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.
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