Clinical Trials /

Efficacy and Safety Study of Niraparib in Melanoma With Genetic Homologous Recombination (HR) Mutation

NCT03925350

Description:

This open-label phase II trial studies how well niraparib works in treating patients with advanced, metastatic melanoma with the homologous recombination (HR) pathway gene mutation / alteration. Niraparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. The trial is designed to assess the efficacy and safety of niraparib 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

Trial Eligibility

Document

Title

  • Brief Title: Efficacy and Safety Study of Niraparib in Melanoma With Genetic Homologous Recombination (HR) Mutation
  • Official Title: A Phase II Study of Niraparib in Patients With Advanced Melanoma With Genetic Homologous Recombination (HR) Mutation / Alteration

Clinical Trial IDs

  • ORG STUDY ID: CPMC17-MEL01
  • NCT ID: NCT03925350

Conditions

  • Metastatic Melanoma

Interventions

DrugSynonymsArms
NiraparibNiraparib

Purpose

This open-label phase II trial studies how well niraparib works in treating patients with advanced, metastatic melanoma with the homologous recombination (HR) pathway gene mutation / alteration. Niraparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. The trial is designed to assess the efficacy and safety of niraparib 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 30.5% of cutaneous melanoma harbors a mutation in at least 1 of the HR genes in
      their tumor. The most commonly altered gene was ARID2, followed by ARID1A, FANCA, ATM, BRCA1,
      ATRX and BRCA2, ATR, BRCA1 and BRIP1.

      These findings provide a strong rationale to evaluate the clinical efficacy of a PARP
      inhibitor in patients with advanced cancers with HR mutation/alteration or HR deficiency.
      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 niraparib 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 niraparib 300 mg a day until disease progresses or they experience intolerable
      toxicity.
    

Trial Arms

NameTypeDescriptionInterventions
NiraparibExperimentalPatients receive niraparib PO daily
  • Niraparib

Eligibility Criteria

        Inclusion Criteria:

          -  Have genetic homologous recombination (HR) mutation/ alteration including ARID1A/B,
             ARID2, ATM, ATR, BARD1, BRCA1/2, BAP1, BRIP1, CHEK2, FANCD2, MRN11A, RAD50, RAD51,
             RAD54B

          -  Disease must have progressed on the standard systemic therapies or they could not have
             tolerated the standard therapies.

          -  ECOG PS >/=1

          -  Have measurable metastatic disease according to RECIST 1.1

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

          -  All adverse events associated with prior treatment must have resolved to ≤ Grade 1
             prior to day 1 of the study drug administration.

        Exclusion Criteria:

          -  Previously treated with a PARP inhibitor

          -  Symptomatic brain metastasis or active brain lesions ≥6 mm size or those

          -  Require steroid treatment for brain lesions or leptomeningeal disease

          -  Systemic cancer therapy within 14 days prior to day 1 of the study drug administration

          -  Any major surgery ≤ 3 weeks of starting the study and patient must have recovered from
             any effects of any major surgery

          -  Investigational therapy administered ≤ 4 weeks, or within a time interval less than at
             least 5 half-lives of the investigational

          -  Prior radiotherapy encompassing > 20% of the bone marrow within 2 weeks; or any
             radiation therapy within 1 week prior to Day 1 of protocol therapy

          -  Medical history of immunocompromised condition

          -  Systemic treatment of another type of cancer ≤ 2 years prior to registration

          -  Known history of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML)
      
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 niraparib 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 niraparib
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 niraparib
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 niraparib treatment 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
  • Niraparib
  • PARP inhibitor

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