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

NCT ID: NCT03925350

Last Updated: 2021-10-22

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

UNKNOWN

Clinical Phase

PHASE2

Total Enrollment

41 participants

Study Classification

INTERVENTIONAL

Study Start Date

2019-03-20

Study Completion Date

2023-02-28

Brief Summary

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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

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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.

Conditions

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Metastatic Melanoma

Study Design

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Allocation Method

NA

Intervention Model

SINGLE_GROUP

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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Niraparib

Patients receive niraparib PO daily

Group Type EXPERIMENTAL

Niraparib

Intervention Type DRUG

300 mg PO daily

Interventions

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Niraparib

300 mg PO daily

Intervention Type DRUG

Eligibility Criteria

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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)
Minimum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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Tesaro, Inc.

INDUSTRY

Sponsor Role collaborator

Vanderbilt-Ingram Cancer Center

OTHER

Sponsor Role collaborator

Huntsman Cancer Institute

OTHER

Sponsor Role collaborator

California Pacific Medical Center Research Institute

OTHER

Sponsor Role lead

Responsible Party

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Kevin Kim

Principal Investigator

Responsibility Role PRINCIPAL_INVESTIGATOR

Principal Investigators

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Kevin Kim, MD

Role: PRINCIPAL_INVESTIGATOR

California Pacific Medical Center

Locations

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California Pacific Medical Center Research Institute

San Francisco, California, United States

Site Status RECRUITING

Countries

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United States

Central Contacts

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Emilia Janiczek

Role: CONTACT

415-600-1544

Facility Contacts

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Emilia Janiczek

Role: primary

415-600-1544

References

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Kim KB, Desprez PY, de Semir D, Woo RWL, Sharma A, Jones R, Caressi C, Nosrati M, Janiczek E, Rivera Penafiel J, Kashani-Sabet M. Phase II Study of Niraparib in Patients With Advanced Melanoma With Homologous Recombination Pathway Gene Mutations. JCO Precis Oncol. 2025 May;9:e2400658. doi: 10.1200/PO-24-00658. Epub 2025 May 15.

Reference Type DERIVED
PMID: 40373259 (View on PubMed)

Other Identifiers

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CPMC17-MEL01

Identifier Type: -

Identifier Source: org_study_id