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

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ClinicalTrials.gov Identifier: NCT04633902
Recruitment Status : Recruiting
First Posted : November 18, 2020
Last Update Posted : May 3, 2021
Sponsor:
Information provided by (Responsible Party):
California Pacific Medical Center Research Institute

Study Description
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Brief Summary:
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

Condition or disease Intervention/treatment Phase
Metastatic Melanoma Drug: Olaparib Drug: Pembrolizumab Phase 2

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.

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 41 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase II Study of Olaparib in Combination With Pembrolizumab in Patients With Advanced Melanoma With Homologous Recombination (HR) Pathway Gene Mutation
Actual Study Start Date : March 3, 2021
Estimated Primary Completion Date : June 30, 2023
Estimated Study Completion Date : December 31, 2024

Resource links provided by the National Library of Medicine

MedlinePlus Genetics related topics: Melanoma
MedlinePlus related topics: Melanoma

Arms and Interventions
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Arm Intervention/treatment
Experimental: Olaparib + Pembrolizumab
This 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.
 Drug: Olaparib
Olaparib 300 mg BID daily
Other Name: Lynparza

Drug: Pembrolizumab
Pembrolizumab 200 mg IV eveyr 3 weeks (for up to 2 years)
Other Name: Keytruda


Outcome Measures
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Primary Outcome Measures :
  1. Objective Response Rate (ORR) [ Time Frame: 6 months ]
    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 :
  1. Progression-free survival (PFS) [ Time Frame: 2 years ]
    PFS of patients with advanced melanoma with genetic HR mutation/ alteration who are treated with olaparib in combination with pembrolizumab

  2. Overall survival (OS) [ Time Frame: 2 years ]
    OS of patients with advanced melanoma with genetic HR mutation/ alteration who are treated with olaparib in combination with pembrolizumab

  3. Number of Participants With Adverse Events as a Measure of Safety and Tolerability [ Time Frame: 2 years ]
    Evaluation of the safety profile of olaparib in combination with pembrolizumab in patients with advanced melanoma with genetic homologous recombination (HR) mutation/ alteration


Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04633902


Contacts
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Contact: Kevin B Kim, MD 415-885-8600 ClinicalResearch@sutterhealth.org

Locations
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United States, California
California Pacific Medical Center Research Institute Recruiting
San Francisco, California, United States, 94115
Sponsors and Collaborators
California Pacific Medical Center Research Institute
Investigators
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Principal Investigator: Kevin B Kim, MD California Pacific Medical Center Research Institute
More Information
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Responsible Party: California Pacific Medical Center Research Institute
ClinicalTrials.gov Identifier: NCT04633902    
Other Study ID Numbers: CPMC19-MEL01
First Posted: November 18, 2020    Key Record Dates
Last Update Posted: May 3, 2021
Last Verified: January 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Keywords provided by California Pacific Medical Center Research Institute:
Homologous recombination (HR)
Mutation
Olaparib
 Pembrolizumab
PARP inhibitor
anti PD-1 antibody
Additional relevant MeSH terms:
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Melanoma
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Nevi and Melanomas
 Pembrolizumab
Olaparib
Antineoplastic Agents, Immunological
Antineoplastic Agents
Poly(ADP-ribose) Polymerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action