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.
|First Received Date||June 26, 2017|
|Last Changed Date||August 20, 2018|
|Start Date||August 13, 2018|
|Anticipated Primary Completion Date||December 2021|
|Primary Outcome Measures||
Objective Response Rate [Time Frame: 1 year]
|Secondary Outcome Measures||
Progression Free Survival [Time Frame: 1 year]
Progression Free Survival [Time Frame: 3 months]
Progression Free Survival [Time Frame: 6 months]
Overall Survival [Time Frame: 2 years]
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]
|Study Arms / Comparison Groups||2 / 0|
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.
|Ages||18 Years - 80 Years|
|Accepts Healthy Volunteers||No|
Ashton Monismith, RN
Phone: (352) 265-0680 x87657
- 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.
- 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
|Sponsor||University of Florida|
|Verification Date||August 2018|