Clinical Trials /

Measuring the Effects of Talazoparib in Patients With Advanced Cancer and DNA Repair Variations

NCT04550494

Description:

This phase II trial studies if talazoparib works in patients with cancer that has spread to other places in the body (advanced) and has mutation(s) in deoxyribonucleic acid (DNA) damage response genes who have or have not already been treated with another PARP inhibitor. Talazoparib is an inhibitor of PARP, a protein that helps repair damaged DNA. Blocking PARP may help keep cancer cells from repairing their damaged DNA, causing them to die. PARP inhibitors are a type of targeted therapy. All patients who take part on this study must have a gene aberration that changes how their tumors are able to repair DNA. This trial may help scientists learn whether some patients might benefit from taking different PARP inhibitors "one after the other" and learn how talazoparib works in treating patients with advanced cancer who have aberration in DNA repair genes.

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Measuring the Effects of Talazoparib in Patients With Advanced Cancer and DNA Repair Variations
  • Official Title: A Pharmacodynamics-Driven Trial of Talazoparib, an Oral PARP Inhibitor, in Patients With Advanced Solid Tumors and Aberrations in Genes Involved in DNA Damage Response

Clinical Trial IDs

  • ORG STUDY ID: NCI-2020-06906
  • SECONDARY ID: NCI-2020-06906
  • SECONDARY ID: 10371
  • SECONDARY ID: 10371
  • NCT ID: NCT04550494

Conditions

  • Advanced Breast Carcinoma
  • Advanced Malignant Solid Neoplasm
  • Advanced Ovarian Carcinoma
  • Advanced Pancreatic Carcinoma
  • Advanced Prostate Carcinoma
  • Anatomic Stage III Breast Cancer AJCC v8
  • Anatomic Stage IIIA Breast Cancer AJCC v8
  • Anatomic Stage IIIB Breast Cancer AJCC v8
  • Anatomic Stage IIIC Breast Cancer AJCC v8
  • Anatomic Stage IV Breast Cancer AJCC v8
  • Castration-Resistant Prostate Carcinoma
  • Clinical Stage III Gastric Cancer AJCC v8
  • Clinical Stage IV Gastric Cancer AJCC v8
  • Clinical Stage IVA Gastric Cancer AJCC v8
  • Clinical Stage IVB Gastric Cancer AJCC v8
  • HER2 Positive Breast Carcinoma
  • Metastatic Prostate Carcinoma
  • Pathologic Stage III Gastric Cancer AJCC v8
  • Pathologic Stage IIIA Gastric Cancer AJCC v8
  • Pathologic Stage IIIB Gastric Cancer AJCC v8
  • Pathologic Stage IIIC Gastric Cancer AJCC v8
  • Pathologic Stage IV Gastric Cancer AJCC v8
  • Platinum-Sensitive Ovarian Carcinoma
  • Postneoadjuvant Therapy Stage III Gastric Cancer AJCC v8
  • Postneoadjuvant Therapy Stage IV Gastric Cancer AJCC v8
  • Prognostic Stage III Breast Cancer AJCC v8
  • Prognostic Stage IIIA Breast Cancer AJCC v8
  • Prognostic Stage IIIB Breast Cancer AJCC v8
  • Prognostic Stage IIIC Breast Cancer AJCC v8
  • Prognostic Stage IV Breast Cancer AJCC v8
  • Stage II Pancreatic Cancer AJCC v8
  • Stage IIA Pancreatic Cancer AJCC v8
  • Stage IIB Pancreatic Cancer AJCC v8
  • Stage III Pancreatic Cancer AJCC v8
  • Stage III Prostate Cancer AJCC v8
  • Stage IIIA Ovarian Cancer AJCC v8
  • Stage IIIA Prostate Cancer AJCC v8
  • Stage IIIA1 Ovarian Cancer AJCC v8
  • Stage IIIA2 Ovarian Cancer AJCC v8
  • Stage IIIB Ovarian Cancer AJCC v8
  • Stage IIIB Prostate Cancer AJCC v8
  • Stage IIIC Ovarian Cancer AJCC v8
  • Stage IIIC Prostate Cancer AJCC v8
  • Stage IV Ovarian Cancer AJCC v8
  • Stage IV Pancreatic Cancer AJCC v8
  • Stage IV Prostate Cancer AJCC v8
  • Stage IVA Ovarian Cancer AJCC v8
  • Stage IVA Prostate Cancer AJCC v8
  • Stage IVB Ovarian Cancer AJCC v8
  • Stage IVB Prostate Cancer AJCC v8

Interventions

DrugSynonymsArms
TalazoparibBMN 673, BMN-673Treatment (talazoparib)

Purpose

This phase II trial identifies if talazoparib works in tumor cells and if it works differently in patients with cancer that has spread to other places in the body (advanced) who have or have not already been treated with another poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor. Talazoparib is a type of drug called a PARP inhibitor that works by preventing DNA repair in tumor cells. This trial may help scientists learn if some patients might benefit from taking different PARP inhibitors "one after the other" and understand how PARP inhibitors work in treating patients with advanced cancer.

Detailed Description

      PRIMARY OBJECTIVE:

      I. Determine the pharmacodynamic (PD) effect of talazoparib in tumor biopsies for patients
      with aberrations in deoxyribonucleic acid (DNA) damage response genes who have or have not
      received prior PARP inhibitor treatment (separately).

      SECONDARY OBJECTIVE:

      I. Determine the response rate (complete response [CR] + partial response [PR]) of treatment
      with talazoparib in patients with aberrations in DNA damage response genes.

      EXPLORATORY OBJECTIVE:

      I. Investigate tumor genomic alterations potentially associated with sensitivity or acquired
      resistance to talazoparib.

      OUTLINE:

      Patients receive talazoparib orally (PO) once daily (QD) on days 1-28. Cycles repeat every 28
      days in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up at 30 days.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (talazoparib)ExperimentalPatients receive talazoparib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Talazoparib

Eligibility Criteria

        Inclusion Criteria:

          -  Adult patients with solid tumors and documented germline or somatic aberrations in
             genes involved in DNA damage response (DDR) and whose disease has progressed following
             at least one standard therapy or who have no acceptable standard treatment options.
             Molecular testing performed at an National Cancer Institute (NCI)-Molecular Analysis
             for Therapy Choice (MATCH) (NCT02465060) study-designated Clinical Laboratory
             Improvement Act (CLIA) laboratory or the Frederick National Laboratory for Cancer
             Research (FNLCR) Molecular Characterization Laboratory (MoCha) will be acceptable for
             determination of eligibility

          -  Patients with the following germline or somatic genetic aberrations will be eligible
             based on compelling preclinical and/or clinical data suggesting that these deleterious
             mutations confer sensitivity to PARP inhibitors; this list is restricted to genes from
             the NCI-Molecular Profiling-Based Assignment of Cancer Therapy (MPACT) protocol aMOIs
             panel for temozolomide plus veliparib (NCT01827384), the ongoing trial of Rucaparib in
             Patients with Metastatic Hormone-Sensitive Prostate Cancer Harboring Germline DNA
             Repair Gene Mutations (TRIUMPH) (NCT03413995), and published results from TRITON2: A
             Phase 2 Study of Rucaparib in Patients with Metastatic Castration-Resistant Prostate
             Cancer Associated with Homologous Recombination Repair Gene Alterations:

               -  Deleterious BRCA1 or BRCA2 mutations

               -  Loss of function mutations (including novel loss of function frameshift or
                  nonsense mutations) in the following Fanconi anemia genes: FANCA, FANCB, FANCC,
                  FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ, FANCL, FANCM, FANCN

               -  A known functional mutation (including novel loss of function frameshift or
                  nonsense mutations) in any of the following DDR genes: ATM, BACH1 (BRIP1), BARD1,
                  CDK12, CHK1, CHK2, IDH1, IDH2, MRE11A, NBN, PALB2, RAD50, RAD51, RAD51B, RAD51C,
                  RAD51D, RAD54L

          -  Eastern Cooperative Oncology Group (ECOG) performance status =< 2

          -  Life expectancy of greater than 3 months

          -  Leukocytes >= 3,000/mcL

          -  Absolute neutrophil count >= 1,500/mcL

          -  Platelets >= 100,000/mcL

          -  Total bilirubin =< 1.5 x institutional upper limit of normal

          -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) /
             alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 3 x
             institutional upper limit of normal

          -  Creatinine =< 1.5 x institutional upper limit of normal OR creatinine clearance
             glomerular filtration rate (GFR) >= 60 mL/min/1.73m^2 unless data exists supporting
             safe use at lower kidney function values, no lower than 30 mL/min/1.73m^2

          -  Patients must have measurable disease, defined as at least one lesion that can be
             accurately measured in at least one dimension (longest diameter to be recorded for
             non-nodal lesions and short axis for nodal lesions) as >= 20 mm (>= 2 cm) by chest
             x-ray or as >=10 mm (>= 1 cm) with computed tomography (CT) scan, magnetic resonance
             imaging (MRI), or calipers by clinical exam

          -  Patients must have biopsiable disease in addition to a Response Evaluation Criteria in
             Solid Tumors (RECIST) measurable lesion

          -  The effects of talazoparib on the developing human fetus are unknown. For this reason
             and because PARP inhibitors are known to be teratogenic, women of child-bearing
             capacity and men must agree to use adequate contraception (hormonal or barrier method
             of birth control; abstinence) prior to study entry, for the duration of study
             participation, and for 30 days after completing study treatment. Should a woman become
             pregnant or suspect she is pregnant while she or her partner is participating in this
             study, she should inform her treating physician immediately. Men treated or enrolled
             on this protocol must also agree to use adequate contraception prior to the study, for
             the duration of study participation, and for 4 months after completion of talazoparib
             administration

          -  Patients must be able to swallow whole tablets or capsules. Nasogastric or
             gastric-tube (G-tube) administration is not allowed. Any gastrointestinal disease
             which would impair ability to swallow, retain, or absorb drug is not allowed

          -  Ability to understand and the willingness to sign a written informed consent document

          -  Patients must have recurrent, locally advanced or metastatic disease

          -  Patients must have progressed on or after at least one line of standard-of-care (SOC)
             intervention, except for those patients without SOC or for whom talazoparib is SOC

          -  PATIENTS WITH OVARIAN CANCER:

          -  All patients with ovarian cancer should have one prior platinum-based therapy

          -  Patients with ovarian cancer with platinum-sensitive disease are eligible. Patients
             with platinum-refractory disease are not eligible

          -  Patients with gBRCAm ovarian cancer must also have progressed on a PARP inhibitor. The
             time and treatment between the prior PARP inhibitor and protocol initiation must be
             documented

          -  PATIENTS WITH PANCREATIC CANCER:

          -  All patients with pancreatic cancer should have received prior platinum-containing
             therapy

          -  PATIENTS WITH BREAST CANCER:

          -  Patients with HER2+ breast cancer should have had 2 prior systemic lines of therapy

          -  Patients with breast cancer who are eligible for a PARP inhibitor by Food and Drug
             Association (FDA) approvals must have had prior PARP inhibitor. The time and treatment
             between the prior PARP inhibitor and protocol initiation must be documented

          -  PATIENTS WITH GASTRIC CANCER:

          -  Patients with HER2+ gastric cancer should have had received anti-HER2 therapy

          -  PATIENTS WITH PROSTATE CANCER:

          -  Patients with prostate cancer who are eligible for a PARP inhibitor by FDA approvals
             must have had prior PARP inhibitor for eligibility. The time and treatment between the
             prior PARP inhibitor and protocol initiation must be documented

          -  All patients with prostate cancer can continue to receive treatment with GnRH agonists
             while on study, as long as there is evidence of disease progression on prior therapy

          -  Patients with castration resistant prostate cancer must have castrate levels of
             testosterone (< 50 ng/dL [1.74 nmol/L])

          -  Patients with metastatic hormone receptor (HR) prostate cancer and mutations in either
             BRCA1, BRCA2, or ATM should continue to receive anti-AR therapy

        Exclusion Criteria:

          -  Patients who have had chemotherapy or radiotherapy within 4 weeks or 5 half-lives,
             whichever is shorter (6 weeks for nitrosoureas or mitomycin C). Patients must be >= 2
             weeks since any prior administration of a study drug in a phase 0 or equivalent study
             and be >= 1 week from palliative radiation therapy. Patients must have recovered to
             eligibility levels from prior toxicity or adverse events

          -  Patients who have had prior treatment with talazoparib are ineligible

          -  Patients who have had prior monoclonal antibody therapy must have completed that
             therapy >= 6 weeks (or 3 half-lives of the antibody, whichever is shorter) prior to
             enrollment on protocol (minimum of 1 week between prior therapy and study enrollment)

          -  Patients who are receiving any other investigational agents

          -  Patients with active brain metastases or carcinomatous meningitis are excluded from
             this clinical trial. Patients with treated brain metastases, whose brain metastatic
             disease has remained stable for >= 3 months without requiring steroid and anti-seizure
             medication are eligible to participate

          -  Eligibility of subjects receiving any medications or substances with the potential to
             affect the activity or pharmacokinetics of talazoparib will be determined following
             review by the principal investigator

          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
             arrhythmia, or psychiatric illness/social situations that would limit compliance with
             study requirements

          -  Pregnant women are excluded from this study because the effects of the study drugs on
             the developing fetus are unknown

          -  Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral
             therapy with undetectable viral load within 6 months are eligible for this trial

          -  Patients who require use of coumarin-derivative anticoagulants such as warfarin are
             excluded. Low molecular weight heparin is permitted for prophylactic or therapeutic
             use. Low-dose warfarin (=< 1 mg/day) is permitted

          -  Women who are currently lactating

          -  History of prior malignancies within the past 3 years other than non-melanomatous skin
             cancers that have been controlled
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Percent of patients who demonstrate simultaneous Rad51 activation
Time Frame:At cycle 2 day 1
Safety Issue:
Description:Will be measured as the percent of patients who demonstrate simultaneous Rad51 activation, defined to be at least 5% cells with at least 5 Rad51 foci, and lack of gamma-H2AX activation, defined to be less than 4% nuclear area positive, at the cycle 2 day 1 biopsy.

Secondary Outcome Measures

Measure:Overall response rate
Time Frame:Up to 30 days after last dose
Safety Issue:
Description:Will estimate the overall response rate (complete response + partial response) among eligible patients who have received at least one dose of talazoparib. A 95% confidence interval for this response rate will also be computed. For this analysis, response classifications will follow Response Evaluation Criteria in Solid Tumors version 1.1 guidelines.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

September 15, 2020