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

  • STATUS
    Recruiting
  • End date
    Dec 31, 2023
  • participants needed
    36
  • sponsor
    National Cancer Institute (NCI)
Updated on 13 January 2021

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.

Details
Condition Solid Tumors, Solid Neoplasm, Solid Tumour
Treatment Talazoparib
Clinical Study IdentifierNCT04692662
SponsorNational Cancer Institute (NCI)
Last Modified on13 January 2021

Eligibility

Yes No Not Sure

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
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