This phase I trial studies the side effects and best dose of gemcitabine hydrochloride and berzosertib when given together with carboplatin in treating patients with ovarian, primary peritoneal, or fallopian tube cancer that has come back (recurrent) and has spread to other places in the body (metastatic). Chemotherapy drugs, such as carboplatin and gemcitabine hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Berzosertib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving berzosertib with chemotherapy (carboplatin and gemcitabine hydrochloride) may work better in treating patients with ovarian, primary peritoneal, or fallopian tube cancer compared to chemotherapy alone.
PRIMARY OBJECTIVES: I. Assess safety and tolerability of the combination therapy carboplatin, gemcitabine hydrochloride (gemcitabine), and berzosertib (M6620 \[VX-970\]) in adult women with platinum sensitive recurrent high grade serous or high grade endometrioid ovarian, primary peritoneal or fallopian tube cancer. (Phase I Dose Escalation/Safety Lead-in) II. Determine the dose of the triple therapy to be used in the dose expansion cohort of the study. (Phase I Dose Escalation/Safety Lead-in) III. Confirm the safety at the maximum tolerated dose (MTD) for the addition of M6620 (VX-970) to carboplatin and gemcitabine in first or second recurrence of platinum sensitive high grade serous or endometrioid ovarian, primary peritoneal or fallopian tube carcinoma. (Expansion Cohort) SECONDARY OBJECTIVES: I. To determine if the MTD for the combination of carboplatin, gemcitabine and M6620 (VX-970) improves the confirmed response rate in adult women with platinum sensitive recurrent high grade serous or high grade endometrioid ovarian, primary peritoneal or fallopian tube cancer. II. To determine the impact of the MTD on overall survival (OS), duration of response, and progression-free survival (PFS). INTEGRATED CORRELATIVE STUDY OBJECTIVES: I. Collection of specimens for biomarker studies to provide preliminary proof of mechanism. Assess, in an exploratory fashion, whether the combination of gemcitabine and carboplatin activates the ATR/CHK1 pathway at achievable concentrations and also whether M6620 inhibits the activated pathway. II. To determine whether increased deoxyribonucleic acid (DNA) damage as assessed by two different multiplex assays correlates with response to combination therapy with M6620 (VX-970). III. To determine whether mutations in homologous recombination repair genes correlate with response to combination therapy with M6620 (VX-970). IV. To ascertain modulation of ATR autophosphorylation and other pharmacodynamic readouts for ATR inhibition by M6620 (VX-970). OUTLINE: This is a dose-escalation study of gemcitabine hydrochloride and berzosertib. Patients receive carboplatin intravenously (IV) over 30 minutes on day 1, gemcitabine hydrochloride IV over 30 minutes on days 1 and 8, and berzosertib IV over 60 minutes on days 2 and 9. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up for 3 years.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
35
Mayo Clinic Hospital in Arizona
Phoenix, Arizona, United States
Mayo Clinic in Arizona
Scottsdale, Arizona, United States
UCHealth University of Colorado Hospital
Aurora, Colorado, United States
UF Health Cancer Institute - Gainesville
Gainesville, Florida, United States
Mayo Clinic in Florida
Jacksonville, Florida, United States
University of Kentucky/Markey Cancer Center
Lexington, Kentucky, United States
Wayne State University/Karmanos Cancer Institute
Detroit, Michigan, United States
Weisberg Cancer Treatment Center
Farmington Hills, Michigan, United States
Mayo Clinic in Rochester
Rochester, Minnesota, United States
Washington University School of Medicine
St Louis, Missouri, United States
...and 4 more locations
Maximum tolerated dose (MTD) (phase I dose escalation)
The MTD in this study will be defined as the highest safely tolerated dose, up to a maximum of dose level 4, where at most 1 out of six patients experience a dose limiting toxicity (DLT) with the next higher dose having at least 2 DLTs in 3 or more patients. Will be reported descriptively.
Time frame: Up to 28 days
Incidence of adverse events
The maximum grade for each type of adverse event will be summarized using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
Time frame: Up to 3 years
Confirmed response rate
Will be assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria.
Time frame: Up to 3 years
Overall survival (OS)
OS will be estimated using the Kaplan-Meier method.
Time frame: From study entry to death from any cause, assessed up to 3 years
Duration of response
The duration of confirmed responses will be assessed using the Kaplan-Meier method.
Time frame: From first documented date of confirmed response (complete response [CR] or partial response [PR]), to the date at which progression is first documented, up to 3 years
Progression free survival (PFS)
Disease progression will be determined based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. PFS will be estimated using the Kaplan-Meier method.
Time frame: From registration to the first of either disease progression or death from any cause, up to 3 years
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