Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Rare Diseases

Melanoma

Neuroendocrine Tumors

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Nerve Tissue

Nevus, Pigmented

Nevus

Nevi and Melanomas

Skin Neoplasms

Skin Diseases

Neuroendocrine Tumor

Neuroepithelioma

Antineoplastic Agents

All Drugs and Chemicals

Niraparib

Poly(ADP-ribose) Polymerase Inhibitors

Enzyme Inhibitors

Emilia Janiczek

Kevin Kim, MD

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.

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.

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

ORR of niraparib in patients with advanced melanoma with genetic homologous recombination (HR) mutation/ alteration using RECIST v1.1

PFS of patients with advanced melanoma with genetic HR mutation/ alteration who are treated with niraparib

OS of patients with advanced melanoma with genetic HR mutation/ alteration who are treated with niraparib

Evaluation of the safety profile of niraparib treatment in patients with advanced melanoma with genetic homologous recombination (HR) mutation/ alteration

Tesaro, Inc.

Vanderbilt-Ingram Cancer Center

Huntsman Cancer Institute

California Pacific Medical Center Research Institute

Principal Investigator

Antibodies

Temozolomide

Fluzoparib

Immunoglobulins

Antineoplastic Agents, Alkylating

Alkylating Agents

This arm will enroll patients who has advanced melanoma with a genetic HR mutation/ alteration .

Fluzoparib 50-150mg bid po, d1-21, q3w Camrelizumab 200mg iv, d1, q3w Temozolomide 50mg/m2-200mg/m2 d1-5,q3w

Fluzoparib Camrelizumab Temozolomide

Jun Guo

Bin Lian

The purpose of this study is to evaluate how well fuzoparib in combination with camrelizumab and temozolomide works in treating patients with advanced, metastatic melanoma with the homologous recombination (HR) pathway gene mutation / alteration.

Treatment with PARP inhibitors could represent a novel opportunity to selectively kill a subset of cancer cells with deficiencies in DNA repair pathways. Non-BRCA deficiencies in homologous recombination DNA repair genes could also enhance tumor cell sensitivity to PARP inhibitors. 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 nearly18-40% of 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 BRIP1 and SF3B1. 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 this clinical study, clinical efficacy of fluzoparib in combination with camrelizumab and temozolomide 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.

Fluzoparib in Combination With Camrelizumab and Temozolomide in Advanced Melanoma

Phase Ib Study of Fluzoparib in Combination With Camrelizumab and Temozolomide in Advanced Melanoma With Homologous Recombination (HR) Mutation ，a Single-center Open-label Exploratory Clinical Trial

ORR of Fluzoparib in combination with Camrelizumab and Temozolomide in patients with advanced melanoma with genetic homologous recombination (HR) mutation/ alteration using RECIST v1.1

Director

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Efficacy and Safety Study of Niraparib in Melanoma With Genetic Homologous Recombination (HR) Mutation	NCT03925350	Metastatic Mela...	Niraparib	18 Years -	California Pacific Medical Center Research Institute
Efficacy and Safety Study of Niraparib in Melanoma With Genetic Homologous Recombination (HR) Mutation	NCT03925350	Metastatic Mela...	Niraparib	18 Years -	California Pacific Medical Center Research Institute
Fluzoparib in Combination With Camrelizumab and Temozolomide in Advanced Melanoma	NCT05983237	Melanoma	Fluzoparib Camr...	18 Years -	Peking University Cancer Hospital & Institute

Spots Global Cancer Trial Database for homologous recombination (hr)