A Trial of Niraparib in BAP1 and Other DNA Double-Strand Break Repair

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

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https://clinicaltrials.gov/ct2/show/NCT03207347

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 double-strand break repair pathway genes.

Condition Intervention Phase
Mesothelioma
Uveal Melanoma
Renal Cell Carcinoma
Cholangiocarcinoma
Drug: Niraparib
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
Patients in both cohorts will receive niraparib.
Masking: No masking
Primary Purpose: Treatment
Official Title: A Phase II Trial of the PARP Inhibitor, Niraparib, in BAP1 and Other DNA Double-Strand Break Repair Pathway Deficient Neoplasms

Resource links provided by NLM:

Genetics Home Reference related topics: cholangiocarcinoma
Drug Information available for: Niraparib Niraparib hydrochloride
Genetic and Rare Diseases Information Center resources: Renal Cell Carcinoma Malignant Mesothelioma Intraocular Melanoma Carcinoid Tumor Neuroepithelioma
U.S. FDA Resources

Further study details as provided by University of Florida:

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

Estimated Enrollment: 47
Anticipated Study Start Date: September 2017
Estimated Study Completion Date: September 2023
Estimated Primary Completion Date: September 2020 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Cohort A
This cohort will enroll patients with mesothelioma, uveal melanoma, renal cell carcinoma, and cholangiocarcinoma.
Drug: Niraparib
Patients will take 300 mg of niraparib orally once daily each day of a 28 day cycle.
Other Name: Zejula
Experimental: Cohort B
This cohort will enroll patients whose tumors have a known DNA double-strand break repair mutation in any of the following genes: BAP1, PALB2, ATM, ATR, RAD51, RAD54, XRCC, ERCC, BLM, BARD, FANCD2, PTEN, IDH1/IDH2 or BACH. This cohort is open to patients with any type of malignancy.
Drug: Niraparib
Patients will take 300 mg of niraparib orally once daily each day of a 28 day cycle.
Other Name: Zejula

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 double-strand break repair 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.
Eligibility

Ages Eligible for Study: 18 Years to 80 Years (Adult, Senior)
Sexes Eligible for Study: All
Accepts Healthy Volunteers: No
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 0-2
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
Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT03207347

Contacts
Contact: Alisha Daniels, MD (352) 294-8568 alisha.daniels@ufl.edu

Locations
United States, Florida
University of Florida Not yet recruiting
Gainesville, Florida, United States, 32610
Principal Investigator: Thomas George, MD, FACP
Sponsors and Collaborators
University of Florida
Tesaro, Inc.
Investigators
Principal Investigator: Thomas George, MD, FACP University of Florida
More Information

Responsible Party: University of Florida
ClinicalTrials.gov Identifier: NCT03207347 History of Changes
Other Study ID Numbers: UF-STO-ETI-001
Study First Received: June 26, 2017
Last Updated: June 30, 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by University of Florida:
BAP1
niraparib
DNA repair
PARP inhibitor
homologous repair deficiency
renal cell carcinoma
cholangiocarcinoma
mesothelioma
uveal melanoma

Additional relevant MeSH terms:
Neoplasms
Melanoma
Carcinoma, Renal Cell
Mesothelioma
Cholangiocarcinoma
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Nerve Tissue
Nevi and Melanomas
Adenocarcinoma
Carcinoma
Neoplasms, Glandular and Epithelial
Kidney Neoplasms
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Kidney Diseases
Urologic Diseases
Adenoma
Neoplasms, Mesothelial
Niraparib
Poly(ADP-ribose) Polymerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents

ClinicalTrials.gov processed this record on July 03, 2017