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

• ClinicalTrials.gov Identifier: NCT03207347
• Recruitment Status: Recruiting
• First Posted: July 2, 2017
• Last Update Posted: December 4, 2020
• Sponsor: University of Florida
• Collaborator: TESARO/GlaxoSmithKline
• Information provided by (Responsible Party): University of Florida

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Mesothelioma; Uveal Melanoma; Renal Cell Carcinoma; Cholangiocarcinoma	Drug: Niraparib	Phase 2

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 47 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Patients in both cohorts will receive niraparib.
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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)
• Actual Study Start Date: August 13, 2018
• Estimated Primary Completion Date: December 2021
• Estimated Study Completion Date: December 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: Cohort A; This cohort will enroll patients with mesothelioma, uveal melanoma, renal cell carcinoma (clear cell type), 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 (Closed to enrollment); This 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).	Drug: Niraparib; Patients will take 300 mg of niraparib orally once daily each day of a 28 day cycle.; Other Name: Zejula

Outcome Measures

Primary Outcome Measures :

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

Secondary Outcome Measures :

1. Progression Free Survival [ Time Frame: 1 year ]
   Determine the median progression free survival
2. Progression Free Survival [ Time Frame: 3 months ]
   Determine the progression free survival at 3 months in each cohort and histologic subset of subjects
3. Progression Free Survival [ Time Frame: 6 months ]
   Determine the progression free survival at 6 months in each cohort and histologic subset of subjects
4. Overall Survival [ Time Frame: 2 years ]
   Estimate the median overall survival
5. 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:

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

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 80 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Age ≥18 years
• Histologically confirmed clinical diagnosis of incurable cancer
• 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)
• Prior treatment with standard systemic therapy (must have exhausted or declined all known and currently approved effective life prolonging therapies)
• Must have formalin-fixed paraffin embedded (FFPE) tissue available for research purposes. Tissue must have been obtained within the last 3 years from a core or excisional biopsy.
• 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 or urine pregnancy test within 7 days prior to the first dose AND be using an adequate method of contraception to avoid pregnancy throughout the study and for at least 180 days after the last dose of study drug to minimize the risk of pregnancy.
• Males with female partners of child-bearing potential must agree to use physician-approved contraceptive methods (e.g., abstinence, condoms, vasectomy) throughout the study and should avoid conceiving children for 180 days following the last dose of study drug. In addition, men must not donate sperm during niraparib therapy and for 180 days after receiving the last dose of niraparib.
• Subjects must agree to not donate blood during the study or for 90 days after the last dose of study treatment.
• Subjects receiving oral corticosteroids may continue as long as their dose is stable for least 4 weeks prior to initiating protocol therapy.
• If a new biopsy is needed for diagnostic reasons, the biopsy must be performed from a tumor site that is not the only site of measurable disease.

Exclusion Criteria:

• Prior exposure to PARP inhibitors
• Subject has received or is planning to receive live vaccines within 30 days prior to the first dose of oral treatment and while participating in the trial
• Known BRCA1 or BRCA2 mutation
• Pathologic diagnosis of prostate cancer as the cancer to be treated in cohort B
• Simultaneous enrollment in any other interventional clinical trial
• Major surgery ≤ 3 weeks of study enrollment (Subject must have recovered from any effects of any major sugery.)
• 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 the components of niraparib or the excipients
• 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
• More than one active malignancy at the time of enrollment (Subjects 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 of birth control 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.
• Subjects demonstrating an inability to comply with the study and/or follow-up procedures

Contacts and Locations

Contacts

Contact: Erin Monari, PhD; (352) 273-8128; PMO@cancer.ufl.edu

Locations

United States, Florida

University of Florida; Recruiting

Gainesville, Florida, United States, 32610

Contact: Chrystal Bailey 352-265-0680 ext 58003 cbailey1@ufl.edu

Principal Investigator: Thomas George, MD, FACP

University of Miami; Recruiting

Miami, Florida, United States, 33136

Contact: Carla Montoya ccm162@miami.edu

Principal Investigator: Peter J Hosein, MD

Orlando Health UF Health Cancer Center; Not yet recruiting

Orlando, Florida, United States, 32806

Contact: Karin Donaldson 321-841-9821 Karin.donaldson@orlandohealth.com

Principal Investigator: Thomas Sajeve, MD

Sponsors and Collaborators

University of Florida

TESARO/GlaxoSmithKline

Investigators

• Principal Investigator: Thomas George, MD, FACP; University of Florida

More Information

• Responsible Party: University of Florida
• ClinicalTrials.gov Identifier: NCT03207347
• Other Study ID Numbers: UF-STO-ETI-001; IRB201701827 -A ( Other Identifier: University of Florida ); OCR15732 ( Other Identifier: Universiy of Florida )
• First Posted: July 2, 2017
• Last Update Posted: December 4, 2020
• Last Verified: December 2020

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:

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