Gedatolisib Plus Talazoparib in Advanced Triple Negative or BRCA1/2 Positive, HER2 Negative Breast Cancers
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|ClinicalTrials.gov Identifier: NCT03911973|
Recruitment Status : Not yet recruiting
First Posted : April 11, 2019
Last Update Posted : April 11, 2019
|Condition or disease||Intervention/treatment||Phase|
|TNBC - Triple-Negative Breast Cancer||Drug: Gedatolisib Drug: Talazoparib||Phase 1 Phase 2|
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).
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||54 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|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|
|Estimated Study Start Date :||May 2019|
|Estimated Primary Completion Date :||May 2021|
|Estimated Study Completion Date :||May 2022|
Experimental: Talazoparib + Gedatolisib
Talazoparib + 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, 150-180MG IV
- Maximum Tolerated Dose (MTD) of talazoparib in combination with gedatolisib (Phase I) [ Time Frame: 28 days ]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.
- Objective Response Rate (ORR) (Phase II) [ Time Frame: 24 Months ]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.
- Investigator-assessed Progression-Free Survival (PFS) (Cohort B only) [ Time Frame: 24 Months ]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.
- Objective Response Rate (Cohort B only) [ Time Frame: 24 Months ]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.
- Duration of Response (DOR) [ Time Frame: 24 Months ]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).
- Clinical Benefit Rate (CBR) at 16 weeks [ Time Frame: 16 Weeks ]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).
- Overall Survival [ Time Frame: 24 Months ]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).
- Rates of Adverse Events [ Time Frame: 24 Months ]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).
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03911973
|Contact: Donna Sullivan||317-634-5842 ext email@example.com|
|United States, Wisconsin|
|University of Wisconsin|
|Madison, Wisconsin, United States, 53792|
|Principal Investigator:||Kari Wisinski, MD||University of Wisconsin, Madison|