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Patients receive megestrol acetate PO QD on days 1-28 and ipatasertib PO QD on days 1-21 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo a CT or MRI during screening, on study, and during follow-up. Patients also undergo collection of blood samples throughout the trial.

Arm I: Patients receive megestrol acetate PO QD on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo a CT or MRI during screening, on study, and during follow-up. Patients also undergo collection of blood samples throughout the trial.

Arm II: Patients receive megestrol acetate PO QD on days 1-28 and ipatasertib PO QD on days 1-21 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo a CT or MRI during screening, on study, and during follow-up. Patients also undergo collection of blood samples throughout the trial.

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Site Public Contact

Setsuko K. Chambers

Bradley R. Corr

Merry J. Markham

Sharad A. Ghamande

Bryan A. Faller

David P. Bender

Jean H. Siedel

Deanna G. Teoh

Jay W. Carlson

Carolyn Y. Muller

Olivia D. Lara

Amy Armstrong

Michael S. Guy

Peter G. Rose

David M. O'Malley

Debra L. Richardson

Ida Micaily

Cara A. Mathews

Michaela O. Grinsfelder

Stephen H. Bush

Janelle Sobecki

Elizabeth Hopp

Michaela O Grinsfelder

This phase Ib/II trial tests the safety, side effects, best dose, and effectiveness of the combination of ipatasertib with megestrol acetate to megestrol acetate alone in patients with endometrial cancer that has come back (recurrent) or has spread to other places in the body (metastatic). Ipatasertib may stop the growth of tumor cells and may kill them by blocking some of the enzymes needed for cell growth. Megestrol acetate lowers the amount of estrogen and also blocks the use of estrogen made by the body. This may help stop the growth of tumor cells that need estrogen to grow. The combination of ipatasertib and megestrol acetate may be more effective in treating endometrial cancer than megestrol acetate alone.

PRIMARY OBJECTIVES:

I. Determine the toxicity of ipatasertib in combination with megestrol acetate in women with metastatic grade 1-2 endometrioid endometrial cancer and establish the recommended phase II dose. (Phase I) II. Compare the progression free survival of the combination of ipatasertib with megestrol acetate to megestrol acetate alone among women with metastatic grade 1-2 endometrioid adenocarcinoma of the endometrium. (Phase II) III. Compare the toxicity of the combination of ipatasertib with megestrol acetate to megestrol acetate alone. (Phase II)

SECONDARY OBJECTIVES:

I. Compare objective response rate per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 between the two arms.

II. Examine the pharmacokinetics of ipatasertib + megestrol acetate to assess potential drug-drug interactions.

III. Assess the association between biomarkers and response to therapy.

EXPLORATORY OBJECTIVE:

I. Explore whether pS6/total S6 and pPRAS40/total PRAS40 expression is impacted by the use of ipatasertib and megestrol acetate.

OUTLINE: This is a phase Ib, dose de-escalation study of ipatasertib followed by a phase II study.

PHASE Ib: Patients receive megestrol acetate orally (PO) once daily (QD) on days 1-28 and ipatasertib PO QD on days 1-21 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo a computed tomography (CT) or magnetic resonance imaging (MRI) during screening, on study, and during follow-up. Patients also undergo collection of blood samples throughout the trial.

PHASE II: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive megestrol acetate PO QD on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo a CT or MRI during screening, on study, and during follow-up. Patients also undergo collection of blood samples throughout the trial.

ARM II: Patients receive megestrol acetate PO QD on days 1-28 and ipatasertib PO QD on days 1-21 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo a CT or MRI during screening, on study, and during follow-up. Patients also undergo collection of blood samples throughout the trial.

After completion of study treatment, patients are followed up at 30 days for the phase I study. Patients are followed up every 3 months for 2 years, then every 6 months for 3 years for the phase II study.

Testing the Addition of the AKT Inhibitor, Ipatasertib, to Treatment With the Hormonal Agent Megestrol Acetate for Recurrent or Metastatic Endometrial Cancers

A Phase IB and Randomized Phase II Trial of Megestrol Acetate With or Without Ipatasertib in Recurrent or Metastatic Endometrioid Endometrial Cancer

NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.

Exploratory objectives include assessing whether pS6/total S6 and pPRAS40/total PRAS40 expression is impacted by the use of ipatasertib and megestrol acetate. Exploratory biomarker results will be provided to the NRG Oncology Statistical and Data Management Center for analysis.

To determine frequency and severity of adverse events for all dose combinations of megestrol acetate plus ipatasertib. Descriptive statistics will be used to summarize AEs. These analyses will focus on individuals who initiated their assigned treatment and will summarize maximum grade of AEs occurring during treatment classified by Common Toxicity Criteria (CTC) category. The primary summary of AEs will present counts and percentages, regardless of whether the AE was attributed to any of the study agents.

Descriptive statistics will be used to summarize AEs. These analyses will focus on individuals who initiated their assigned treatment and will summarize maximum grade of AEs occurring during treatment classified by CTC category. The primary summary of AEs will present counts and percentages, regardless of whether the AE was attributed to any of the study agents.

Compare PFS of the combination of ipatasertib with megestrol acetate to megestrol acetate alone among women with recurrent/metastatic endometrioid adenocarcinoma of the endometrium. A product-limit method will be used to estimate the cumulative distribution of PFS duration for each of the study treatments used in this population.

Summarize the toxicity/adverse events of the combination of ipatasertib with megestrol acetate and megestrol acetate alone. Adverse events will be categorized using Common Terminology Criteria for Adverse Events version 5.0.

Examine the pharmacokinetics of ipatasertib + megestrol acetate to assess potential drug-drug interactions. This data will be summarized descriptively.

Response is defined as complete response or partial response (CR+PR) evaluated by Response Evaluation Criteria in Solid Tumors RECIST version 1.1. A logistic model will be used to estimate the relative odds of responding (CR+PR) to megestrol acetate + ipatasertib relative to megestrol acetate alone after adjusting for prior progesterone therapy.

The association between biomarkers and response to therapy will be assessed. Integrated biomarker endpoints include: PTEN immunohistochemistry, estrogen receptor and progesterone receptor, whole exome sequencing, ribonucleic acid sequencing. Proportional hazards models will be used to examine the prognostic association of integrated biomarkers with PFS; and interactions between markers and treatment arm will be used to examine the markers' predictive association with PFS.

NRG Oncology

National Cancer Institute (NCI)

Spots Global Cancer Trial Database for metastatic endometrial endometrioid adenocarcinoma