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.
- 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.
