- The new drug BMN 673 (talazoparib) has been shown to fight tumor cells in animals and some
people. It is a PARP inhibitor. It works on tumor cell DNA damage repair process.
Researchers want to see if BMN 673 shrinks cancer again in women with ovarian cancer and
whose cancer initially got shrunk but grew back on the first PARP inhibitor.
- To study BMN 673 (talazoparib) in people with ovarian cancer born with a BRCA mutation and
whose cancer got shrunk but became worse after they took a similar drug.
- Women at least 18 years old:
- with recurrent and/or metastatic gBRCAm-associated ovarian cancer AND
- whose disease is growing after already being treated with PARP inhibitors AND
- with no other treatment(s) in between the first PARP inhibitors and a screening visit.
- Participants will be screened with medical history, physical exam, and heart and blood
- Participants will take the study drug by mouth once daily. They will take the drug in
- They will keep a diary of doses and any side effects.
- Participants will have 4 study visits in cycle 1, then 1 visit every cycle. Visits may
- Blood tests
- Physical exam
- Computed tomography (CT) or magnetic resonance imaging (MRI) scans. Participants will
lie in a machine that takes pictures of their body.
- Participants will have a biopsy before starting the study drug. A small piece of tumor
tissue will be removed by needle, guided by a scan. They may have two more biopsies
- Participants will be followed for 30 days after taking the last dose of study drug. A
physical exam, blood tests, and CT or other scans will be done.
- Participants will have follow-up calls to ask about any side effects.
- Patients with germline BRCA1/2 mutations (gBRCAm) demonstrate repeated therapeutic
susceptibility to DNA damaging agents, especially platinums, even if they have
previously progressed on a similar (platinum-based) regimen.
- PARP inhibitors (PARPi) have clinical activity in gBRCAm-associated malignancies,
although patients eventually develop progressive disease.
- BMN 673 (talazoparib) is a novel PARPi, with excellent oral bioavailability and greater
anti-tumor activity in vitro and in vivo at lower concentrations than first generation
- It is unknown whether secondary BRCA mutations or other potential mechanisms of
clinical resistance portend cross-resistance to a highly potent PARPi.
-To determine the objective response rate (CR+PR) of single agent BMN 673 (talazoparib) in
ovarian cancer patients with gBRCAm who have progressed on prior PARPi therapy.
- Women with recurrent and/or metastatic gBRCAm-associated ovarian cancer, with
progression on PARPi monotherapy within the immediate prior 2 months of the time of
- Patients should have responded to their prior PARPi therapy (CR, PR or SD>4months).
- Patients cannot have received another therapy between stopping their first PARPi
therapy\ and initiating therapy on this trial, but must be off the prior PARPi for at
least 4 weeks.
- ECOG performance status 0-2 and adequate organ and marrow function.
- This is an open label, single arm phase II trial to examine activity of BMN 673
- Patients will receive BMN 673 (talazoparib) at the RP2D of 1mg p.o. once daily on 28
- Research samples including whole blood, plasma, CTCs, and tumor biopsies will be
obtained for PD endpoints at baseline, cycle 1 day 29 (prior to cycle 2 day 1), and/or
at progression in all patients.
- Patients will be evaluated every two cycles for response using RECISTv1.1 criteria and
every cycle for safety using CTCAEv4.0.
- INCLUSION CRITERIA:
- Recurrent, and/or metastatic germline BRCA 1/2 mutation-associated ovarian cancer,
with progression on a PARP inhibitor monotherapy after attaining a response to that
PARPi (CR, PR, or SD greater than or equal to 4mo)
- Progression should have occurred within the immediate prior 2 months of the time of
screening visit, with no intervening anti-cancer therapy.
- Patients must be at least 4 weeks from the last dose of prior PARP inhibitor.
- All patients must have at least one lesion deemed safe to biopsy and be willing to
undergo mandatory baseline biopsy. It is preferred that this lesion be a lesion that
progressed or arose while on the prior PARP therapy.
- Histopathologic diagnosis of ovarian cancer (including primary peritoneal and
fallopian tube cancers) must be confirmed in the Laboratory of Pathology, NCI.
- Age greater than or equal to18 years.
- ECOG performance status less than or equal to 2 (Karnofsky greater than or equal to
- 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 to100,000/mcL
- total bilirubin less than or equal to 1.5X upper limit of normal, unless known
Gilbert s syndrome
- AST(SGOT)/ALT(SGPT) less than or equal to 3 x institutional upper limit of
- creatinine < 1.5 X upper limit of normal
- measured creatinine clearance >60 mL/min/1.73 m2 for patients with serum creatinine
levels > 1.5 x upper limit of normal.
- hemoglobin greater than or equal to 10 mg/dL (in the absence of transfusion within 24
hours prior to dosing).
- All patients must have measurable disease by RECIST.
- Use of raloxifene for bone health is allowed.
- Patients must be at least 1 week from the last dose of complementary or
- Patients who have had major surgery must be fully recovered and greater than or
equal to 4 weeks postoperative prior to enrolling on study.
- Women of child-bearing potential must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) prior to study entry,
for the duration of study
participation, and for at least three months following the last dose of experimental
therapy and must have a negative urine or serum pregnancy test within 7 days prior to the
start of the study.
- Patient must be able to swallow pills.
- Integral biomarkers: all patients who are eligible for the study due to a history of
positive BRCA1/2 mutation must provide documented evidence of their deleterious
germline mutation status, obtained in a CLIA-certified laboratory, including but not
limited to Myriad Genetics prior to study enrollment. Variants of uncertain
significance (VUS) of BRCA1/2 and BRCA1/2 somatic mutations are not considered
deleterious germline BRCA1/2 mutations. Due to the long acceptance of BRCA 1 and BRCA
2 mutation testing through Myriad, Myriad results will be acceptable. If testing for
BRCA 1 and BRCA 2 mutation is done by other organizations, a genetic consultation
report from a qualified medical professional confirming that the laboratory results
showed a recognized germ line deleterious BRCA 1 or BRCA 2 mutation or deleterious
BRCA 1 rearrangement is required.
- Ability to understand and the willingness to sign a written informed consent
- Patients who have had prior BMN 673 (talazoparib) therapy.
- Patients with known brain metastases diagnosed within 1 year will be excluded from
this clinical trial because of their poor prognosis and because they often develop
progressive neurologic dysfunction that would confound the evaluation of neurologic
and other adverse events. Exception: patients with brain metastases diagnosed greater
than 1 year prior to study entry may be considered if they received sterilizing
therapy to the CNS (resection or radiation) and have been CNS progression-free for
the 1-year period.
- Lack of recovery of prior cancer therapy-related adverse events to Grade less than or
equal to 1 (NCI CTCAE v4.03; except alopecia). Stable persistent grade 2 peripheral
neuropathy may be allowed as determined on a case-by-case basis at the discretion of
the PI. Patients with platinum-related grade 2 or greater hypomagnesemia (on
replacement) will be eligible.
- Uncontrolled intercurrent illness including, but not limited to, symptomatic
congestive heart failure, unstable angina pectoris, cardiac arrhythmia, clinically
significant GI bleeding or hemoptysis within 28 days prior to the start of the study,
or psychiatric illness/social situations that would limit compliance with study
- Patients with active infection will not be eligible, but may become eligible once
infection has resolved and they are at least 7 days from completion of antibiotics.
- Another previous or current invasive malignancy within the last 2 years, with the
exception of curatively treated stage Ia cervical carcinoma, or resected stage Ia
endometrial cancer, and noninvasive nonmelanoma skin cancers.
- HIV-positive patients on combination antiretroviral therapy are ineligible because of
the potential for pharmacokinetic interactions with BMN 673 (talazoparib). HIV-
positive patients who are not on cART and have CD4 counts > 500 are eligible.
- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to BMN 673 (talazoparib)
Patients who are receiving any other investigational or commercial agents with the intent
to treat the malignancy.
- Patients with gastrointestinal conditions that might predispose for drug
intolerability or poor drug absorption.
- Use of nasogastric or G-tube administration.