This phase I/IB trial tests the safety, side effects, and best dose of ipatasertib in combination with paclitaxel and carboplatin in treating patients with stage III or IV epithelial ovarian cancer. Ipatasertib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Paclitaxel is in a class of medications called taxanes. It stops tumor cells from growing and dividing and may kill them. Carboplatin is in a class of medications known as platinum-containing compounds. It works in a way similar to the anticancer drug cisplatin, but may be better tolerated than cisplatin. Carboplatin works by killing, stopping or slowing the growth of tumor cells. Giving ipatasertib in combination with paclitaxel and carboplatin may lower the chance of the tumor growing or spreading for longer than the paclitaxel and carboplatin alone.
PRIMARY OBJECTIVES: I. To estimate the maximum tolerated dose (MTD) and the dose limiting toxicities (DLTs) of ipatasertib in combination with paclitaxel and carboplatin as neoadjuvant chemotherapy for ovarian cancer. II. To determine the feasibility of the treatment regimen once the MTD is estimated. III. To assess the toxicities of ipatasertib in combination with paclitaxel and carboplatin by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. SECONDARY OBJECTIVE: I. Objective response rate by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 prior to interval debulking surgery (IDS). TRANSLATIONAL RESEARCH OBJECTIVES: I. To evaluate the change of phosphorylated (p)PRAS40 expression in the pre-treatment tumor versus (vs.) on-treatment tumor. II. To identify the pharmacokinetics of ipatasertib in the tissue and blood. III. To correlate antitumor response with genomic alterations in PI3K pathway genes (PTEN, PIK3CA, PIK3R1, AKT1, p53 loss, KRAS, NF1, TSC1/TSC1). IV. To correlate antitumor response with transcriptomic alterations in PI3K pathway genes (PTEN, PIK3CA, PIK3R1, AKT1, p53 loss, KRAS, NF1, TSC1/TSC1). V. To correlate response with PTEN loss. OUTLINE: This is a dose-escalation study of ipatasertib followed by a dose-expansion study. Patients receive paclitaxel intravenously (IV) over 3 hours and carboplatin IV over 30-60 minutes on day 1. Treatment repeats every 21 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive ipatasertib orally (PO) once daily (QD) until 24 hours before surgery in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 and 90 days.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
25
UCSF Medical Center-Mission Bay
San Francisco, California, United States
Augusta University Medical Center
Augusta, Georgia, United States
Cleveland Clinic Foundation
Cleveland, Ohio, United States
University of Oklahoma Health Sciences Center
Oklahoma City, Oklahoma, United States
Fox Chase Cancer Center
Philadelphia, Pennsylvania, United States
Women and Infants Hospital
Providence, Rhode Island, United States
Virginia Commonwealth University/Massey Cancer Center
Richmond, Virginia, United States
Medical College of Wisconsin
Milwaukee, Wisconsin, United States
Incidence of Dose Limiting Toxicities (DLTs) During Dose Escalation Phase
The incidence of DLTs was assessed based on the number of participants who experienced at least one dose-limiting toxicity (DLT) during the Dose Escalation phase, which was used to estimate the maximum tolerated dose (MTD). A DLT was defined as any protocol-specified adverse event that was possibly, probably, or definitely related to study drug combination and occurred during the first cycle of neoadjuvant chemotherapy, unless the event was clearly unrelated to the study therapy. Adverse events were assessed and graded according to NCI CTCAE v5.0.
Time frame: First cycle of 21 days
Incidence of Dose-limiting Toxicities (DLTs) During Dose Expansion Phase
The incidence of DLTs was assessed based on the number of participants who experienced at least one DLT during the Dose Expansion phase. This assessment was used to evaluate the feasibility of the treatment regimen at the estimated MTD, specially dose level 1. A DLT was defined as any protocol-specified adverse effect that was possibly, probably, or definitely related to study drug combination and occurred during the first cycle of neoadjuvant chemotherapy, unless the event was clearly unrelated to study therapy. Adverse events were assessed and graded according to NCI CTCAE v.5.0.
Time frame: First cycle of 21 days
Incidence of Grade 3 or Higher Adverse Events (AEs)
The incidence of grade 3 or higher AEs was assessed based on the number of participants who experienced at least one grade 3 or higher adverse event. Adverse events were graded and categorized according to NCI CTCAE v5.0.
Time frame: During treatment period and up to 90 days after the last dose of ipatasertib. The median duration of study treatment was 68 days with a range from 1 day to 90 days.
Tumor Response
Tumor response was assessed by RECIST 1.1 at 3 weeks (+/- 7 days) post Cycle 3 of the study treatment and prior to interval debulking surgery (IDS), and it could be repeated any other time if clinically indicated based on symptoms or physical signs suggestive of new or progressive disease.
Time frame: At 3 weeks (+/- 7 days) post Cycle 3 of the study treatment and prior to IDS.
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