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

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.

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 0-2

- 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 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

- 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

- 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