Clinical Trials /

Gedatolisib Plus Talazoparib in Advanced Triple Negative or BRCA1/2 Positive, HER2 Negative Breast Cancers

NCT03911973

Description:

This study is designed to determine the RP2D 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 (deficient).

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Gedatolisib Plus Talazoparib in Advanced Triple Negative or BRCA1/2 Positive, HER2 Negative Breast Cancers
  • Official Title: Phase 2 Trial With Safety Run-In of Gedatolisib Plus Talazoparib in Advanced Triple Negative or BRCA1/2 Positive, HER2 Negative Breast Cancers Big Ten Cancer Research Consortium BTCRC-BRE18-337

Clinical Trial IDs

  • ORG STUDY ID: BTCRC-BRE18-337
  • NCT ID: NCT03911973

Conditions

  • TNBC - Triple-Negative Breast Cancer

Interventions

DrugSynonymsArms
GedatolisibTalazoparib + Gedatolisib
TalazoparibTalazoparib + Gedatolisib

Purpose

This study is designed to determine the RP2D 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 (deficient).

Detailed Description

      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
      chemotherapy.

      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
      (mutated/deficient).
    

Trial Arms

NameTypeDescriptionInterventions
Talazoparib + GedatolisibExperimentalTalazoparib + Gedatolisib Dose Level -1: Gedatolisib 150mg IV, Days 1,8,15,22; Talazoparib 0.75 mg/orally qd, Days 1-28 Dose Level 1: Gedatolisib 180mg IV, Days 1,8,15,22; Talazoparib 0.75 mg/orally qd, Days 1-28 Dose Level 2: Gedatolisib 180mg IV, Days 1,8,15,22; Talazoparib 1.00 mg/orally qd, Days 1-28
  • Gedatolisib
  • Talazoparib

Eligibility Criteria

        Inclusion Criteria:

          -  Male or female ≥ 18 years of age at time of consent.

          -  Subjects with histologically or 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.

               -  Phase II Cohort B: Patients with advanced HER2 negative breast cancer and a
                  germline BRCA1 or 2 (1/2) mutation

               -  Phase I run-in: meets criteria for either cohort A or B

          -  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 2 lines of prior
                  chemotherapy for advanced disease are allowed.

               -  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
                  registration.

          -  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
             separately.

          -  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.

        Exclusion Criteria:

          -  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
             physician.

          -  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
             major surgery).

          -  Any prior or concurrent malignancy whose natural history or treatment has the
             potential to interfere with the safety or efficacy assessment of this investigational
             regimen.

          -  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)
                  <50%

               -  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
                  QT syndrome.

               -  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
                  significant bleeding.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum Tolerated Dose (MTD) of talazoparib in combination with gedatolisib (Phase I)
Time Frame:28 days
Safety Issue:
Description:Determine the recommended Phase 2 dose (RP2D) of talazoparib in combination with gedatolisib in patients with advanced human epidermal growth factor receptor 2 (HER2) negative (triple negative or BRCA1/2 deficient) breast cancer.

Secondary Outcome Measures

Measure:Investigator-assessed Progression-Free Survival (PFS) (Cohort B only)
Time Frame:24 Months
Safety Issue:
Description:Investigator-assessed PFS; this is defined as time from treatment initiation with talazoparib in combination with gedatolisib to radiological disease progression by RECIST 1.1 or death from any cause on treatment in patients with BRCA1/2 deficient advanced HER2 negative breast cancer.
Measure:Objective Response Rate (Cohort B only)
Time Frame:24 Months
Safety Issue:
Description:Ojbective Reponse Rate (Cohort B only), which will include confirmed complete response (CR) + confirmed partial response (PR) determined as per RECIST1.1 on treatment with talazoparib in combination with gedatolisib in patients with BRCA1/2 deficient advanced HER2 negative breast cancer.
Measure:Duration of Response (DOR)
Time Frame:24 Months
Safety Issue:
Description:Duration of Response (DoR) on treatment with talazoparib in combination with gedatolisib in all patients (Phase I run-in, Cohorts A and B). DoR is defined as the time that measurement criteria are met for complete or partial response (whichever status is recorded first) until the date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since treatment started).
Measure:Clinical Benefit Rate (CBR) at 16 weeks
Time Frame:16 Weeks
Safety Issue:
Description:Clinical Benefit Rate (CBR) at 16 weeks; this will include sum of confirmed complete plus partial responses plus stable disease at 16 weeks on treatment with talazoparib in combination with gedatolisib in patients with advanced TNBC or BRCA1/2 deficient breast cancer (Cohorts A and B).
Measure:Overall Survival
Time Frame:24 Months
Safety Issue:
Description:Overall Survival (OS) defined as the time from treatment initiation with talazoparib in combination with gedatolisib until death as a result of any cause in patients with advanced TNBC or BRCA1/2 deficient breast cancer or TNBC (Cohorts A and B).
Measure:Rates of Adverse Events
Time Frame:24 Months
Safety Issue:
Description:Rates of adverse events by NCI Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5 on treatment with talazoparib in combination with gedatolisib in patients with advanced TNBC or BRCA1/2 deficient breast cancer (Cohorts A and B).

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Kari Wisinski

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