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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Mesothelioma, Uveal Melanoma, Renal Cell Carcinoma, Cholangiocarcinoma

Intervention / Treatment
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* Drug: Niraparib


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Patients in both cohorts will receive niraparib.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort A<br>This cohort will enroll patients with mesothelioma, uveal melanoma, renal cell carcinoma (clear cell type), and cholangiocarcinoma. | Drug: Niraparib<br>* Patients will take 300 mg of niraparib orally once daily each day of a 28 day cycle.<br>* Other names: Zejula;|
| Experimental: Cohort B<br>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<br>* Patients will take 300 mg of niraparib orally once daily each day of a 28 day cycle.<br>* Other names: Zejula;|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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BAP1, niraparib, DNA repair, PARP inhibitor, homologous repair deficiency, renal cell carcinoma, cholangiocarcinoma, mesothelioma, uveal melanoma