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Talazoparib and Gedatolisib in Treating Patients with Advanced Triple Negative or BRCA1 / 2 Positive, HER2 Negative Breast Cancer

Trial Status: Active

This phase I / II trial studies the best dose of talazoparib when given together with gedatolisib and to see how well they work in treating patients with triple negative or BRCA1 / 2 positive, HER2 negative breast cancer that has spread to other places in the body (advanced) and cannot be removed by surgery. Talazoparib and gedatolisib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Talazoparib blocks an enzyme called PARP. Talazoparib causes cancer cells to die by breaking the tumor DNA and then stopping the tumor from repairing the damaged DNA. Gedatolisib blocks two receptors called PI3K and mTOR. By blocking these pathways, gedatolisib may cause cancer cells to die and stop growing.

Inclusion Criteria

  • 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 * Note: most recent tumor biopsy must be estrogen receptor/progesterone receptor (ER/PR) negative or have ER and PR <10% and all prior biopsies of metastatic sites cannot have ever had ER or PR >= 20%. * Note: HER2 is considered negative if in situ hybridization (ISH) negative by American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines or HER2+ 0 or 1+ on immunohistochemistry (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
  • 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 targeted therapies * 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
  • Platelet count >= 100,000/uL (obtained within 28 days prior to registration) * Transfusion of packed red blood cell (pRBC) or platelets to meet study eligibility criteria are NOT allowed within 14 days of study registration
  • Absolute neutrophil count (ANC) >= 1500/uL (obtained within 28 days prior to registration) * Transfusion of pRBC or platelets to meet study eligibility criteria are NOT allowed within 14 days of study registration
  • Hemoglobin (Hgb) >= 10 g/dL (obtained within 28 days prior to registration) * Transfusion of pRBC or platelets to meet study eligibility criteria are NOT allowed within 14 days of study registration
  • Creatinine/calculated creatinine clearance (CrCl). CrCl >= 60 mL/min (using Cockcroft-Gault formula) (obtained within 28 days prior to registration)
  • Bilirubin =< 1.5 x upper limit of normal (ULN) (obtained within 28 days prior to registration) (direct bilirubin will be used for Gilbert’s syndrome)
  • Aspartate aminotransferase (AST) =< 2.5 x ULN, < 5 x ULN if metastatic liver disease (obtained within 28 days prior to registration)
  • Alanine aminotransferase (ALT) =< 2.5 x ULN, < 5 x ULN if metastatic liver disease (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, stereotactic body radiation therapy (SBRT) or whole-brain radiotherapy (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 Health Insurance Portability and Accountability Act (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 * 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
  • 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 human immunodeficiency virus (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 including PD-L1 or PD-1 inhibitors, 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 adverse events (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 hepatitis C (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 atrioventricular (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.

Illinois

Chicago
University of Illinois
Status: ACTIVE
Contact: Oana Cristina Danciu
Phone: 312-996-1581

Indiana

Indianapolis
Indiana University / Melvin and Bren Simon Cancer Center
Status: IN_REVIEW
Contact: Kathy Durham Miller
Phone: 317-944-0920

Iowa

Iowa City
University of Iowa / Holden Comprehensive Cancer Center
Status: ACTIVE
Contact: Sneha Deepak Phadke
Phone: 319-384-9502

Wisconsin

Madison
University of Wisconsin Hospital and Clinics
Status: ACTIVE
Contact: Kari Braun Wisinski
Phone: 608-265-1700

PRIMARY OBJECTIVES:

I. Determine the recommended phase 2 dose (RP2D) of talazoparib in combination with gedatolisib in patients with advanced HER2 negative (triple negative or BRCA1/2 deficient) breast cancer. (Phase I)

II. Estimate the objective response rate (ORR) in patients with BRCA negative, or unknown, advanced triple negative breast cancer (Cohort A). (Phase II)

SECONDARY OBJECTIVES:

I. Estimate duration of response (DoR) of talazoparib in combination with gedatolisib in patients with advanced HER2 negative breast cancer. (Phase I)

II. Estimate clinical benefit rate (CBR) (CBR: complete response, partial response, or stable disease) at 16 weeks of talazoparib in combination with gedatolisib in patients with advanced HER2 negative breast cancer and measurable disease by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) at baseline. (Phase I)

III. Estimate overall survival (OS) in patients with triple negative breast cancer (TNBC) treated with talazoparib in combination with gedatolisib. (Phase I)

IV. Estimate the safety and tolerability of talazoparib in combination with gedatolisib in patients with advanced HER2 negative breast cancer. (Phase I)

V. Estimate the median progression-free survival (PFS) in patients with BRCA1/2 deficient advanced breast cancer (Cohort B) treated with the combination of gedatolisib and talazoparib. (Phase II)

VI. Estimate the ORR in patients with BRCA1/2 deficient advanced breast cancer (Cohort B) treated with the combination of gedatolisib and talazoparib. (Phase II)

VII. Estimate DoR of talazoparib in combination with gedatolisib in patients with BRCA1/2 deficient advanced breast cancer or TNBC (Cohorts A and B). (Phase II)

VIII. Estimate CBR at 16 weeks of talazoparib in combination with gedatolisib in patients with BRCA1/2 deficient advanced breast cancer or TNBC (Cohorts A and B). (Phase II)

IX. Estimate OS in patients with BRCA1/2 deficient advanced breast cancer or TNBC (Cohorts A and B) treated with talazoparib in combination with gedatolisib. (Phase II)

X. Determine the safety and tolerability of talazoparib in combination with gedatolisib in patients with BRCA1/2 deficient advanced breast cancer or TNBC (Cohorts A and B). (Phase II)

CORRELATIVE OBJECTIVES:

I. Correlate the homologous recombination deficiency (HRD) score with clinical response (ORR, CBR at 16 weeks) in patients with TNBC. (Phase I)

II. To explore genomic characteristics in tumor tissue, circulating cell-free deoxyribonucleic acid (cfDNA), and plasma exomes in all patients. (Phase I)

III. Correlate the HRD score with clinical response (ORR, CBR at 16 weeks) in patients with TNBC. (Phase II)

IV. To explore genomic characteristics in tumor tissue, cfDNA, and plasma exomes in all patients. (Phase II)

OUTLINE: This is a phase I, dose-escalation study of talazoparib, followed by a phase II study.

Patients receive talazoparib orally (PO) once daily (QD) on days 1-18 and gedatolisib intravenously (IV) over 30 minutes on days 1, 8, 15, and 22. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and then every 3 months for up to 2 years.

Trial Phase Phase I/II

Trial Type Treatment

Lead Organization
University of Wisconsin Hospital and Clinics

Principal Investigator
Kari Braun Wisinski

  • Primary ID UW18107
  • Secondary IDs NCI-2019-03633, 2019-0104
  • Clinicaltrials.gov ID NCT03911973