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

Trial Status: In Review

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.

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

Location information is not yet available.

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 Phase Phase II

Trial Type Treatment

Lead Organization
National Cancer Institute LAO

Principal Investigator
A P Chen

  • Primary ID 10371
  • Secondary IDs NCI-2020-06906
  • Clinicaltrials.gov ID NCT04550494