Talazoparib, an Oral PARP Inhibitor, in Patients With Advanced Solid Tumors and Aberrations in Genes Involved in DNA Damage Response

Solid Tumors Clinical Trial

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

Status Recruiting

Clinical Trial Summary

Background:

People with advanced cancer are usually treated with surgery, radiation, immunotherapy drugs, or chemotherapy drugs. Talazoparib is a type of drug called a PARP inhibitor. It prevents DNA repair and has shown anticancer activity in early clinical trials. Researchers want to learn more about how it works in different types of patients.

Objective:

To find out how talazoparib works in tumor cells and if it works differently in people who have or have not already been treated with another PARP inhibitor.

Eligibility:

Adults ages 18 and older with locally advanced or metastatic solid tumors, who have a gene variation that changes how their tumors are able to repair DNA

Design:

Participants will be screened with a medical history and physical exam. Their medical records will be reviewed. Their ability to do daily activities will be assessed. They will give blood samples. Screening tests will be repeated during the study.

Participants tumors will be measured. They will have tumor biopsies.

Participants samples will be used for gene testing.

Participants will be put into 1 of 2 groups: those who have never had a PARP inhibitor and those who have had a PARP inhibitor.

Participants will take talazoparib by mouth daily. It is given in cycles that are 4 weeks (28 days) long. They will get the study drug for as long as their cancer does not get worse, they can tolerate the side effects, and they choose to stay on the study.

After treatment ends, participants condition will be followed. They will be watched for side effects. They will be contacted once about 30 days after treatment ends.

Clinical Trial Description

Background:

Talazoparib is a PARP inhibitor (PARPi) with greater in vitro activity than others currently in development. Talazoparib has been shown to cause single-agent synthetic lethality in BRCA1/2- and PTEN-deficient cell lines and has potent antitumor activity in animal models of tumors harboring mutations in DNA repair pathways.

Talazoparib is FDA-approved for patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm), HER2 negative locally advanced or metastatic breast cancer.

This pilot study will evaluate the pharmacodynamic (PD) effects of talazoparib on DNA damage markers in tumor biopsy tissue in both patients who are PARPi-na(SqrRoot) ve and those who have received prior PARPi other than talazoparib, to investigate the potential for differential PARPi responses based on the mechanism of talazoparib action.

Primary Objective:

Determine the PD effect of talazoparib in tumor biopsies for patients with aberrations in DNA damage response genes who have or have not received prior PARP inhibitor treatment (separately). The PD effect of interest is replication stress, as evaluated by activation of Rad51 combined with a lack of >=H2AX activation.

Secondary Objective:

Determine the response rate (CR + PR) of treatment with talazoparib in patients with aberrations in DNA damage response gene.

Exploratory Objectives:

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

Eligibility:

Adult patients with locally advanced or metastatic solid tumors and documented germline or somatic deleterious BRCA1 or BRCA2 mutations, or aberrations in other defined genes involved in DNA damage response, whose disease has progressed following at least one standard therapy or who have no acceptable standard treatment options or talazoparib as a standard treatment option.

No major surgery, radiation, or chemotherapy within 4 weeks prior to study enrollment, and recovered from toxicities of prior therapies to at least eligibility levels.

Age greater than or equal to18 years of age; ECOG performance status 2, with adequate organ function.

Willingness to undergo tumor biopsies

Study Design:

Two sets of patients will be enrolled and assessed in separate cohorts: a) patients who are PARPi-na(SqrRoot) ve, and b) patients who have previously been treated with and had documented progression on a PARPi other than talazoparib either immediately before this trial or with an intervening therapy, to assess reversions in PARPi sensitivity genes.

Talazoparib will be administered orally each day in 28-day cycles. Dosing will be at the established recommended Phase II dose of 1000 g/day each day for 28 days.

Tumor biopsies will be mandatory at baseline (pre-dose), and on cycle 2 day 1 ( 3 days) 4 ( 1) hours post-dose. ;

Related Conditions & MeSH terms

• Neoplasms
• Solid Tumors

• NCT number: NCT04692662
• Study type: Interventional
• Source: National Institutes of Health Clinical Center (CC)
• Contact: Jennifer H Zlott
• Phone: (240) 760-6046
• Email: zlottjh@mail.nih.gov
• Status: Recruiting
• Phase: Phase 2
• Start date: January 15, 2021
• Completion date: December 31, 2023