Description:
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.
Title
- Brief Title: Efficacy and Safety Study of Niraparib in Melanoma With Genetic Homologous Recombination (HR) Mutation
- Official Title: A Phase II Study of Niraparib in Patients With Advanced Melanoma With Genetic Homologous Recombination (HR) Mutation / Alteration
Clinical Trial IDs
- ORG STUDY ID:
CPMC17-MEL01
- NCT ID:
NCT03925350
Conditions
Interventions
Drug | Synonyms | Arms |
---|
Niraparib | | Niraparib |
Purpose
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.
Trial Arms
Name | Type | Description | Interventions |
---|
Niraparib | Experimental | Patients receive niraparib PO daily | |
Eligibility Criteria
Inclusion Criteria:
- Have genetic homologous recombination (HR) mutation/ alteration including ARID1A/B,
ARID2, ATM, ATR, ATRX, BARD1, BRCA1/2, BAP1, BRIP1, CHEK2, FANCD2, MRN11A, PALB2,
RAD50, RAD51, RAD54B
- Disease must have progressed on the standard systemic therapies or they could not have
tolerated the standard therapies.
- ECOG PS >/=1
- Have measurable metastatic disease according to RECIST 1.1
- Prior systemic cytotoxic therapy up to 1 regimens is allowed; There is no limit on the
number of prior immunotherapy or targeted therapy regimens.
- All adverse events associated with prior treatment must have resolved to ≤ Grade 1
prior to day 1 of the study drug administration.
Exclusion Criteria:
- Previously treated with a PARP inhibitor
- Symptomatic brain metastasis or active brain lesions ≥6 mm size or those
- Require steroid treatment for brain lesions or leptomeningeal disease
- Systemic cancer therapy within 14 days prior to day 1 of the study drug administration
- Any major surgery ≤ 3 weeks of starting the study and patient must have recovered from
any effects of any major surgery
- Investigational therapy administered ≤ 4 weeks, or within a time interval less than at
least 5 half-lives of the investigational
- Prior radiotherapy encompassing > 20% of the bone marrow within 2 weeks; or any
radiation therapy within 1 week prior to Day 1 of protocol therapy
- Medical history of immunocompromised condition
- Systemic treatment of another type of cancer ≤ 2 years prior to registration
- Known history of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML)
Maximum Eligible Age: | N/A |
Minimum Eligible Age: | 18 Years |
Eligible Gender: | All |
Healthy Volunteers: | No |
Primary Outcome Measures
Measure: | Objective Response Rate (ORR) |
Time Frame: | 6 months |
Safety Issue: | |
Description: | ORR of niraparib in patients with advanced melanoma with genetic homologous recombination (HR) mutation/ alteration using RECIST v1.1 |
Secondary Outcome Measures
Measure: | Progression-free survival (PFS) |
Time Frame: | 2 years |
Safety Issue: | |
Description: | PFS of patients with advanced melanoma with genetic HR mutation/ alteration who are treated with niraparib |
Measure: | overall survival (OS) |
Time Frame: | 2 years |
Safety Issue: | |
Description: | OS of patients with advanced melanoma with genetic HR mutation/ alteration who are treated with niraparib |
Measure: | Number of Participants With Adverse Events as a Measure of Safety and Tolerability |
Time Frame: | 2 years |
Safety Issue: | |
Description: | Evaluation of the safety profile of niraparib treatment in patients with advanced melanoma with genetic homologous recombination (HR) mutation/ alteration |
Details
Phase: | Phase 2 |
Primary Purpose: | Interventional |
Overall Status: | Recruiting |
Lead Sponsor: | California Pacific Medical Center Research Institute |
Trial Keywords
- Homologous recombination (HR)
- Mutation
- Niraparib
- PARP inhibitor
Last Updated
May 18, 2020