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出境医 / 临床实验 / Efficacy and Safety Study of Niraparib in Melanoma With Genetic Homologous Recombination (HR) Mutation

Efficacy and Safety Study of Niraparib in Melanoma With Genetic Homologous Recombination (HR) Mutation

Study Description
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.

Condition or disease Intervention/treatment Phase
Metastatic Melanoma Drug: Niraparib Phase 2

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.

Study Design
Layout table for study information
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
Arms and Interventions
Arm Intervention/treatment
Experimental: Niraparib
Patients receive niraparib PO daily
Drug: Niraparib
300 mg PO daily

Outcome Measures
Primary Outcome Measures :
  1. 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


Secondary Outcome Measures :
  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

  2. overall survival (OS) [ Time Frame: 2 years ]
    OS of patients with advanced melanoma with genetic HR mutation/ alteration who are treated with niraparib

  3. 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


Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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)
Contacts and Locations

Contacts
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Contact: Laurel Brechtel 415-600-1654 BrechtLA@sutterhealth.org

Locations
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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   
Sponsors and Collaborators
California Pacific Medical Center Research Institute
Tesaro, Inc.
Vanderbilt-Ingram Cancer Center, Nashville, TN
University of Utah Huntsman Cancer Institute, Salt Lake City, UT
Investigators
Layout table for investigator information
Principal Investigator: Kevin Kim, MD California Pacific Medical Center
Tracking Information
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
 (submitted: April 19, 2019)
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
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 19, 2019)
  • 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
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.

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
Condition  ICMJE Metastatic Melanoma
Intervention  ICMJE Drug: Niraparib
300 mg PO daily
Study Arms  ICMJE Experimental: Niraparib
Patients receive niraparib PO daily
Intervention: Drug: Niraparib
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: April 19, 2019)
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:

  • 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)
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Laurel Brechtel 415-600-1654 BrechtLA@sutterhealth.org
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
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party Kevin Kim, California Pacific Medical Center Research Institute
Study Sponsor  ICMJE California Pacific Medical Center Research Institute
Collaborators  ICMJE
  • Tesaro, Inc.
  • Vanderbilt-Ingram Cancer Center, Nashville, TN
  • University of Utah Huntsman Cancer Institute, Salt Lake City, UT
Investigators  ICMJE
Principal Investigator: Kevin Kim, MD California Pacific Medical Center
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

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