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

Sponsor

University of Florida (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT03207347

Collaborator

GlaxoSmithKline (Industry)

Enrollment

Locations

Arms

63.6

Anticipated Duration (Months)

11.7

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

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

Actual Enrollment :

35 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Patients in both cohorts will receive niraparib.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 :

Aug 13, 2018

Anticipated Primary Completion Date :

Dec 1, 2022

Anticipated Study Completion Date :

Dec 1, 2023

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 Names: 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 Names: Zejula

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 Names:

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 Names:

Zejula

Outcome Measures

Primary Outcome Measures

Objective Response Rate (ORR) [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

Progression Free Survival [1 year]
Determine the median progression free survival
Progression Free Survival [3 months]
Determine the progression free survival at 3 months in each cohort and histologic subset of subjects
Progression Free Survival [6 months]
Determine the progression free survival at 6 months in each cohort and histologic subset of subjects
Overall Survival [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 [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 [1 year]
Explore the impact that specific DNA repair mechanism deficiencies have on tumor PARP inhibition
Biomarker identification [1 year]
Explore alternate biomarkers that predict response to PARP inhibition

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 80 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Locations

	Site	City	State	Country	Postal Code
1	University of Florida	Gainesville	Florida	United States	32610
2	University of Miami	Miami	Florida	United States	33136
3	Orlando Health UF Health Cancer Center	Orlando	Florida	United States	32806