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

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Brief Title

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

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)

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.
    

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 Phase

Phase 2

Study Type

Interventional


Primary Outcome

Objective Response Rate (ORR)

Secondary Outcome

 Progression Free Survival

Condition

Mesothelioma

Intervention

Niraparib

Study Arms / Comparison Groups

 Cohort A
Description:  This cohort will enroll patients with mesothelioma, uveal melanoma, renal cell carcinoma (clear cell type), and cholangiocarcinoma.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

47

Start Date

August 13, 2018

Completion Date

December 2022

Primary Completion Date

December 2021

Eligibility 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
      

Gender

All

Ages

18 Years - 80 Years

Accepts Healthy Volunteers

No

Contacts

Thomas George, MD, FACP, (352) 273-9785, [email protected]

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT03207347

Organization ID

UF-STO-ETI-001

Secondary IDs

IRB201701827 -A

Responsible Party

Sponsor

Study Sponsor

University of Florida

Collaborators

 TESARO/GlaxoSmithKline

Study Sponsor

Thomas George, MD, FACP, Principal Investigator, University of Florida


Verification Date

June 2021