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

  • Clinicaltrials.gov identifier

    NCT03925350

  • Recruitment Status

    Recruiting

  • First Posted

    April 24, 2019

  • Last update posted

    May 18, 2020

Study Description

Brief summary:

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.

  • Condition or Disease:Metastatic Melanoma
  • Intervention/Treatment: Drug: Niraparib
  • Phase: 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 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.

Study Design

  • Study Type: Interventional
  • Estimated Enrollment: 41 participants
  • Intervention Model: Single Group Assignment
  • Masking: None (Open Label) ()
  • Primary Purpose: Treatment
  • Official Title: A Phase II Study of Niraparib in Patients With Advanced Melanoma With Genetic Homologous Recombination (HR) Mutation / Alteration
  • Actual Study Start Date: March 2019
  • Estimated Primary Completion Date: February 2021
  • Estimated Study Completion Date: February 2023

Arms and interventions

Arm Intervention/treatment
Experimental: Niraparib
Patients receive niraparib PO daily
Drug: Niraparib
300 mg PO daily

Outcome Measures

  • Primary Outcome Measures: 1. Objective Response Rate (ORR) [ Time Frame: 6 months ]
    ORR of niraparib 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 niraparib
  • 2. overall survival (OS) [ Time Frame: 2 years ]
    OS of patients with advanced melanoma with genetic HR mutation/ alteration who are treated with niraparib
  • 3. Number of Participants With Adverse Events as a Measure of Safety and Tolerability [ Time Frame: 2 years ]
    Evaluation of the safety profile of niraparib treatment in patients with advanced melanoma with genetic homologous recombination (HR) mutation/ alteration

Eligibility Criteria

  • Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
  • Sexes Eligible for Study: All
  • Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

- Have genetic homologous recombination (HR) mutation/ alteration including ARID1A/B,
ARID2, ATM, ATR, ATRX, BARD1, BRCA1/2, BAP1, BRIP1, CHEK2, FANCD2, MRN11A, PALB2,
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)

Contacts and Locations

Contacts

Contact: Laurel Brechtel 415-600-1654 BrechtLA@sutterhealth.org

Locations

United States, California
California Pacific Medical Center Research Institute
San Francisco

Sponsors and Collaborators

California Pacific Medical Center Research Institute

Tesaro, Inc.

Vanderbilt-Ingram Cancer Center, Nashville, TN

University of Utah Huntsman Cancer Institute, Salt Lake City, UT

Investigators

Principal Investigator: Kevin Kim, MD California Pacific Medical Center

More Information

  • Responsible Party: California Pacific Medical Center Research Institute
  • ClinicalTrials.gov Identifier: NCT03925350 History of Changes
  • Other Study ID Numbers: CPMC17-MEL01
  • First Posted: April 24, 2019 Key Record Dates
  • Last Update Posted: May 18, 2020
  • Last Verified: May 2020
  • Individual Participant
    Data (IPD) Sharing
    Statement:

  • Plan to Share IPD: Undecided
  • Studies a U.S. FDA-regulated Drug Product: Yes
  • Studies a U.S. FDA-regulated Device Product: No
  • Keywords provided by California Pacific Medical Center Research Institute: Mutation
    Homologous recombination (HR)
    Niraparib
    PARP inhibitor
  • Additional relevant MeSH terms: Melanoma