Triple negative breast cancers (TNBC) are tumors that lack the hormone receptors and the
human epidermal growth factor receptor-2 (HER2). TNBC represents about 15% of all invasive
breast cancers diagnosed in the United States each year. This aggressive breast cancer
subtype has the lowest overall survival rate of all advanced breast cancers with median
survival of 12-13 months. Due to the lack of expression of the hormone receptors and
HER2,chemotherapy remains the current treatment for women with advanced TNBC.
A subset of breast cancers have defects in homologous recombination (HR) DNA repair due to
germline BRCA mutations, and these cases are often triple negative. Poly(ADP-ribose)
polymerase (PARP) enzymes are involved in DNA repair and are activated by DNA strand breaks.
PARP function is particularly critical in tumors with BRCA1/2 mutations, making PARP
inhibition a rationale therapeutic strategy.
Two PARP inhibitors, Talazoparib and Olaparib, were approved by the FDA in 2018 for patients
who have advanced HER2 negative breast cancer and a germline BRCA 1/2 mutation. These
approvals were based on results from the EMBRACA and OLYMPIAD trials, respectively, which
both showed an improvement in progression-free survival (PFS) versus physician choice
Gedatolisib is an intravenously administered PI3K and mTOR inhibitor which has been shown to
be safe in patients with metastatic breast cancer, either alone or in combination with oral
therapies. Previous research has shown that PI3K inhibitors lower nucleotide pools required
for DNA synthesis and S-phase progression. Additionally, inhibition of PI3K/mTOR could impede
PI3K interaction with the homologous recombination complex, increasing dependency on PARP
enzymes for DNA repair. Based on this data, the combination of a PI3K inhibitor and PARP
inhibitor could potentially lead to a new, non-chemotherapy treatment option for TNBC with
wild-type BRCA and improve the modest PFS seen with the PARP inhibitors as single agents in
BRCA1/2 mutant advanced breast cancer. The hypothesis for this trial is that the gedatolisib
will sensitize advanced TNBC or BRCA1/2 mutant breast cancers to PARP inhibition with
talazoparib. This study is thus designed to determine the recommended phase 2 dose of
gedatolisib in combination with talazoparib and to evaluate the efficacy of this combination
in advanced HER2 negative breast cancer that is triple negative or BRCA1/2 positive
- Male or female ≥ 18 years of age at time of consent.
- Subjects with histologically confirmed breast cancer that is advanced (defined as
metastatic or unresectable).
- Phase II Cohort A: Patients with advanced triple negative breast cancer (TNBC)
with negative or unknown germline BRCA status. Variants of undetermined
significance in BRCA 1/2 should be considered negative.
- Note: most recent tumor biopsy must be ER/PR negative or have ER and PR <10%
and all prior biopsies of metastatic sites cannot have ever had ER or PR
- Note: HER2 is considered negative if ISH negative by ASCO/CAP guidelines or
HER2+ 0 or 1+ on IHC or 2+ with negative ISH
- Phase II Cohort B: Patients with advanced HER2 negative breast cancer and a
germline BRCA1 or 2 (1/2) mutation
---Note: HER2 is considered negative if ISH negative by ASCO/CAP guidelines or
HER2+ 0 or 1+ on IHC or 2+ with negative ISH
- Phase I run-in: meets criteria for either cohort A or B
- Phase I run-in: Measurable or evaluable (non-measurable) disease (see
section 9.2 for more detail).
- Phase II: Measurable disease by RECIST 1.1 is required.
- Prior therapy:
- Cohort A: At least one line of prior systemic therapy for advanced breast cancer
(chemotherapy or other targeted therapy allowed). No more than 3 lines of prior
chemotherapy for advanced disease are allowed. No limit on prior endocrine or
- Cohort B: No more than 2 lines of prior chemotherapy for advanced disease are
allowed. No limit on prior endocrine or targeted therapies.
- Both cohorts: no prior PARP inhibitor for advanced breast cancer
- Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
within 28 days prior to study registration.
- Life expectancy of 12 weeks or greater as determined by the treating physician.
- Demonstrate adequate organ function as defined in the table in the protocol; all
screening labs to be obtained within 28 days prior to registration.
- Archived tumor tissue available (Metastatic disease from non-bone and non-brain sites
preferred, but primary breast or lymph node tissue is permitted. Confirmation of
available tissue only- tumor samples do not need to be shipped for eligibility
purposes. Tumor samples do not need to be shipped until subject is confirmed eligible
and is registered for treatment.
- Ability to take oral medications.
- No history of type I diabetes. For patients with known type II diabetes, must have
controlled diabetes (Hgb A1c < 7.0 mmol/L within 30 days of study entry) with no more
than one oral anti-diabetic agent and no insulin.
- No active central nervous system (CNS) metastatic disease. NOTE: Subjects with CNS
involvement must meet ALL of the following to be eligible:
- At least 28 days from prior definitive treatment of their CNS disease by surgical
resection, SBRT or WBRT at the time of registration
- Asymptomatic and off systemic corticosteroids and/or enzyme-inducing
antiepileptic medications for brain metastases for >14 days prior to
- Provided written informed consent and HIPAA authorization for release of personal
health information, approved by an Institutional Review Board (IRB).
- NOTE: HIPAA authorization may be included in the informed consent or obtained
- Women of childbearing potential (WOCP) must not be pregnant or breast-feeding. A
negative serum or urine pregnancy test is required within 14 days of study
registration. If the urine test cannot be confirmed as negative, a serum pregnancy
test will be required.
- Women of childbearing potential (WOCP) must be willing to use two effective methods of
birth control such as an oral, implantable, injectable, or transdermal hormonal
contraceptive, an intrauterine device (IUD), use of a double barrier method (condoms,
sponge, diaphragm, or vaginal ring with spermicidal jellies or cream), vasectomized
partner, or total abstinence for the course of the study until 7 months after the last
dose of study drug.
- NOTE; Women are considered to be of childbearing potential unless they are
postmenopausal (≥45 years of age and has not had menses for greater than 12
consecutive months) or bilateral oophorectomy or surgically sterile (bilateral tubal
ligation or hysterectomy) or not heterosexually active for the duration of the study
and willing to continue for at least 7 months after the last dose of study drug.
- Men who are not surgically sterile (vasectomy) must agree to use an acceptable method
of contraception. Male subjects with female sexual partners who are pregnant, possibly
pregnant, or who could become pregnant during the study must agree to use condoms from
the first dose of study drug through at least 4 months after the last dose of study
drug. Total abstinence for the same time period is an acceptable alternative.
- As determined by the enrolling physician or protocol designee, ability of the subject
to understand and comply with study procedures for the entire length of the study.
- Active infection requiring systemic therapy. Patients with a known history of HIV must
have a CD4 count ≥ the institutional lower limit of normal within 28 days prior to
registration. Patients with HIV must also be on a stable anti-retroviral regimen for ≥
28 days before registration.
- Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the
mother is being treated on study).
- Patients who have had chemotherapy, targeted therapy, or radiotherapy within 2 weeks
(6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who
have not recovered from acute effects of any prior therapy to baseline or Grade ≤1.
Grade 2 or higher exceptions include alopecia, up to grade 2 neuropathy or other Grade
2 AEs or lab values not constituting a safety risk in the opinion of the treating
- Treatment with any investigational drug within 14 days prior to registration or within
5 half-lives of the investigational product, whichever is longer.
- Subject has had major surgery within 14 days prior to registration or has not
recovered from major side effects of the surgery (tumor biopsy is not considered as
- Any prior or concurrent malignancy whose natural history or treatment has the
potential to interfere with the safety or efficacy assessment of this investigational
- Known hypersensitivity to any of the excipients of gedatolisib or talazoparib.
- Any impairment of gastrointestinal (GI) function or GI disease that may significantly
alter the absorption of talazoparib (e.g., ulcerative diseases, uncontrolled nausea,
vomiting, diarrhea, malabsorption syndrome, or small bowel resection).
- Known active hepatitis B or C (testing not mandatory). Patients who have completed
curative therapy for HCV are eligible.
- Known history of myelodysplastic syndrome or acute myeloid leukemia.
- Subjects with any of the following conditions:
- History of drug-induced pneumonitis within last 12 months or any history of
pneumonitis related to an mTOR inhibitor or current clinically significant
pulmonary disease not due to the breast cancer.
- History of abdominal fistula, gastrointestinal perforation, or intra- abdominal
abscess within 28 days prior to registration.
- Any history of cerebrovascular accident (CVA) or transient ischemic attack within
12 months prior to registration.
- History of acute coronary syndromes (including myocardial infarction, unstable
angina, coronary artery bypass grafting, coronary angioplasty, or stenting) or
symptomatic pericarditis within 6 months prior to registration.
- Symptomatic congestive heart failure (New York Heart Association III-IV) or
documented current cardiomyopathy with left ventricular ejection fraction (LVEF)
- Clinically significant cardiac ventricular arrhythmias (e.g. sustained
ventricular tachycardia/ventricular fibrillation) or high-grade AV block (e.g.
bifascicular block, Mobitz type II and third-degree AV block) unless a pacemaker
is in place.
- Long QT syndrome or family history of idiopathic sudden death or congenital long
- Any concurrent severe and/or uncontrolled medical condition that would, in the
investigator's judgment, cause unacceptable safety risks, contraindicate subject
participation in the clinical study or compromise compliance with the protocol.
- Subject is currently receiving warfarin or other coumarin-derived anticoagulant
for treatment, prophylaxis or otherwise. Therapy with heparin, low molecular
weight heparin (LMWH), direct thrombin inhibitors (such as dabigatran) or novel
oral anticoagulants (such as rivaroxaban or apixaban) are allowed as long as the
patient has been on this therapy for at least 14 days with no clinically