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

A Phase II Trial of the PARP Inhibitor, Niraparib, in BAP1 and Other DNA Damage Response (DDR) Pathway Deficient Neoplasms (UF-STO-ETI-001)

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.

Study Overview

• Status: Completed
• Conditions: Renal Cell Carcinoma; Mesothelioma; Cholangiocarcinoma; Uveal Melanoma
• Intervention / Treatment: Drug: Niraparib

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 Type: Interventional
• Enrollment (Actual): 37
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Florida
    • Gainesville, Florida, United States, 32610
      • University of Florida
    • Miami, Florida, United States, 33136
      • University of Miami
    • Orlando, Florida, United States, 32806
      • Orlando Health UF Health Cancer Center

Participation Criteria

Eligibility Criteria

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

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / 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; 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rate (ORR)	Determine the objective response rate (ORR), which is defined as the percentage of subjects achieving a best overall response of partial or complete response (according to RECIST v1.1 criteria) from the start of the treatment until disease progression/recurrence or 30 days after the end of treatment, whichever occurs first. Per RECIST v1.1 criteria, a partial response is defined as a 30% or more decrease in the sum of the largest diameters of the target lesions. Per RECIST v1.1 criteria, a complete response is defined as the disappearance of target lesions (lymph nodes identified as lesions must have reduction in short axis to <10 mm).	1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-Free Survival	Determine the median progression-free survival. Progression-free survival is defined as the duration of time from study entry to time of progression or death or the date of last contact, whichever occurs first. Progression is defined by RECIST v1.1 criteria and is defined as an increase of at least 20% in the sum of the largest diameters of target lesions and/or the appearance of new lesions.	8 months
Progression-Free Survival Rate at 3 Months	Determine the progression-free survival rate at 3 months after study entry in each cohort. This is the percentage of subjects that both have not had disease progression and are alive 3 months after study entry. Disease progression is defined by RECIST v1.1 criteria and is defined as an increase of at least 20% in the sum of the largest diameters of target lesions and/or the appearance of new lesions.	3 months
Progression-Free Survival Rate at 6 Months	Determine the progression-free survival rate at 6 months after study entry in each cohort. This is the percentage of subjects that both have not had disease progression and are alive 6 months after study entry. Progression is defined by RECIST v1.1 criteria and is defined as an increase of at least 20% in the sum of the largest diameters of target lesions and/or the appearance of new lesions.	6 months
Overall Survival	Estimate the median overall survival. Overall survival is defined as the duration of time from date of study entry until date of death or date of last contact.	10 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of DNA repair mechanism deficiencies	Explore the impact that specific DNA repair mechanism deficiencies have on tumor PARP inhibition	1 year
Biomarker identification	Explore alternate biomarkers that predict response to PARP inhibition	1 year

Collaborators and Investigators

• Sponsor: University of Florida
• Collaborators: GlaxoSmithKline
• Investigators: Principal Investigator: Thomas George, MD, FACP, University of Florida

Study record dates

Study Major Dates

• Study Start (Actual): August 13, 2018
• Primary Completion (Actual): August 30, 2022
• Study Completion (Actual): August 30, 2022

Study Registration Dates

• First Submitted: June 26, 2017
• First Submitted That Met QC Criteria: June 30, 2017
• First Posted (Actual): July 2, 2017

Study Record Updates

• Last Update Posted (Actual): September 15, 2023
• Last Update Submitted That Met QC Criteria: September 13, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: PARP inhibitor; mesothelioma; cholangiocarcinoma; uveal melanoma; renal cell carcinoma; niraparib; DNA repair; BAP1; homologous repair deficiency
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms by Histologic Type; Lung Diseases; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Kidney Diseases; Urologic Diseases; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Kidney Neoplasms; Lung Neoplasms; Neuroendocrine Tumors; Nevi and Melanomas; Adenoma; Neoplasms, Mesothelial; Pleural Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Neoplasms; Carcinoma, Renal Cell; Melanoma; Cholangiocarcinoma; Mesothelioma; Mesothelioma, Malignant; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Poly(ADP-ribose) Polymerase Inhibitors; Niraparib
• Other Study ID Numbers: UF-STO-ETI-001; IRB201701827 -A (Other Identifier: University of Florida); OCR15732 (Other Identifier: Universiy of Florida)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• 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