Clinical Trials /

A Trial of Niraparib in BAP1 and Other DNA Damage Response (DDR) Deficient Neoplasms (UF-STO-ETI-001)

NCT03207347

Description:

This open-label, non-randomized study will investigate the use of niraparib in patients with tumors known to have mutations in BAP1 and other select DNA damage response pathway genes.

Related Conditions:
  • Cholangiocarcinoma
  • Clear Cell Renal Cell Carcinoma
  • Malignant Solid Tumor
  • Mesothelioma
  • Uveal Melanoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Trial of Niraparib in BAP1 and Other DNA Damage Response (DDR) Deficient Neoplasms (UF-STO-ETI-001)
  • Official Title: A Phase II Trial of the PARP Inhibitor, Niraparib, in BAP1 and Other DNA Damage Response (DDR) Pathway Deficient Neoplasms (UF-STO-ETI-001)

Clinical Trial IDs

  • ORG STUDY ID: UF-STO-ETI-001
  • SECONDARY ID: IRB201701827 -A
  • SECONDARY ID: OCR15732
  • NCT ID: NCT03207347

Conditions

  • Mesothelioma
  • Uveal Melanoma
  • Renal Cell Carcinoma
  • Cholangiocarcinoma

Interventions

DrugSynonymsArms
NiraparibZejulaCohort A

Purpose

This open-label, non-randomized study will investigate the use of niraparib in patients with tumors known to have mutations in BAP1 and other select DNA damage response pathway genes.

Detailed Description

      BAP1 is an ubiquitin ligase that is critical in helping to regulate the cell cycle, cellular
      differentiation, and cell death. This protein is also intimately involved with DNA
      double-strand break repair. Germline mutations in the BAP1 gene are associated with a
      hereditary cancer syndrome that increases the risk of uveal melanoma, mesothelioma and renal
      cell carcinoma. PARP is another protein that is crucial in DNA repair and enables continued
      cell replication and survival. It is hypothesized that PARP inhibition with niraparib will
      result in significant cytoreduction in patient tumors with mutations in BAP1 and other
      components of the DNA damage response pathway through synthetic lethality. Synthetic
      lethality is the inhibition of a gene that a cell relies on to compensate for the loss of
      another gene, resulting in the cell's demise.
    

Trial Arms

NameTypeDescriptionInterventions
Cohort AExperimentalThis cohort will enroll patients with mesothelioma, uveal melanoma, renal cell carcinoma (clear cell type), and cholangiocarcinoma.
  • Niraparib
Cohort BExperimentalThis cohort will enroll patients whose tumors have a known DNA damage response mutation in any of the following genes: ARID1A, ATM, ATR, BACH1 (BRIP1), BAP1, BARD1, BLM, CHEK1, CHEK2, CDK2, CDK4, ERCC, FAM175A, FEN1, IDH1, IDH2, MRE11A, NBN (NBS1), PALB2, POLD1, PRKDC (DNA-PK) PTEN, RAD50, RAD51, RAD52, RAD54, RPA1, SLX4, WRN, or XRCC. This cohort is open to patients with any type of malignancy (except prostate).
  • Niraparib

Eligibility Criteria

        Inclusion Criteria:

          -  Age ≥18 years

          -  Histologically confirmed diagnosis of incurable cancer

          -  Prior treatment with standard systemic therapy (must have exhausted or declined all
             known effective therapies)

          -  Must be willing to provide blood/serum/plasma for toxicity monitoring and other
             research purposes

          -  Must have formalin-fixed paraffin embedded (FFPE) tissue available for research
             purposes. Tissue must have been obtained within the last 3 years

          -  Measurable disease by RECIST (v 1.1) criteria

          -  Adequate organ function

          -  ECOG Performance Status of 0-1

          -  Life expectancy ≥ 12 weeks

          -  Women of childbearing potential must have a negative serum pregnancy test within 7
             days prior to the first dose

          -  Confirmed diagnosis of uveal melanoma, mesothelioma, renal cell carcinoma (clear cell
             subtype), or cholangiocarcinoma (Cohort A only)

          -  Known DNA damage repair mutation including any one of the following: ARID1A, ATM, ATR,
             BACH1 (BRIP1), BAP1, BARD1, BLM, CHEK1, CHEK2, CDK2, CDK4, ERCC, FAM175A, FEN1, IDH1,
             IDH2, MRE11A, NBN (NBS1), PALB2, POLD1, PRKDC (DNA-PK) PTEN, RAD50, RAD51, RAD52,
             RAD54, RPA1, SLX4, WRN, or XRCC. Only CLIA certified next generation sequencing (NGS)
             assays are acceptable. Variants of unknown significance (VUS) will be allowed to
             enroll on study (Cohort B only)

          -  Subjects must agree to not donate blood during the study or for 90 days after the last
             dose of study treatment.

          -  Subjects receiving corticosteroids may continue as long as their dose is stable for
             least 4 weeks prior to initiating protocol therapy.

        Exclusion Criteria:

          -  Prior exposure to PARP inhibitors

          -  Known BRCA1 or BRCA2 mutation

          -  Pathologic diagnosis of prostate cancer (cohort B only)

          -  Simultaneous enrollment in any other interventional clinical trial

          -  Major surgery ≤ 3 weeks of starting the study

          -  Investigational therapy ≤ 4 weeks of first day of dosing of study drug

          -  Radiotherapy to > 20% of the bone marrow within 4 weeks of the first dose of study
             drug

          -  Known hypersensitivity to niraparib

          -  Platelet or red blood cell transfusion ≤ 4 weeks of first dose of study drug

          -  Colony-stimulating factors within 4 weeks prior to starting protocol therapy

          -  Subjects must not have more than one active malignancy at the time of enrollment
             (Patients with a prior or concurrent malignancy whose natural history or treatment
             does not have the potential to interfere with the safety or efficacy assessment of the
             investigational regimen [as determined by the treatment physician and approved by the
             PI] may be included).

          -  Known, active symptomatic brain or leptomeningeal metastases

          -  Subject has had any known Grade 3 or 4 anemia, neutropenia or thrombocytopenia due to
             prior chemotherapy that persisted > 4 weeks and was related to the most recent
             treatment

          -  Known history of myelodysplastic syndrome or acute myeloid leukemia

          -  Females or males of childbearing potential who are unwilling or unable to use an
             acceptable method to avoid pregnancy for the entire study period and for at least 180
             days after the last dose of study drug.

          -  Females who are pregnant or breastfeeding

          -  History of any other disease, metabolic dysfunction, physical examination finding, or
             clinical laboratory finding giving reasonable suspicion of a disease or condition that
             contraindicates the use of protocol therapy or that might affect the interpretation of
             the results of the study or that puts the subject at high risk for treatment
             complications, in the opinion of the treating physician or study PI.

          -  Prisoners or subjects who are involuntarily incarcerated.

          -  Subjects who are compulsorily detained for treatment of either a psychiatric or
             physical illness.

          -  Inability to comply with the study and/or follow-up procedures
      
Maximum Eligible Age:80 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective Response Rate
Time Frame:1 year
Safety Issue:
Description:Determine the objective response rate for patients with BAP1 and other DNA double- strand break repair pathway mutations

Secondary Outcome Measures

Measure:Progression Free Survival
Time Frame:1 year
Safety Issue:
Description:Determine the median progression free survival
Measure:Progression Free Survival
Time Frame:3 months
Safety Issue:
Description:Determine the progression free survival at 3 months
Measure:Progression Free Survival
Time Frame:6 months
Safety Issue:
Description:Determine the progression free survival at 6 months
Measure:Overall Survival
Time Frame:2 years
Safety Issue:
Description:Estimate the median overall survival
Measure:Number of participants with treatment-related adverse events, as assessed by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.0
Time Frame:1 year
Safety Issue:
Description:Determine the incidence, severity, and reversibility of the toxicities of niraparib using CTCAE v4.0

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:University of Florida

Trial Keywords

  • BAP1
  • niraparib
  • DNA repair
  • PARP inhibitor
  • homologous repair deficiency
  • renal cell carcinoma
  • cholangiocarcinoma
  • mesothelioma
  • uveal melanoma

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