Ignite Creation Date:
2024-05-06 @ 3:26 PM
Last Modification Date:
2024-10-26 @ 1:49 PM
Study NCT ID:
NCT04633902
Status:
RECRUITING
Last Update Posted:
2022-12-06
First Post:
2020-11-12
Brief Title:
Phase II Study of Olaparib and Pembrolizumab in Advanced Melanoma With Homologous Recombination HR Mutation
Sponsor:
California Pacific Medical Center Research Institute
Organization:
California Pacific Medical Center Research Institute
Study Overview
Official Title:
Phase II Study of Olaparib in Combination With Pembrolizumab in Patients With Advanced Melanoma With Homologous Recombination HR Pathway Gene Mutation
Status:
RECRUITING
Status Verified Date:
2022-12
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
This open-label phase II trial studies how well olaparib in combination with pembrolizumab works in treating patients with advanced metastatic melanoma with the homologous recombination HR pathway gene mutation alteration Olaparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and potentially augment an anti-tumor immune response to pembrolizumab The trial is designed to assess the efficacy and safety of olaparib in combination with pembrolizumab in patients with HR mutation alteration whose disease progressed on prior immunotherapy andor BRAF-targeting therapy
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 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
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 Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
True
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
True
Is an FDA AA801 Violation?:
None