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

Stage IV Uterine Corpus Cancer AJCC v8 Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05538897
• Other study ID #: NCI-2022-07505
• Secondary ID: NCI-2022-07505NR
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: March 31, 2023
• Est. completion date: January 31, 2027

Study information

• Verified date: May 2024
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 96
• Est. completion date: January 31, 2027
• Est. primary completion date: January 31, 2027
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Patients must have grade 1 or 2 recurrent or metastatic endometrioid endometrial cancer

• Patients must have measurable disease according to RECIST version (v)1.1. Measurable disease is defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded). Each lesion must be >= 10 mm when measured by CT or MRI. Lymph nodes must be >= 15 mm in short axis when measured by CT or MRI. Previously irradiated lesions can be considered as measurable disease only if progressive disease has been unequivocally documented at that site since radiation

• Patients may have received unlimited prior lines of therapy. If patient received prior hormonal therapy (e.g., megestrol acetate, medroxyprogesterone acetate, aromatase inhibitor, tamoxifen, fulvestrant) it must have completed at least 6 months prior to registration

• Age >= 18

• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1 or 2

• Platelets >= 100,000/mcl within 14 days prior to registration

• Absolute neutrophil count (ANC) >= 1,500/mcl within 14 days prior to registration

• Hemoglobin >= 9 g/dL within 14 days prior to registration

• Glomerular filtration rate (GFR) >= 60 mL/min/1.73m^2 measured using Cockcroft-Gault equation or the estimated glomerular filtration rate from the Modification of Diet in Renal Disease Study within 14 days prior to registration

• Total bilirubin =< 1.5 x the upper limit of normal (ULN) within 14 days prior to registration

• Patients with known Gilbert syndrome who have bilirubin =< 3 x ULN may be enrolled

• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x institutional ULN within 14 days prior to registration

• Albumin >= 3 g/dL within 14 days prior to registration

• Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better

• The effects of ipatasertib on the developing human fetus are unknown. For this reason and because AKT inhibitor agents as well as other therapeutic agents used in this trial are known to be teratogenic, participants of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) during study therapy and for 28 days following the last dose of study therapy. Should a participant become pregnant or suspect pregnancy while participating in this study, they should inform their treating physician immediately

• Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial

• For patients with known human immunodeficiency virus (HIV), hepatitis B virus (HBV), and/or hepatitis C virus (HCV) infection:

• HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months of registration are eligible for this trial

• Patients with evidence of chronic hepatitis B virus (HBV) infection must have an undetectable HBV viral load on suppressive therapy, if indicated

• Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load

• Patients with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression

• Patients must be able to swallow and retain oral medications and not have gastrointestinal illnesses that would preclude absorption of megestrol acetate or ipatasertib as judged by the treating physician

• The patient or a legally authorized representative must provide study-specific informed consent prior to study entry and, for patients treated in the United States (U.S.), authorization permitting release of personal health information

Exclusion Criteria:

• Patients who have had prior treatment with an AKT inhibitor (Prior treatment with PI3K or mTOR inhibitors is allowed)

• Patients who have received treatment with strong CYP3A inhibitors or inducers within 14 days or 5 drug-elimination half-lives, whichever is longer, prior to study registration

• Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated medical reference. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product

• Patients with diabetes either requiring insulin therapy or with a baseline fasting glucose > 160 mg/dL and/or high glycosylated hemoglobin A1c (HbA1c) (> 8), suggesting poorly controlled diabetes. Fasting is defined as abstaining from food and drink (with the exception of water) for at least 8 hours

• Patients who require chronic corticosteroid therapy of > 10 mg of prednisone per day or an equivalent dose of other anti-inflammatory corticosteroids or immunosuppressant agents for a chronic disease

• Patients with grade 2 or greater uncontrolled or untreated hypercholesterolemia (> 300 mg/dL) or hypertriglyceridemia (> 300 mg/dL)

• Patients with a history of known or active inflammatory bowel disease (e.g., Crohn disease and ulcerative colitis) or active bowel inflammation (e.g., diverticulitis)

• Patients with a history of or presence of an abnormal electrocardiogram (ECG) that is clinically significant in the investigator's opinion (including complete left bundle branch block, second- or third-degree heart block, or evidence of prior myocardial infarction)

• Patients with known clinically significant history of liver disease consistent with Child-Pugh class B or C, including active viral or other hepatitis, current drug or alcohol abuse, or cirrhosis

• Patients with lung disease: Grade 2 or greater pneumonitis, grade 2 or greater interstitial lung disease, idiopathic pulmonary fibrosis, cystic fibrosis, aspergillosis, active tuberculosis, or history of opportunistic infections (pneumocystis pneumonia or cytomegalovirus pneumonia) within the past 6 months

• No active infection requiring parenteral antibiotics

• Women who are pregnant or unwilling to discontinue nursing

Related Conditions & MeSH terms

• Adenocarcinoma
• Carcinoma, Endometrioid
• Endometrial Neoplasms
• FIGO Grade 1 Endometrial Endometrioid Adenocarcinoma
• FIGO Grade 2 Endometrial Endometrioid Adenocarcinoma
• Recurrence
• Recurrent Endometrial Endometrioid Adenocarcinoma
• Stage IV Uterine Corpus Cancer AJCC v8

Intervention

Procedure:
• Biospecimen Collection
Undergo blood sample collection
• Computed Tomography
Undergo CT scan

Drug:
• Ipatasertib
Given PO

Procedure:
• Magnetic Resonance Imaging
Undergo MRI

Drug:
• Megestrol Acetate
Given PO

Locations

Country	Name	City	State
United States	University of New Mexico Cancer Center	Albuquerque	New Mexico
United States	University of Michigan Comprehensive Cancer Center	Ann Arbor	Michigan
United States	Augusta University Medical Center	Augusta	Georgia
United States	UCHealth University of Colorado Hospital	Aurora	Colorado
United States	UHHS-Chagrin Highlands Medical Center	Beachwood	Ohio
United States	Miami Valley Hospital South	Centerville	Ohio
United States	UNC Lineberger Comprehensive Cancer Center	Chapel Hill	North Carolina
United States	Geauga Hospital	Chardon	Ohio
United States	West Virginia University Charleston Division	Charleston	West Virginia
United States	Case Western Reserve University	Cleveland	Ohio
United States	Cleveland Clinic Foundation	Cleveland	Ohio
United States	Ohio State University Comprehensive Cancer Center	Columbus	Ohio
United States	Cancer Care Specialists of Illinois - Decatur	Decatur	Illinois
United States	Decatur Memorial Hospital	Decatur	Illinois
United States	Crossroads Cancer Center	Effingham	Illinois
United States	University of Florida Health Science Center - Gainesville	Gainesville	Florida
United States	Lyndon Baines Johnson General Hospital	Houston	Texas
United States	M D Anderson Cancer Center	Houston	Texas
United States	University of Iowa/Holden Comprehensive Cancer Center	Iowa City	Iowa
United States	Jefferson Hospital	Jefferson Hills	Pennsylvania
United States	University of Kansas Cancer Center	Kansas City	Kansas
United States	University of Kansas Cancer Center - North	Kansas City	Missouri
United States	University of Wisconsin Carbone Cancer Center - University Hospital	Madison	Wisconsin
United States	UH Seidman Cancer Center at Lake Health Mentor Campus	Mentor	Ohio
United States	Medical College of Wisconsin	Milwaukee	Wisconsin
United States	University of Minnesota/Masonic Cancer Center	Minneapolis	Minnesota
United States	Forbes Hospital	Monroeville	Pennsylvania
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	Thomas Jefferson University Hospital	Philadelphia	Pennsylvania
United States	West Penn Hospital	Pittsburgh	Pennsylvania
United States	Women and Infants Hospital	Providence	Rhode Island
United States	Mercy Hospital Saint Louis	Saint Louis	Missouri
United States	Southern Illinois University School of Medicine	Springfield	Illinois
United States	Banner University Medical Center - Tucson	Tucson	Arizona
United States	University of Arizona Cancer Center-North Campus	Tucson	Arizona
United States	Oklahoma Cancer Specialists and Research Institute-Tulsa	Tulsa	Oklahoma
United States	UH Seidman Cancer Center at Saint John Medical Center	Westlake	Ohio
United States	University of Kansas Hospital-Westwood Cancer Center	Westwood	Kansas
United States	Wexford Health and Wellness Pavilion	Wexford	Pennsylvania
United States	Asplundh Cancer Pavilion	Willow Grove	Pennsylvania

Sponsors (2)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)	NRG Oncology

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	pS6/total S6 and pPRAS40/total PRAS40 expression (Phase II)	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.	Up to 5 years
Primary	Incidence of adverse events (AEs) (Phase Ib)	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.	Up to 5 years
Primary	Maximum tolerated dose for phase II (Phase Ib)	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.	Up to 5 years
Primary	Progression free survival (PFS) (Phase II)	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.	From study entry to time of progression or death, whichever occurs first, or date of last contact if neither progression nor death has occurred, assessed up to 5 years
Primary	Incidence of AEs (Phase II)	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.	Up to 5 years
Secondary	Pharmacokinetics of ipatasertib + megestrol acetate (Phase Ib)	Examine the pharmacokinetics of ipatasertib + megestrol acetate to assess potential drug-drug interactions. This data will be summarized descriptively.	On cycle 1, day 8
Secondary	Objective response rate (ORR) (Phase II)	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.	Up to 5 years
Secondary	Biomarkers (Phase II)	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.	Up to 5 years