Measuring The Effects Of Talazoparib In Patients With Advanced Cancer And DNA Repair Variations

Study Overview

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

This phase II trial studies if talazoparib works in patients with cancer that may have spread from where it first started to nearby tissue, lymph nodes, or distant parts of 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.

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 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo biopsy and blood sample collection, as well as computed tomography (CT) scan or magnetic resonance imaging (MRI) throughout the study. After completion of study treatment, patients are followed up at 30 days.

Anatomic Stage III 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
HER2-Positive Breast Carcinoma
Locally Advanced Breast Carcinoma
Locally Advanced Gastric Carcinoma
Locally Advanced Malignant Solid Neoplasm
Locally Advanced Ovarian Carcinoma
Locally Advanced Pancreatic Carcinoma
Locally Advanced Prostate Carcinoma
Metastatic Breast Carcinoma
Metastatic Gastric Carcinoma
Metastatic Malignant Solid Neoplasm
Metastatic Ovarian Carcinoma
Metastatic Pancreatic Carcinoma
Metastatic Prostate Carcinoma
Platinum-Sensitive Ovarian Carcinoma
Recurrent Breast Carcinoma
Recurrent Gastric Carcinoma
Recurrent Ovarian Carcinoma
Recurrent Pancreatic Carcinoma
Recurrent Prostate Carcinoma
Stage II Pancreatic Cancer AJCC v8
Stage III Ovarian Cancer AJCC v8
Stage III Pancreatic Cancer AJCC v8
Stage III Prostate Cancer AJCC v8
Stage IV Ovarian Cancer AJCC v8
Stage IV Pancreatic Cancer AJCC v8
Stage IV Prostate Cancer AJCC v8

PROCEDURE: Biopsy Procedure
PROCEDURE: Biospecimen Collection
PROCEDURE: Computed Tomography
PROCEDURE: Magnetic Resonance Imaging
DRUG: Talazoparib

NCI-2020-06906
NCI-2020-06906 (REGISTRY Identifier) (REGISTRY: CTRP (Clinical Trial Reporting Program))
000264
000246
10371 (OTHER Identifier) (OTHER: National Cancer Institute LAO)
10371 (OTHER Identifier) (OTHER: CTEP)

Study Record Dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Registration Dates	Results Reporting Dates	Study Record Updates
First Submitted 2020-09-15	Results First Submitted N/A	Last Update Submitted that met QC Criteria 2025-04-08
First Submitted that Met QC Criteria 2020-09-15	Results First Submitted that Met QC Criteria N/A	Last Update Posted (ACTUAL) 2025-04-09
First Posted (ACTUAL) 2020-09-16	Results First Posted N/A	Last Verified 2024-12

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

Design Details

Primary Purpose:
Treatment

Allocation:
Na

Interventional Model:
Single Group

Masking:
None

Arms and Interventions

Participant Group/Arm	Intervention/Treatment
EXPERIMENTAL: Treatment (talazoparib) Patients receive talazoparib PO QD on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo biopsy and blood sample collection as well as CT scan or MRI throughout the study.	PROCEDURE: Biopsy Procedure Undergo biopsy PROCEDURE: Biospecimen Collection Undergo blood sample collection PROCEDURE: Computed Tomography Undergo CT scan PROCEDURE: Magnetic Resonance Imaging Undergo MRI DRUG: Talazoparib Given PO

Participant Group/Arm

Intervention/Treatment

EXPERIMENTAL: Treatment (talazoparib)

Patients receive talazoparib PO QD on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo biopsy and blood sample collection as well as CT scan or MRI throughout the study.

PROCEDURE: Biopsy Procedure

Undergo biopsy

PROCEDURE: Biospecimen Collection

Undergo blood sample collection

PROCEDURE: Computed Tomography

Undergo CT scan

PROCEDURE: Magnetic Resonance Imaging

Undergo MRI

DRUG: Talazoparib

Given PO

Primary Outcome Measures	Measure Description	Time Frame
Percent of patients who demonstrate simultaneous Rad51 activation	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 (NAP), at the cycle 2 day 1 biopsy.	At cycle 2 day 1

Secondary Outcome Measures	Measure Description	Time Frame
Overall response rate	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.	Up to 30 days after last dose

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person’s general health condition or prior treatments.

Ages Eligible for Study:
ALL

Sexes Eligible for Study:
18 Years

Accepts Healthy Volunteers:

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-Molecular Analysis for Therapy Choice (NCI-MATCH) (NCT02465060) study-designated Clinical Laboratory Improvement Act (CLIA) laboratory or at Myriad Genetics, GeneDx, Invitae, 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; no more than 6 patients (across both cohorts) with an eligibility mutation in any one gene will be enrolled

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: ARID1A, ATM, ATR, BACH1 (BRIP1), BAP1, BARD1, CDK12, CHK1, CHK2, IDH1, IDH2, MRE11A, NBN, PALB2, RAD50, RAD51, RAD51B, RAD51C, RAD51D, RAD54L
Age >= 18 years of age
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
Hemoglobin >= 10 g/dL
Total bilirubin =< 1.5 x institutional upper limit of normal (=< 3 x upper limit of normal in the presence of documented Gilbert's syndrome or liver metastases at baseline)
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 (CrCl) >= 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 CT scan, MRI, or calipers by clinical exam
Patients must have a tumor site amenable to biopsy. If avoidable, the lesion for biopsy should not be selected as a target lesion for RECIST measurements
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 potential must agree to use a highly effective method of contraception for the duration of study participation and for at least 7 months 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. Male patients with female partners of reproductive potential and pregnant partners who are treated or enrolled on this protocol must also agree to use adequate contraception for the duration of study participation and for at least 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 in the metastatic setting
PATIENTS WITH BREAST CANCER:
Patients with HER2+ breast cancer should have had 2 prior systemic lines of therapy in the metastatic setting, including anti-HER2 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 as per FDA indication. 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 in the metastatic setting
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 gonadotropin-releasing hormone (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-androgen receptor (anti-AR) therapy

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) except for monoclonal antibody therapies that have been proven to be safe when combined with PARP inhibitor (PARPi) treatment (such as anti-PD-1/PD-L1 and anti-HER2), which must be completed >= 4 weeks prior to 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 >= 1 month 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-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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Investigators

PRINCIPAL_INVESTIGATOR: A P Chen, National Cancer Institute LAO

Publications

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

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Resources

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Caregivers

Clinical Trial Record