19-08
  • SECONDARY ID: 01783
  • SECONDARY ID: 01781
  • SECONDARY ID: CX001963-01
  • NCT ID: NCT04038502

Conditions

  • Metastatic Castrate Resistant Prostate Cancer
  • BRCA1, BRCA2, PALB2 Genetic Mutations

Interventions

DrugSynonymsArms
CarboplatinParaplatinTreatment Arm 1 - Carboplatin to Olaparib
OlaparibLynparzaTreatment Arm 1 - Carboplatin to Olaparib

Purpose

This is an unblinded, randomized clinical study comparing the efficacy of DNA damaging chemotherapy using carboplatin, to standard of care therapy for patients who have metastatic castrate resistant prostate cancer. This trial will use olaparib or carboplatin as initial therapy with crossover to the alternate or second-line drug after first progression for patients with tumors containing BRCA1, BRCA2 or PALB2 inactivating DNA mutations. Participants are randomized (1:1) and receive either carboplatin (AUC 5, IV) every 21 days, first or olaparib taken orally (300 mg), twice daily in 28 day cycles, until intolerance, complete response, or progression by Prostate Cancer Working Group 3 (PCWG3) criteria. Participants then crossover from the first-line therapy to the second-line therapy with the opposite study medication and receive treatment to intolerance or progression (whichever is first). Enrolled participants will be allowed to crossover to second line therapy if they continue to meet initial eligibility criteria, and at least three weeks have elapsed since last administration of either carboplatin or olaparib. Throughout the study, safety and tolerability will be assessed. Progression will be evaluated with bone scan, CT of the abdomen/pelvis, or MRI and PSA as per PCWG3 criteria.

Detailed Description

      Study General Trial Over-view

      This study is designed to help better understand treatment options compared to standard
      therapies for patients who have targeted BRCA1, BRCA1 and/or PALB2 genetic mutations and
      metastatic castrate resistant prostate cancer (mCRPC).

      Cancer therapies are aimed at finding a way to kill the cancer cells while causing minimal
      damage to normal (non-cancer) cells. This often works because cancers cells grow faster than
      many normal cells, many treatments are aimed at to take advantage of that difference. One of
      the ways to do this is to damage the DNA of these more rapidly growing cells. However, if the
      cells have a way of repairing that damage then therapies may not work as well. Some research
      shows that when specific changes or mutations occur in the genes involved with repairing DNA
      damage, resulting cancers have responded well to drugs which damage DNA.

      Olaparib is known as a PARP inhibitor and is standard of care therapy for men with BRCA
      altered mCRPC. Carboplatin is a synthetic antineoplastic agent which has been used in the
      treatment of solid tumors and BRCA related cancers. When mutations occur in critical
      DNA-repair genes, research has found that treatment with carboplatin is also effective.

      This research is being done to determine the response of mCRPC in patients with DNA repair
      mutations to treatment with olaparib compared to carboplatin. This study will test whether
      giving one drug or the other a has a better response.

      Patients wishing to participate in this study are screened for safety and health eligibility
      before enrolling.

      This study is enrolling 100 male participants total, from across the VAMC nationally who have
      the following:

        -  Metastatic castration-resistant prostate cancer (mCRPC)

        -  Cancer that has gotten worse, after any number of first-line treatments

        -  Mutations in DNA-repair genes discovered as part of a patient's routine care.

      Once eligibility is determined, enrolled participants are randomized into one of two groups:

        -  Group A will start with carboplatin (IV) first, given every 21 days, then have the
           option to switch to the second treatment with olaparib taken daily, (orally) with cycles
           of every 28 days.

        -  Group B will start with olaparib first, taken (orally), with 28 day cycles, then have
           the option to switch to the second treatment with carboplatin (IV) every 21 days.

      Both study drugs in this trial are currently FDA approved, and are prescribed at the
      participating VAMC clinical sites per institutional guidelines. Carboplatin given in IV is
      also given as prescribed at the participating VAMC, and administered per institutional
      guidelines.

      Participants are monitored for health and body function, cancer progression, toxicity and
      life quality at every visit during the trial and at an end of treatment visit (28 days after
      completion of the trial or after withdrawal). For participants who respond well to treatment
      during the trial, additional treatment cycles may be added and the study can be extended.
      Participants who experience intolerable toxicity, cancer progression, or whose doctors decide
      to change treatment, will either be switched to the opposite study drug or withdrawn from the
      study.

      This important trial is designed to compare response rate and duration of response using
      carboplatin compared to olaparib in patients who have mCRPC which contains DNA repair gene
      mutations.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment Arm 1 - Carboplatin to OlaparibActive ComparatorParticipants are administered carboplatin AUC 5 IV first, which is administered Cycle-1, Day-1, and then every 21 days as first line therapy. For second line (crossover), olaparib is prescribed and taken orally at home, twice daily, 300 mg in 28 day cycles.
  • Carboplatin
  • Olaparib
Treatment Arm 2 - Olaparib to CarboplatinActive ComparatorParticipants are prescribed olaparib which is taken orally at home, twice daily, 300 mg in 28 day cycles, as first line therapy. For second line (crossover), carboplatin is administered AUC 5 IV every 21 days thereafter.
  • Carboplatin
  • Olaparib

Eligibility Criteria

        Inclusion Criteria:

          -  Signed study informed consent form (ICF)

          -  Male age > 18 years

          -  Diagnosis of prostate cancer (pure small-cell histology or pure high-grade
             neuroendocrine histology are excluded; neuroendocrine differentiation is allowed)

          -  Ongoing gonadal androgen deprivation therapy with gonadotropin-releasing hormone
             (GnRH) analogues, antagonists or orchiectomy. Patients who have not had an orchiectomy
             must be maintained on effective GnRH analogue/antagonist therapy

          -  mCRPC as defined by serum testosterone < 50 ng/ml (for patients on GnRH analogues or
             antagonists) and one of the following:

               -  PSA level of at least 2 ng/ml that has risen on at least 2 successive occasions
                  at least 1 week apart

               -  Evaluable disease progression by modified RECIST 1.1 (Response Evaluation
                  Criteria in Solid Tumors)

               -  Progression of metastatic bone disease on bone scan, CT or MRI with > 2 new
                  lesions

          -  Prior therapy with abiraterone acetate, enzalutamide, apalutamide or darolutamide

          -  Eastern Cooperative Oncology Group (ECOG) Performance Status of < 2 (See Appendix 3,
             ECOG Grading Scale)

          -  Results of previous standard DNA testing, or previous research testing, which confirms
             BRCA1, BRCA2, or PALB2 mutations from primary, metastatic tumor or circulating tumor
             DNA, or pathogenic/likely pathogenic germline variant as assessed by a CLIA certified
             laboratory level assay for DNA sequencing.

        Exclusion Criteria:

          -  Currently receiving active therapy for other neoplastic disorder(s)

          -  Concurrent enrollment in another clinical investigational drug or device study

          -  Morphologic evidence of neuroendocrine or small cell carcinoma of the prostate

          -  Prior treatment with platinum or docetaxel chemotherapy for CRPC

          -  Parenchymal brain metastasis

          -  Active or symptomatic viral hepatitis or chronic liver disease

          -  Clinically significant heart disease as evidenced by myocardial infarction, or
             arterial thrombotic events in the past 6 months, severe or unstable angina, or New
             York Heart Association (NYHA) Class II-IV heart disease or cardiac ejection fraction
             measurement of < 35 % at baseline

          -  Treatment with an investigational therapeutic within 30 days of Cycle-1

          -  Presence of dementia, psychiatric illness, and/or social situations limiting
             compliance with study requirements or understanding and/or giving of informed consent

          -  Any condition(s), medical or otherwise, which, in the opinion of the Investigators,
             would jeopardize either the patient or the integrity of the data obtained
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Male
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression-free survival (PFS-1L) defined as the time interval between randomization and first documented disease progression or death due to any cause reported during, or after, first-line treatment.
Time Frame:Through duration of the study, up to six years
Safety Issue:
Description:Progression free survival (PFS) by bone scan or measurable disease, Response Evaluation Criteria in Solid Tumors (RECIST 1.1) to initial therapy (PFS-1L) with either study drug.

Secondary Outcome Measures

Measure:time interval between randomization and second documented disease progression during or after second-line or death (due to any cause)
Time Frame:Through duration of the study, up to six years
Safety Issue:
Description:Progression-free survival combined, a composite endpoint defined as the time interval between randomization and second documented disease progression reported during or after second-line or death due to any cause
Measure:PSA measurements/response
Time Frame:Through duration of the study, up to six years
Safety Issue:
Description:To assess PSA response to initial therapy with carboplatin vs. olaparib
Measure:PSA measurements/response
Time Frame:Through duration of the study, up to six years
Safety Issue:
Description:To assess PSA response duration to second line therapy with olaparib vs carboplatin
Measure:Grade 3 and 4 toxicities in first and second-line setting
Time Frame:Through duration of the study, up to six years
Safety Issue:
Description:To assess Grade 3 and 4 toxicities for each regimen in the first- and second-line setting

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:VA Office of Research and Development

Trial Keywords

  • metastatic prostate cancer

Last Updated

November 6, 2020