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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04692662
• Other study ID #: 10000264
• Secondary ID: 000264-C
• Status: Recruiting
• Phase: Phase 2
• Start date: January 15, 2021
• Est. completion date: December 31, 2023

Study information

• Verified date: December 29, 2020
• Source: National Institutes of Health Clinical Center (CC)
• Contact: Jennifer H Zlott
• Phone: (240) 760-6046
• Email: zlottjh[@]mail.nih.gov
• Is FDA regulated: No
• Study type: Interventional

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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 36
• Est. completion date: December 31, 2023
• Est. primary completion date: December 31, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

• INCLUSION CRITERIA:

ELIGIBLE GERMLINE OR SOMATIC MUTATION

• 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-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 [75]:

• 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.

Age greater than or equal to18 years of age.

ECOG performance status less than or equal to 2 (see Appendix A).

Life expectancy of greater than 3 months.

Patients must have normal organ and marrow function as defined below:

• absolute neutrophil count greater than or equal to 1,500/mcL

• platelets greater than or equal to 100,000/mcL

• hemoglobin greater than or equal to 10g/dL

• total bilirubin less than or equal to 1.5 X institutional upper limit of normal

• AST(SGOT)/ALT(SGPT) less than or equal to 3 X institutional upper limit of normal

• creatinine less than or equal to 1.5 X institutional upper limit of normal OR

• creatining clearance GFR greater than or equal to 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 greater than or equal to 20 mm (greater than or equal to 2 cm) by chest x-ray or as greater than or equal to 10 mm (greater than or equal to 1 cm) with CT scan, MRI, or calipers by clinical exam. See Section 11 (Measurement of Effect) for the evaluation of measurable disease.

Patients must have a tumor site amenable to biopsy, and this needs to be a lesion separate to those considered for RECIST measurable lesions.

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 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

DISEASE SPECIFIC CRITERIA:

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 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 (less than 50 ng/dL [1.74 nmol/L].

• Patients with metastatic hormone-resistant (HR) prostate cancer and mutations in either BRCA1, BRCA2, or ATM should continue to receive anti-androgen receptor (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)<TAB>Patients must be greater than or equal to 2 weeks since any prior administration of a study drug in a Phase 0 or equivalent study and be (Bullet) 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 greater than or equal to 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 PARPi treatment (such as anti-PD-1/PD-L1 and anti- HER2), which must be completed greater than or equal to 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 greater than or equal to 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.

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 (less than or equal to 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.

Related Conditions & MeSH terms

• Neoplasms
• Solid Tumors

Intervention

Drug:
• talazoparib
Talazoparib will be administered orally at the FDA-approved dose of 1000 (Micro)g/day each day in 28-day cycles.

Locations

Country	Name	City	State
United States	National Institutes of Health Clinical Center	Bethesda	Maryland

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

References & Publications (3)

Murai J, Huang SY, Das BB, Renaud A, Zhang Y, Doroshow JH, Ji J, Takeda S, Pommier Y. Trapping of PARP1 and PARP2 by Clinical PARP Inhibitors. Cancer Res. 2012 Nov 1;72(21):5588-99. doi: 10.1158/0008-5472.CAN-12-2753. — View Citation

Pommier Y, O'Connor MJ, de Bono J. Laying a trap to kill cancer cells: PARP inhibitors and their mechanisms of action. Sci Transl Med. 2016 Oct 26;8(362):362ps17. Erratum in: Sci Transl Med. 2016 Dec 7;8(368):368er7. — View Citation

Wilsker DF, Barrett AM, Dull AB, Lawrence SM, Hollingshead MG, Chen A, Kummar S, Parchment RE, Doroshow JH, Kinders RJ. Evaluation of Pharmacodynamic Responses to Cancer Therapeutic Agents Using DNA Damage Markers. Clin Cancer Res. 2019 May 15;25(10):3084-3095. doi: 10.1158/1078-0432.CCR-18-2523. Epub 2019 Feb 21. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	the pharmacodynamic effect of talazoparib in tumor biopsies	The PD effect of interest is replication stress, as evaluated by activation of Rad51 combined with a lack of ?H2AX activation in an immunofluorescence assay.	cycle 2 day 1
Secondary	overall response rate (complete and partial responses)	clinical outcome will be measured using RECIST 1.1 criteria.	best response during the course of treatment

External Links

•   NIH Clinical Center Detailed Web Page