Abemaciclib + Letrozole +/- Metformin in Recurrent or Persistent Endometrial Cancer

A Phase 2 Study of Abemaciclib in Combination With Letrozole or in Combination With Letrozole and Metformin in Recurrent or Persistent Endometrial Cancer

This research study is studying a combination of targeted therapies as a possible treatment for estrogen-receptor positive (ER+) endometrial cancer.

The drugs involved in this study are:

• Abemaciclib (also known as Verzenio™)
• Letrozole (also known as Femara®)
• Metformin (also known as Glucophage®)

Study Overview

• Status: Recruiting
• Conditions: Endometrial Cancer
• Intervention / Treatment: Drug: Letrozole; Drug: Abemaciclib; Drug: LY3023414; Drug: Metformin

Detailed Description

This is a Phase II clinical trial. Phase II clinical trials evaluate whether investigational drugs are effective against a specific disease. "Investigational" means that the drugs are being studied.

The U.S. Food and Drug Administration (FDA) has not approved abemaciclib or letrozole for your specific disease but it has been approved for other uses. The FDA has approved metformin for diabetes but is considered investigational for its use in cancer.

Abemaciclib is a cyclin-dependent kinase (CDK) inhibitor. CDK inhibitors work to stop cancer cell growth. Letrozole is a hormonal therapy that works by lowering the production of estrogen in your body. Estrogen may help to stimulate cancer cells to grow, so lowering the levels of estrogen in your body may work to slow cancer cell growth. Metformin is an antihyperglycemic drug most commonly used to lower the amount of blood sugar in the blood and increase the body's sensitivity to insulin. Metformin also works on cancer cells to stop cancer cell growth and promote cancer cell death. In this research study, we are hoping to learn whether the combination of abemaciclib, letrozole, and metformin is effective at slowing or stopping endometrial cancer cell growth.

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Panagiotis Konstantinopoulos, MD; Phone Number: 877-338-7425; Email: PanagiotisA_Konstantinopoulos@DFCI.HARVARD.EDU

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Recruiting
      • Dana Farber Cancer Institute
      • Contact: Panagiotis Konstantinopoulos, MD; Phone Number: 877-338-7425; Email: PanagiotisA_Konstantinopoulos@DFCI.HARVARD.EDU
      • Principal Investigator: Panagiotis Konstantinopoulos, MD
    • Boston, Massachusetts, United States, 02215
      • Recruiting
      • Beth Israel Deaconess Medical Center (BIDMC)
      • Contact: Meghan Shea, MD; Phone Number: 617-667-5661
      • Principal Investigator: Meghan Shea, MD
    • Boston, Massachusetts, United States, 02214
      • Recruiting
      • Massachusetts General Hospital Cancer Center
      • Contact: Cesar Castro, MD; Phone Number: 617-724-4000
      • Principal Investigator: Cesar Castro, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.Participants enrolled in the second stage of Cohort 1A, or into Cohort 3, must have histologically confirmed either i) endometrioid endometrial cancer or ii) endometrial carcinosarcoma with endometrioid epithelial component
• Participants must have 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 CLIA-certified laboratory.
• 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 CT scan, MRI, or calipers by clinical exam.
• Age ≥ 18 years
• ECOG performance status of 0 or 1

• Participants must have normal organ and bone marrow function as defined below:

  • Absolute neutrophil count ≥ 1,500/mcL
  • Platelets ≥ 100,000/mcL
  • Total bilirubin ≤ 1.5 × institutional upper limit of normal (ULN). Patients with Gilbert's syndrome with a total bilirubin </= 2.0 times ULN and direct bilirubin within normal limits are permitted.
  • AST(SGOT)/ALT(SGPT) ≤ 3× institutional ULN
  • Creatinine ≤ 1.5 × institutional ULN, OR
  • Creatinine clearance ≥ 60 mL/min/1.73 m2 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 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 are currently receiving metformin therapy (if enrolling to Cohort 3).
• 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 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 HIV-positive participants are ineligible because of the increased risk of lethal infections when treated with marrow-suppressive therapy.
• Participants with a history of uncontrolled hypertension despite optimal medical management, defined as systolic blood pressure > 150 mmHg or diastolic blood pressure > 90 mmHg

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1A; Abemaciclib is administered by mouth twice daily; Letrozole is administered by mouth once daily	Drug: Letrozole; Letrozole is a hormonal therapy that works by lowering the production of estrogen in the body.; Other Names: Femara; Drug: Abemaciclib; Abemaciclib is a cyclin-dependent kinase (CDK) inhibitor.; Other Names: Verzenio
Experimental: Cohort 1; Abemaciclib is administered by mouth twice daily; LY3023414 is administered by mouth twice daily; Letrozole is administered by mouth once daily	Drug: Letrozole; Letrozole is a hormonal therapy that works by lowering the production of estrogen in the body.; Other Names: Femara; Drug: Abemaciclib; Abemaciclib is a cyclin-dependent kinase (CDK) inhibitor.; Other Names: Verzenio; Drug: LY3023414; LY3023414 is a potent selective inhibitor of the class I PI3K isoforms, mTOR, and DNA-PK.
Experimental: Cohort 2; Abemaciclib is administered by mouth twice daily; LY3023414 is administered by mouth twice daily	Drug: Abemaciclib; Abemaciclib is a cyclin-dependent kinase (CDK) inhibitor.; Other Names: Verzenio; Drug: LY3023414; LY3023414 is a potent selective inhibitor of the class I PI3K isoforms, mTOR, and DNA-PK.
Experimental: Cohort 3; Abemaciclib is administered by mouth twice daily; Letrozole is administered by mouth once daily; Metformin is administered by mouth once daily	Drug: Letrozole; Letrozole is a hormonal therapy that works by lowering the production of estrogen in the body.; Other Names: Femara; Drug: Abemaciclib; Abemaciclib is a cyclin-dependent kinase (CDK) inhibitor.; Other Names: Verzenio; Drug: Metformin; Metformin inhibits mitochondrial adenosine-5'-triphosphate (ATP) synthesis, resulting in activation of the AMPK (5' AMP-activated protein kinase) pathway through LKB1, eventually causing inhibition of the mTOR pathway and subsequent reduction in protein synthesis and cellular proliferation.; Other Names: Glucophage

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival Rate	Number of patients alive and disease progression-free per RECIST 1.1 criteria.	6 months
Objective Tumor Response Rate	Number of patients who experience objective tumor responses per RECIST 1.1 criteria.	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival Rate	Length of time from study enrollment to death from any cause.	3 years
Treatment-related toxicities	Toxicities measured by CTCAE version 5.0 criteria.	3 years

Collaborators and Investigators

• Sponsor: Dana-Farber Cancer Institute
• Collaborators: Eli Lilly and Company
• Investigators: Principal Investigator: Panagiotis Konstantininopoulos, MD, Dana-Farber Cancer Institute

Publications and helpful links

General Publications

• Konstantinopoulos PA, Lee EK, Xiong N, Krasner C, Campos S, Kolin DL, Liu JF, Horowitz N, Wright AA, Bouberhan S, Penson RT, Yeku O, Bowes B, Needham H, Hayes M, Sawyer H, Polak M, Shea M, Cheng SC, Castro C, Matulonis UA. A Phase II, Two-Stage Study of Letrozole and Abemaciclib in Estrogen Receptor-Positive Recurrent Endometrial Cancer. J Clin Oncol. 2023 Jan 20;41(3):599-608. doi: 10.1200/JCO.22.00628. Epub 2022 Sep 29.

Study record dates

Study Major Dates

• Study Start (Actual): December 24, 2018
• Primary Completion (Estimated): May 1, 2024
• Study Completion (Estimated): May 1, 2026

Study Registration Dates

• First Submitted: September 14, 2018
• First Submitted That Met QC Criteria: September 14, 2018
• First Posted (Actual): September 18, 2018

Study Record Updates

• Last Update Posted (Estimated): June 13, 2023
• Last Update Submitted That Met QC Criteria: June 12, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: Endometrial Cancer; ER+; CDK4/6; Estrogen Receptor
• Additional Relevant MeSH Terms: Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Uterine Neoplasms; Genital Neoplasms, Female; Uterine Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Genital Diseases, Female; Endometrial Neoplasms; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Hormone Antagonists; Aromatase Inhibitors; Steroid Synthesis Inhibitors; Estrogen Antagonists; Letrozole; Metformin
• Other Study ID Numbers: 18-301

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No