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

NCT03911973 | Active Not Recruiting Phase 1 DMC FDA Drug

• 1 other identifier: BTCRC-BRE18-337
• Study Type: interventional
• Target: 37
• Locations: 1 country
• Sites: 5

Brief Summary

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).

Conditions

TNBC - Triple-Negative Breast Cancer

Outcome Measures

Primary Outcomes (2)

• Maximum Tolerated Dose (MTD) of talazoparib in combination with gedatolisib (Phase I)

  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.

  28 days

• Objective Response Rate (ORR) (Phase II)

  Calculate ORR, 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.

  24 Months

Secondary Outcomes (4)

• Duration of Response (DOR)

  24 Months

• Clinical Benefit Rate (CBR) at 16 weeks

  16 Weeks

• Overall Survival

  24 Months

• Rates of Adverse Events

  24 Months

Study Arms (1)

Talazoparib + Gedatolisib

EXPERIMENTAL

Talazoparib + Gedatolisib Phase 1: 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 Phase 2: Gedatolisib 180 mg IV on days 1, 8, 15 and 22; Talazoparib 1.00 mg once daily, Days 1-28. Subjects receiving weekly gedatolisib may continue current regimen or may switch to gedatolisib 180 mg IV on days 1, 8, and 15; Talazoparib 1.00 mg once daily, Days 1-28 (3 weeks on/ 1 week off). All changes will be permanent.

Drug: Gedatolisib; Drug: Talazoparib

Interventions

Gedatolisib DRUG

Gedatolisib, 150-180MG IV

Talazoparib + Gedatolisib

Talazoparib DRUG

.75-1.00mg

Talazoparib + Gedatolisib

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Individuals from populations who are underrepresented in clinical research (e.g., racial and ethnic minorities, women, individuals from rural/frontier communities, older individuals) will be enrolled with a goal of ensuring that all eligible patients are given the opportunity to participate in novel clinical trials and that research findings can be generalizable to the entire population.
• 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 ≥20%.
• 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 \[CLOSED\]: 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 targeted therapies.
• Cohort B \[CLOSED\]: 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

You may not qualify if:

• 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. NOTE: Investigational imaging agents are not included in the definition and are allowed.
• 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.

Sponsors & Collaborators

• Kari Wisinski: lead
• Pfizer: collaborator
• Celcuity Inc: collaborator

Study Sites (5)

Northwestern University Feinberg School of Medicine

Chicago, Illinois, 60611, United States

Location

University of Illinois Cancer Center

Chicago, Illinois, 60612, United States

Location

Indiana University Melvin and Bren Simon Comprehensive Cancer Center

Indianapolis, Indiana, 46202, United States

Location

University of Iowa Hospital and Clinics

Iowa City, Iowa, 52242, United States

Location

University of Wisconsin

Madison, Wisconsin, 53792, United States

Location

Related Publications (1)

• Phadke S, Miller KD, Shah A, Danciu OC, Chen Y, Yu M, Burkard ME, Wisinski KB. Phase I/II trial investigating gedatolisib plus talazoparib in advanced triple negative or BRCA1/2 positive, HER2 negative breast cancers. Breast Cancer Res Treat. 2025 Aug;212(3):521-530. doi: 10.1007/s10549-025-07747-x. Epub 2025 Jun 5.

  PMID: 40471518 DERIVED

MeSH Terms

Conditions

Triple Negative Breast Neoplasms

Interventions

gedatolisib; talazoparib

Condition Hierarchy (Ancestors)

Breast Neoplasms; Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Study Officials

• Kari Wisinski, MD

  University of Wisconsin, Madison

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Faculty, University of Wisconsin School of Medicine and Public Health

Study Record Dates

• First Submitted: April 8, 2019
• First Posted: April 11, 2019
• Study Start: April 17, 2019
• Primary Completion: July 1, 2024
• Study Completion: July 1, 2024
• Last Updated: June 7, 2024

Record last verified: 2024-06

Locations

US (5)