Efficacy and Safety Study of Niraparib in Melanoma With Genetic Homologous Recombination (HR) Mutation
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|ClinicalTrials.gov Identifier: NCT03925350|
Recruitment Status : Recruiting
First Posted : April 24, 2019
Last Update Posted : April 24, 2019
|Condition or disease||Intervention/treatment||Phase|
|Metastatic Melanoma||Drug: Niraparib||Phase 2|
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 (Clinical Trial)|
|Estimated Enrollment :||41 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|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 20, 2019|
|Estimated Primary Completion Date :||February 2021|
|Estimated Study Completion Date :||February 2023|
Patients receive niraparib PO daily
300 mg PO daily
- 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
- Progression-free survival (PFS) [ Time Frame: 2 years ]PFS of patients with advanced melanoma with genetic HR mutation/ alteration who are treated with niraparib
- overall survival (OS) [ Time Frame: 2 years ]OS of patients with advanced melanoma with genetic HR mutation/ alteration who are treated with niraparib
- 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
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03925350
|Contact: Peter Gasperemail@example.com|
|United States, California|
|California Pacific Medical Center Research Institute||Recruiting|
|San Francisco, California, United States, 94115|
|Contact: Peter Gasper 415-600-3472 firstname.lastname@example.org|
|Principal Investigator:||Kevin Kim, MD||California Pacific Medical Center|