Abemaciclib With Letrozole in Recurrent or Persistent Endometrial Cancer

• ClinicalTrials.gov Identifier: NCT03675893
• Recruitment Status: Recruiting
• First Posted: September 18, 2018
• Last Update Posted: January 31, 2020
• Sponsor: Dana-Farber Cancer Institute
• Collaborator: Eli Lilly and Company
• Information provided by (Responsible Party): Panagiotis Konstantinopoulos, MD, PhD, Dana-Farber Cancer Institute

Study Description

Brief Summary:

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®)

Condition or disease	Intervention/treatment	Phase
Endometrial Cancer	Drug: Letrozole; Drug: Abemaciclib	Phase 2

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 FDA has not approved abemaciclib or letrozole for ER+ endometrial cancer, but both drugs have been approved for other uses.

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 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. In this research study, the investigators are hoping to learn whether the combination of abemaciclib and letrozole is effective at slowing or stopping endometrial cancer cell growth.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 40 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 2 Study of Abemaciclib With Letrozole in Recurrent or Persistent Endometrial Cancer
• Actual Study Start Date: December 24, 2018
• Estimated Primary Completion Date: May 1, 2021
• Estimated Study Completion Date: May 1, 2024

Arms and Interventions

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 Name: Femara; Drug: Abemaciclib; Abemaciclib is a cyclin-dependent kinase (CDK) inhibitor.; Other Name: Verzenio

Outcome Measures

Primary Outcome Measures :

1. Progression Free Survival Rate [ Time Frame: 6 months ]
   Number of patients alive and disease progression-free per RECIST 1.1 criteria.
2. Objective Tumor Response Rate [ Time Frame: 6 months ]
   Number of patients who experience objective tumor responses per RECIST 1.1 criteria.

Secondary Outcome Measures :

1. Overall Survival Rate [ Time Frame: 3 years ]
   Length of time from study enrollment to death from any cause.
2. Treatment-related toxicities [ Time Frame: 3 years ]
   Toxicities measured by CTCAE version 5.0 criteria.

Eligibility Criteria

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

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.
• 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)

  • AST(SGOT)/ALT(SGPT) ≤ 2.5 × institutional ULN, OR

    • 5 × institutional ULN if liver metastases are present
  • 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 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 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

Contacts and Locations

Contacts

Contact: Panagiotis Konstantinopoulos, MD; 877-338-7425; PanagiotisA_Konstantinopoulos@DFCI.HARVARD.EDU

Locations

United States, Massachusetts

Massachusetts General Hospital Cancer Center; Recruiting

Boston, Massachusetts, United States, 02214

Contact: Cesar Castro, MD 617-724-4000

Principal Investigator: Cesar Castro, MD

Beth Israel Deaconess Medical Center (BIDMC); Recruiting

Boston, Massachusetts, United States, 02215

Contact: Meghan Shea, MD 617-667-5661

Principal Investigator: Meghan Shea, MD

Dana Farber Cancer Institute; Recruiting

Boston, Massachusetts, United States, 02215

Contact: Panagiotis Konstantinopoulos, MD 877-338-7425 PanagiotisA_Konstantinopoulos@DFCI.HARVARD.EDU

Principal Investigator: Panagiotis Konstantinopoulos, MD

Sponsors and Collaborators

Dana-Farber Cancer Institute

Eli Lilly and Company

Investigators

• Principal Investigator: Panagiotis Konstantininopoulos, MD; Dana-Farber Cancer Institute

More Information

• Responsible Party: Panagiotis Konstantinopoulos, MD, PhD, Principal Investigator, Dana-Farber Cancer Institute
• ClinicalTrials.gov Identifier: NCT03675893
• Other Study ID Numbers: 18-301
• First Posted: September 18, 2018
• Last Update Posted: January 31, 2020
• Last Verified: January 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Panagiotis Konstantinopoulos, MD, PhD, Dana-Farber Cancer Institute:

Endometrial Cancer; CDK4/6; ER+; Estrogen Receptor

Additional relevant MeSH terms:

Endometrial Neoplasms; Uterine Neoplasms; Genital Neoplasms, Female; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Uterine Diseases; Genital Diseases, Female; Letrozole; Antineoplastic Agents; Aromatase Inhibitors; Steroid Synthesis Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Estrogen Antagonists; Hormone Antagonists; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs