Clinical Trials /

Phase II Study of Olaparib and Pembrolizumab in Advanced Melanoma With Homologous Recombination (HR) Mutation

NCT04633902

Description:

This open-label phase II trial studies how well olaparib in combination with pembrolizumab works in treating patients with advanced, metastatic melanoma with the homologous recombination (HR) pathway gene mutation / alteration. Olaparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth, and potentially augment an anti-tumor immune response to pembrolizumab. The trial is designed to assess the efficacy and safety of olaparib in combination with pembrolizumab in patients with HR mutation/ alteration whose disease progressed on prior immunotherapy and/or BRAF-targeting therapy

Related Conditions:
  • Melanoma
Recruiting Status:

Recruiting

Phase:

Phase 2

URL:

https://clinicaltrials.gov/show/NCT04633902

Trial Eligibility

Document

Title

  • Brief Title: Phase II Study of Olaparib and Pembrolizumab in Advanced Melanoma With Homologous Recombination (HR) Mutation
  • Official Title: Phase II Study of Olaparib in Combination With Pembrolizumab in Patients With Advanced Melanoma With Homologous Recombination (HR) Pathway Gene Mutation

Clinical Trial IDs

  • ORG STUDY ID: CPMC19-MEL01
  • NCT ID: NCT04633902

Conditions

  • Metastatic Melanoma

Interventions

DrugSynonymsArms
OlaparibLynparzaOlaparib + Pembrolizumab
PembrolizumabKeytrudaOlaparib + Pembrolizumab

Purpose

This open-label phase II trial studies how well olaparib in combination with pembrolizumab works in treating patients with advanced, metastatic melanoma with the homologous recombination (HR) pathway gene mutation / alteration. Olaparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth, and potentially augment an anti-tumor immune response to pembrolizumab. The trial is designed to assess the efficacy and safety of olaparib in combination with pembrolizumab in patients with HR mutation/ alteration whose disease progressed on prior immunotherapy and/or BRAF-targeting therapy

Detailed Description

      Treatment with PARP inhibitors could represent a novel opportunity to selectively kill a
      subset of cancer cells with deficiencies in DNA repair pathways. For example, a tumor arising
      in a patient with a germline BRCA mutation (gBRCAmut) has a defective homologous
      recombination DNA repair pathway and would be increasingly dependent on NHEJ, alt-NHEJ, and
      BER for maintenance of genomic integrity. PARP inhibitors block alt-NHEJ and BER, forcing
      tumors with BRCA deficiencies to use the error-prone NHEJ to fix double-strand breaks.
      Non-BRCA deficiencies in homologous recombination DNA repair genes could also enhance tumor
      cell sensitivity to PARP inhibitors. The rationale for anticancer activity in a subset of
      non-gBRCAmut tumors is that they share distinctive DNA repair defects with gBRCAmut carriers,
      a phenomenon broadly described as "BRCAness." DNA repair defects can be caused by germline or
      somatic alterations to the homologous recombination DNA repair pathway. Homologous
      recombination is a complex pathway, and several genes other than BRCA1 and BRCA2 are required
      either to sense or repair DNA double-strand breaks via the homologous recombination pathway.
      Therefore, PARP inhibitors are also selectively cytotoxic for cancer cells with deficiencies
      in DNA repair proteins other than BRCA1 and BRCA2.

      In melanoma, genetic HR mutation/ alterations are rather common. Retrospective data showed
      that nearly 20-30% of cutaneous melanoma harbors a mutation in at least 1 of the HR genes in
      their tumor. The commonly altered genes were ARID1A, FANCA, ATM, BRCA1, ATRX and BRCA2, ATR,
      BRCA1 and BRIP1. These findings indicate that HR mutations / alterations are frequently
      observed in metastatic melanoma, and they suggest that PARP inhibitors could potentially be
      of a great clinical value in a substantial portion of the patients with advanced melanoma. In
      addition, the retrospective data also showed that presence of HR mutation was associated with
      high TMB and clinical response to checkpoint immunotherapy. Therefore, the investigators
      propose a phase II study of niraparib in patients with advanced melanoma with genetic
      homologous recombination mutation/ alteration.

      In this clinical study, clinical efficacy of olaparib in combination with pembrolizumab will
      be evaluated by assessing an objective clinical response rate in patients with advanced,
      metastatic melanoma with the homologous recombination (HR) pathway gene mutation /
      alteration. All participating patients will receive olaparib 300 mg a day and pembrolizumab
      200 mg every 3 weeks (for up to 2 years) until disease progresses or they experience
      intolerable toxicity.

Trial Arms

NameTypeDescriptionInterventions
Olaparib + PembrolizumabExperimentalThis arm will enroll patients who has advanced melanoma with a genetic HR mutation/ alteration including mutation/ deletion in ARID1A/B, ARID2, ATM, ATR, BARD1, BRCA1/2, BAP1, BRIP1, CHEK2, FANCA, FANCD2, MRN11A, PALB2, RAD50, RAD51, RAD54B.
  • Olaparib
  • Pembrolizumab

Eligibility Criteria

        Inclusion Criteria:

          -  Histologically confirmed diagnosis of unresectable or metastatic stage III or IV
             melanoma

          -  Must have genetic HR mutation/ alteration including ARID1A/B, ARID2, ATM, ATR, BARD1,
             BRCA1/2, BAP1, BRIP1, CHEK2, FANCA, FANCD2, MRN11A, PALB2, RAD50, RAD51, RAD54B

          -  Disease must be refractory or resistant to anti PD-1 therapy (defined as disease
             progression within 6 months after the last dose of anti PD-1 antibody therapy) and,
             for V600 BRAF mutation, disease must be progressed after BRAF inhibitor therapy; or
             patients could not have tolerated the standard therapies.

          -  Must have measurable disease based on RECIST 1.1.

          -  Must have an ECOG performance status of 0 to 1.

          -  Prior systemic cytotoxic therapy up to 1 regimens is allowed; There is no limit on the
             number of prior immunotherapy or targeted therapy regimens.

          -  Must have recovered from all AEs due to previous therapies to ≤Grade 1 or baseline.

        Exclusion Criteria:

          -  Previously treated with a PARP inhibitor

          -  Has received prior radiotherapy within 2 weeks of start of study treatment. A 1-week
             washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS
             disease.

          -  Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy
             (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of
             immunosuppressive therapy within 7 days prior to the first dose of study drug.

          -  Has a known additional malignancy that is progressing or has required active treatment
             within the past 2 years

          -  Previous solid organ or allogenic bone marrow transplant or double umbilical cord
             blood transplantation (dUCBT) for solid tumors.

          -  Has known active CNS metastases and/or carcinomatous meningitis. Participants with
             previously treated brain metastases may participate provided they are radiologically
             stable, i.e. without evidence of progression for at least 4 weeks by repeat imaging
             (note that the repeat imaging should be performed during study screening), clinically
             stable and without requirement of steroid treatment for at least 14 days prior to
             first dose of study treatment.

          -  Has active autoimmune disease that has required systemic treatment in the past 2 years

          -  Has a history of (non-infectious) pneumonitis due to a single agent PD-1 / PD-L1
             antibody therapy that required steroids or has current pneumonitis.
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective Response Rate (ORR)
Time Frame:6 months
Safety Issue:
Description:ORR of olaparib in combination with pembrolizumab in patients with advanced melanoma with genetic homologous recombination (HR) mutation/ alteration using RECIST v1.1

Secondary Outcome Measures

Measure:Progression-free survival (PFS)
Time Frame:2 years
Safety Issue:
Description:PFS of patients with advanced melanoma with genetic HR mutation/ alteration who are treated with olaparib in combination with pembrolizumab
Measure:Overall survival (OS)
Time Frame:2 years
Safety Issue:
Description:OS of patients with advanced melanoma with genetic HR mutation/ alteration who are treated with olaparib in combination with pembrolizumab
Measure:Number of Participants With Adverse Events as a Measure of Safety and Tolerability
Time Frame:2 years
Safety Issue:
Description:Evaluation of the safety profile of olaparib in combination with pembrolizumab in patients with advanced melanoma with genetic homologous recombination (HR) mutation/ alteration

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:California Pacific Medical Center Research Institute

Trial Keywords

  • Homologous recombination (HR)
  • Mutation
  • Olaparib
  • Pembrolizumab
  • PARP inhibitor
  • anti PD-1 antibody

Last Updated

May 3, 2021