LY3023414 and Abemaciclib with or without Letrozole in Treating Patients with Recurrent, Metastatic, or Resistant Endometrial Cancer

Status: Active

Description

This phase II trial studies how well LY3023414 and abemaciclib with or without letrozole work in treating patients with endometrial cancer that has come back, spread to other places in the body or is resistant to standard treatments. LY3023414 and abemaciclib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Letrozole is a hormonal therapy that works by lowering the production of estrogen in the body. Estrogen may help to stimulate cancer cells to grow, so lowering the levels of estrogen in the body may work to slow cancer cell growth. Giving LY3023414 and abemaciclib together with letrozole may work better in treating patients with endometrial cancer. In this trial, patients are divided into two treatment groups based on the presence of receptors that bind to estrogen. Patients with tumors that have these receptors may benefit from hormone therapy and are placed in a group that receives all three drugs. Patients whose tumors lack these receptors are treated in another group that receives LY3023414 and abemaciclib, as their tumor growth is independent of estrogen.

Eligibility Criteria

Inclusion Criteria

  • Participants must have cytologically or histologically confirmed endometrial cancer that is recurrent or metastatic and/or resistant to standard therapies, or for which no standard therapy is available
  • COHORT 1: Participants must have estrogen receptor (ER)-positive disease, defined as >= 1 percent of tumor cell nuclei being immunoreactive by immunohistochemistry (IHC). If multiple analyses have been performed, judgment should be based on the most recent biopsy or pathology specimen analyzed in a Clinical Laboratory Improvement Act (CLIA)-certified laboratory
  • COHORT 2: Participants must have ER-negative disease, defined as < 1 percent of tumor cell nuclei being immunoreactive by IHC. If multiple analyses have been performed, judgment should be based on the most recent biopsy or pathology specimen analyzed in a CLIA-certified laboratory
  • COHORT 2: Documented evidence of PI3K pathway dependence including PIK3CA, PIK3R1, PTEN hotspot mutations, PTEN loss, or other (unlisted) alterations as agreed upon with the overall principal investigator. Analysis must have been performed on a tumor tissue specimen in a CLIA-certified laboratory. All genetic findings must be reviewed and approved by the overall principal investigator prior to study entry
  • Participants must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >= 20 mm with conventional techniques or as >= 10 mm with spiral computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
  • Absolute neutrophil count >= 1,500/mcL
  • Platelets >= 100,000/mcL
  • Total bilirubin =< 1.5 x institutional upper limit of normal (ULN)
  • Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional ULN, OR =< 5 x institutional ULN if liver metastases are present
  • Creatinine =< 1.5 x institutional ULN, OR creatinine clearance >= 60 mL/min/1.73 m^2 for participants with creatinine levels above institutional normal
  • The effects of the study agents on the developing human fetus are unknown. For this reason, women of child-bearing potential must agree to use a medically approved contraceptive method during the treatment period and for 3 months following the last dose of study agent. Contraceptive methods may include an intrauterine device (IUD) or barrier method. If condoms are used as a barrier method, a spermicidal agent should be added as a double barrier protection. Should a woman become pregnant or suspect she is pregnant while she is participating in this study, she should inform her treating physician immediately. A negative serum pregnancy test is required for study entry from women of childbearing potential.
  • Ability to understand and the willingness to sign a written informed consent document
  • Ability to swallow and retain oral medication
  • Participants must have a documented baseline hemoglobin A1c (HbA1c) < 7%. Participants with non-insulin dependent diabetes mellitus are eligible if adequate control of blood glucose level is obtained by oral anti-diabetic agents
  • Participants must have archival tissue available for analysis in the form of a formalin-fixed paraffin embedded (FFPE) block or unstained slides * Note: confirmation of availability of archival tissue is the only requirement for eligibility, archival tissue does not need to be received by the study team prior to enrollment

Exclusion Criteria

  • Participants who have had chemotherapy, immune therapy, other investigational therapy, or major surgery within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to the first dose of study medication. Previous hormonal therapy, including prior letrozole, is allowed and there is no required washout period for hormonal therapy
  • Participants who have had tyrosine kinase inhibitor (TKI) therapy within 5 half-lives of study entry
  • Participants who have had radiation therapy within 2 weeks of the first dose of study medication
  • Participants who have received previous treatment with CDK4/6 inhibitors, including but not limited to previous abemaciclib therapy
  • Participants who have received previous treatment with PI3K inhibitors, including but not limited to previous LY3023414 therapy
  • Participants with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to the study agents that the participant will be administered
  • Participants with insulin-dependent diabetes mellitus or histories of gestational diabetes mellitus
  • Participants who at the time of study enrollment are known to require concomitant therapy with moderate or strong CYP3A4 inducers, or strong inhibitors of CYP3A4. Due to potential drug interactions, concomitant use of these medications is not permitted for the duration of treatment on trial. Participants are eligible for study entry if an appropriate substitution is made prior to the first dose of study medication
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
  • Participants with histories or evidence of cardiovascular risk including any of the following: acute coronary syndromes (i.e. myocardial infarction or angina), coronary angioplasty, or stenting within 6 months prior to study enrollment
  • Pregnant women are excluded from this study because the study agents are anti-cancer agents with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with the study agents, breastfeeding must be discontinued if the mother is treated on trial
  • Individuals with a history of a different malignancy are ineligible with the following exceptions: individuals who have been treated and are disease-free for a minimum of 5 years prior to study enrollment, or individuals who are deemed by the treating investigator to be at low risk for disease recurrence. Additionally, individuals with the following cancers are eligible if diagnosed and treated within the past 5 years: basal or squamous cell carcinomas of the skin, and breast or cervical carcinomas in situ
  • Known human immunodeficiency virus (HIV)-positive participants are ineligible because of the increased risk of lethal infections when treated with marrow-suppressive therapy
  • Participants with a history of atrial fibrillation or atrial flutter
  • Participants with a history of uncontrolled hypertension despite optimal medical management, defined as systolic blood pressure > 150 mmHg or diastolic blood pressure > 90 mmHg

Locations & Contacts

Massachusetts

Boston
Beth Israel Deaconess Medical Center
Status: Active
Contact: Meghan Elizabeth C. Shea
Email: mshea4@bidmc.harvard.edu
Brigham and Women's Hospital
Status: Active
Contact: Panagiotis A. Konstantinopoulos
Phone: 617-632-5269
Email: Panagiotis_Konstantinopoulos@dfci.harvard.edu
Dana-Farber Cancer Institute
Status: Active
Contact: Panagiotis A. Konstantinopoulos
Email: Panagiotis_Konstantinopoulos@dfci.harvard.edu
Massachusetts General Hospital Cancer Center
Status: Active
Contact: Cesar Martin Castro
Email: castro.cesar@mgh.harvard.edu

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. To assess the activity of PI3K/mTOR inhibitor LY3023414 (LY3023414) and abemaciclib with or without letrozole in recurrent or persistent endometrial cancer (EC) as determined by the frequency of patients who are alive and progression-free for a minimum of 6 months (PFS6) after initiating therapy, or who have objective tumor responses by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria.

SECONDARY OBJECTIVES:

I. To determine the duration of progression-free survival (PFS) and overall survival (OS) for both cohorts.

II. To determine the nature and degree of toxicity of protocol therapy in each cohort as classified using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

EXPLORATORY OBJECTIVES:

I. To characterize baseline genomic alterations (including those involving the PI3K pathway) by targeted exome sequencing in baseline samples from patients in both cohorts and correlate the results with response to study therapy.

II. To identify biomarkers of response as well as resistance to the protocol therapy from archival tissue and serial blood sample collection.

OUTLINE: This is a dose-escalation study of PI3K/mTOR inhibitor LY3023414. Patients are assigned to 1 of 2 cohorts.

COHORT I: Patients receive PI3K/mTOR inhibitor LY3023414 orally (PO) twice daily (BID), abemaciclib PO BID, and letrozole PO once daily (QD) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

COHORT II: Patients receive PI3K/mTOR inhibitor LY3023414 PO BID and abemaciclib PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days and every 6 months for up to 3 years.

Trial Phase & Type

Trial Phase

Phase II

Trial Type

Treatment

Lead Organization

Lead Organization
Dana-Farber Harvard Cancer Center

Principal Investigator
Panagiotis A. Konstantinopoulos

Trial IDs

Primary ID 18-301
Secondary IDs NCI-2018-03914
Clinicaltrials.gov ID NCT03675893