Phase II Study of Olaparib and Pembrolizumab in Advanced Melanoma With Homologous Recombination (HR) Mutation
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|ClinicalTrials.gov Identifier: NCT04633902|
Recruitment Status : Recruiting
First Posted : November 18, 2020
Last Update Posted : May 3, 2021
|Condition or disease||Intervention/treatment||Phase|
|Metastatic Melanoma||Drug: Olaparib Drug: Pembrolizumab||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 20-30% of cutaneous 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 and BRIP1. 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 addition, the retrospective data also showed that presence of HR mutation was associated with high TMB and clinical response to checkpoint immunotherapy. 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 olaparib in combination with pembrolizumab 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 olaparib 300 mg a day and pembrolizumab 200 mg every 3 weeks (for up to 2 years) 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:||Phase II Study of Olaparib in Combination With Pembrolizumab in Patients With Advanced Melanoma With Homologous Recombination (HR) Pathway Gene Mutation|
|Actual Study Start Date :||March 3, 2021|
|Estimated Primary Completion Date :||June 30, 2023|
|Estimated Study Completion Date :||December 31, 2024|
Experimental: Olaparib + Pembrolizumab
This arm will enroll patients who has advanced melanoma with a genetic HR mutation/ alteration including mutation/ deletion in ARID1A/B, ARID2, ATM, ATR, BARD1, BRCA1/2, BAP1, BRIP1, CHEK2, FANCA, FANCD2, MRN11A, PALB2, RAD50, RAD51, RAD54B.
Olaparib 300 mg BID daily
Other Name: Lynparza
Pembrolizumab 200 mg IV eveyr 3 weeks (for up to 2 years)
Other Name: Keytruda
- Objective Response Rate (ORR) [ Time Frame: 6 months ]ORR of olaparib in combination with pembrolizumab 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 olaparib in combination with pembrolizumab
- Overall survival (OS) [ Time Frame: 2 years ]OS of patients with advanced melanoma with genetic HR mutation/ alteration who are treated with olaparib in combination with pembrolizumab
- Number of Participants With Adverse Events as a Measure of Safety and Tolerability [ Time Frame: 2 years ]Evaluation of the safety profile of olaparib in combination with pembrolizumab 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): NCT04633902
|Contact: Kevin B Kim, MD||415-885-8600||ClinicalResearch@sutterhealth.org|
|United States, California|
|California Pacific Medical Center Research Institute||Recruiting|
|San Francisco, California, United States, 94115|
|Principal Investigator:||Kevin B Kim, MD||California Pacific Medical Center Research Institute|