A Trial of Niraparib in BAP1 and Other DNA Double-Strand Break Repair Deficient Neoplasms (UF-STO-ETI-001)

Primary Outcome Measures

• • Objective Response Rate [ Time Frame: 1 year ]
    Determine the objective response rate for patients with BAP1 and other DNA double- strand break repair pathway mutations

Secondary Outcome Measures

• • • Progression Free Survival [ Time Frame: 1 year ]. Determine the median progression free survival
    • Progression Free Survival [ Time Frame: 3 months ]. Determine the progression free survival at 3 months
    • Progression Free Survival [ Time Frame: 6 months ].Determine the progression free survival at 6 months
    • Overall Survival [ Time Frame: 2 years ]. Estimate the median overall survival
    • 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 ]
      Determine the incidence, severity, and reversibility of the toxicities of niraparib using CTCAE v4.0

Other Outcome Measures

• • • Number of DNA repair mechanism deficiencies [ Time Frame: 1 year ]. Explore the impact that specific DNA repair mechanism deficiencies have on tumor PARP inhibition.
    • Biomarker identification [ Time Frame: 1 year ]. Explore alternate biomarkers that predict response to PARP inhibition

Eligibility

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 0-2

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 double-strand break repair mutation including any one of the following: BAP1, PALB2, ATM, ATR, RAD51, RAD54, XRCC, ERCC, BLM, BARD, FANCD2, PTEN, IDH1/IDH2 or BACH. 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)

Exclusion Criteria

Prior exposure to PARP inhibitors

Known BRCA1 or BRCA2 mutation

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

Patients must not be immunocompromised

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

Diagnosis or treatment of another type of cancer ≤ 2 years prior to cohort assignment (except basal or squamous cell carcinoma of the skin that has been definitively treated)

Known, active symptomatic brain or leptomeningeal metastases

QTc prolongation > 470 milliseconds

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 4 weeks after the last dose of study drug.

Females who are pregnant or breastfeeding

Inability to comply with the study and/or follow-up procedures