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

A Phase II Study of Niraparib in Patients With Advanced Melanoma With Genetic Homologous Recombination (HR) Mutation / Alteration

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.

Study Overview

• Status: Recruiting
• Conditions: Metastatic Melanoma
• Intervention / Treatment: Drug: Niraparib

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 Type: Interventional
• Enrollment (Anticipated): 41
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Emilia Janiczek; Phone Number: 415-600-1544; Email: janicze@sutterhealth.org

Study Locations

• United States
  • California
    • San Francisco, California, United States, 94115
      • Recruiting
      • California Pacific Medical Center Research Institute
      • Contact: Emilia Janiczek; Phone Number: 415-600-1544; Email: janicze@sutterhealth.org

Participation Criteria

Eligibility Criteria

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

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Niraparib; Patients receive niraparib PO daily	Drug: Niraparib; 300 mg PO daily

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rate (ORR)	ORR of niraparib in patients with advanced melanoma with genetic homologous recombination (HR) mutation/ alteration using RECIST v1.1	6 months

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: California Pacific Medical Center Research Institute
• Collaborators: Tesaro, Inc.; Vanderbilt-Ingram Cancer Center; Huntsman Cancer Institute
• Investigators: Principal Investigator: Kevin Kim, MD, California Pacific Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): March 20, 2019
• Primary Completion (Anticipated): February 1, 2022
• Study Completion (Anticipated): February 1, 2023

Study Registration Dates

• First Submitted: March 15, 2019
• First Submitted That Met QC Criteria: April 19, 2019
• First Posted (Actual): April 24, 2019

Study Record Updates

• Last Update Posted (Actual): October 22, 2021
• Last Update Submitted That Met QC Criteria: October 15, 2021
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Keywords: PARP inhibitor; Niraparib; Homologous recombination (HR); Mutation
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Melanoma; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Poly(ADP-ribose) Polymerase Inhibitors; Niraparib
• Other Study ID Numbers: CPMC17-MEL01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No