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 |
Allocation: | N/A |
Intervention Model: | Single Group Assignment |
Masking: | None (Open Label) |
Primary Purpose: | Treatment |
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 |
Arm | Intervention/treatment |
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Experimental: Niraparib
Patients receive niraparib PO daily
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Drug: Niraparib
300 mg PO daily
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Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
Sexes Eligible for Study: | All |
Accepts Healthy Volunteers: | No |
Inclusion Criteria:
Exclusion Criteria:
Contact: Laurel Brechtel | 415-600-1654 | BrechtLA@sutterhealth.org |
United States, California | |
California Pacific Medical Center Research Institute | Recruiting |
San Francisco, California, United States, 94115 | |
Contact: Laurel Brechtel 415-600-1654 BrechtLA@sutterhealth.org |
Principal Investigator: | Kevin Kim, MD | California Pacific Medical Center |
Tracking Information | |||||
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First Submitted Date ICMJE | March 15, 2019 | ||||
First Posted Date ICMJE | April 24, 2019 | ||||
Last Update Posted Date | May 18, 2020 | ||||
Actual Study Start Date ICMJE | March 20, 2019 | ||||
Estimated Primary Completion Date | February 2021 (Final data collection date for primary outcome measure) | ||||
Current Primary Outcome Measures ICMJE |
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
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Original Primary Outcome Measures ICMJE | Same as current | ||||
Change History | |||||
Current Secondary Outcome Measures ICMJE |
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Original Secondary Outcome Measures ICMJE | Same as current | ||||
Current Other Pre-specified Outcome Measures | Not Provided | ||||
Original Other Pre-specified Outcome Measures | Not Provided | ||||
Descriptive Information | |||||
Brief Title ICMJE | Efficacy and Safety Study of Niraparib in Melanoma With Genetic Homologous Recombination (HR) Mutation | ||||
Official Title ICMJE | A Phase II Study of Niraparib in Patients With Advanced Melanoma With Genetic Homologous Recombination (HR) Mutation / Alteration | ||||
Brief Summary | 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. | ||||
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. |
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Study Type ICMJE | Interventional | ||||
Study Phase ICMJE | Phase 2 | ||||
Study Design ICMJE | Allocation: N/A Intervention Model: Single Group Assignment Masking: None (Open Label) Primary Purpose: Treatment |
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Condition ICMJE | Metastatic Melanoma | ||||
Intervention ICMJE | Drug: Niraparib
300 mg PO daily
|
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Study Arms ICMJE | Experimental: Niraparib
Patients receive niraparib PO daily
Intervention: Drug: Niraparib
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Publications * | Not Provided | ||||
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline. |
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Recruitment Information | |||||
Recruitment Status ICMJE | Recruiting | ||||
Estimated Enrollment ICMJE |
41 | ||||
Original Estimated Enrollment ICMJE | Same as current | ||||
Estimated Study Completion Date ICMJE | February 2023 | ||||
Estimated Primary Completion Date | February 2021 (Final data collection date for primary outcome measure) | ||||
Eligibility Criteria ICMJE |
Inclusion Criteria:
Exclusion Criteria:
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Sex/Gender ICMJE |
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Ages ICMJE | 18 Years and older (Adult, Older Adult) | ||||
Accepts Healthy Volunteers ICMJE | No | ||||
Contacts ICMJE |
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Listed Location Countries ICMJE | United States | ||||
Removed Location Countries | |||||
Administrative Information | |||||
NCT Number ICMJE | NCT03925350 | ||||
Other Study ID Numbers ICMJE | CPMC17-MEL01 | ||||
Has Data Monitoring Committee | No | ||||
U.S. FDA-regulated Product |
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IPD Sharing Statement ICMJE |
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Responsible Party | Kevin Kim, California Pacific Medical Center Research Institute | ||||
Study Sponsor ICMJE | California Pacific Medical Center Research Institute | ||||
Collaborators ICMJE |
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Investigators ICMJE |
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PRS Account | California Pacific Medical Center Research Institute | ||||
Verification Date | May 2020 | ||||
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP |