Abemaciclib and Letrozole to Treat Endometrial Cancer

A Phase II Study of Abemaciclib in Combination With Letrozole in Advanced, Recurrent or Metastatic Endometroid Endometrial Cancer

This is a phase II single arm trial to determine the percentage of patients without evidence of disease progression on abemaciclib and letrozole in advanced stage, persistent or recurrent endometrioid endometrial cancer at 6 months. Treatment will continue until either unacceptable toxicity, progression of disease, or investigator/patient request for withdrawal.

Study Overview

• Status: Active, not recruiting
• Conditions: Endometrial Cancer
• Intervention / Treatment: Drug: Abemaciclib; Drug: Letrozole

• Study Type: Interventional
• Enrollment (Actual): 53
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Jennifer Klein, MEd; Phone Number: 2158540770; Email: jklein@gog.org

Study Locations

• United States
  • Alabama
    • Mobile, Alabama, United States, 36604
      • University of South Alabama Mitchell Cancer Center
  • Alaska
    • Anchorage, Alaska, United States, 99508
      • Alaska Women's Cancer Care
  • Connecticut
    • Greenwich, Connecticut, United States, 06830
      • Smillow Cancer Care at Greenwich
    • New Haven, Connecticut, United States, 06520
      • Yale University
  • Florida
    • Coral Gables, Florida, United States, 33146
      • Sylvester Comprehensive Cancer Center-Lennar Foundation Medical Center
    • Deerfield Beach, Florida, United States, 33442
      • Sylevester Comprehensive Cancer Center-Deerfield Beach
    • Gainesville, Florida, United States, 32160
      • UF Health Cancer Center
    • Miami, Florida, United States, 33136
      • University of Miami - Sylvester Cancer Center
    • Miami, Florida, United States, 33136
      • UT Health Tower
    • Orlando, Florida, United States, 32804
      • Advent Health - Orlando
    • Plantation, Florida, United States, 33324
      • Sylvester Comprehensive Cancer Center-Plantation
    • Weston, Florida, United States, 33331
      • Cleveland Clinic Florida
  • Georgia
    • Savannah, Georgia, United States, 31405
      • Lewis Cancer & Research Pavilion
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University Of Chicago
  • Kentucky
    • Lexington, Kentucky, United States, 40503
      • Baptist Healthcare System
  • Massachusetts
    • Boston, Massachusetts, United States, 02111
      • Tufts Medical Center
    • Worcester, Massachusetts, United States, 01605
      • University of Massachusetts
  • Michigan
    • Ann Arbor, Michigan, United States, 48106
      • St. Joseph Mercy Hospital
  • New Jersey
    • New Brunswick, New Jersey, United States, 08903
      • Rutgers Cancer Institute of New Jersey
    • Teaneck, New Jersey, United States, 07666
      • Holy Name Medical Center
  • New York
    • New York, New York, United States, 10032
      • Columbia University Medical Center
    • Syracuse, New York, United States, 13210
      • SUNY Upstate Medical University
  • Oklahoma
    • Tulsa, Oklahoma, United States, 74146
      • Oklahoma Cancer Specialists and Research Institute
  • Pennsylvania
    • Reading, Pennsylvania, United States, 19611
      • Reading Hospital-McGlinn Cancer Institute
    • Willow Grove, Pennsylvania, United States, 19090
      • Abington Memorial Hospital
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • Huntsman Cancer Institute
    • Salt Lake City, Utah, United States, 84112
      • Baptist Health Center Lexington
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University Of Virginia
  • West Virginia
    • Morgantown, West Virginia, United States, 26506
      • West Virginia University

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Patient must have advanced (FIGO 2014 Stage III or IV), persistent, or recurrent endometrial carcinoma, which is not likely to be curable by surgery or radiotherapy. Histologic confirmation of recurrent disease is required. For cases of persistent disease, histologic confirmation of the primary disease with radiologic evidence of progression is required.

2. Patients must have endometrioid histology (all grades allowed) based on hysterectomy or biopsy specimen (Hormone receptor status is not required for enrollment).

   Sites are required to report results of previous MMR, MSI, and ER/PR status testing in Medidata Rave if available.

3. All patients must have measurable disease. Measurable disease is defined by RECIST version 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 greater than or equal to 10mm when measured by CT, MRI or caliper measurement by clinical exam; or greater than or equal to 20mm when measured by chest x-ray. Lymph nodes must be greater than or equal to 15mm in short axis when measured by CT or MRI.

   Patient must have at least one "target lesion" to be used to assess response on this protocol as defined by RECIST 1.1. Tumors within a previously irradiated field will be designated as "non-target" lesions unless progression is documented or a biopsy is obtained to confirm persistence at least 90 days following completion of radiation therapy.

4. Prior chemotherapy in the adjuvant setting for Stage I, II, or III is permitted. Prior chemoradiotherapy for a pelvic recurrence is permitted.

   Note: Chemotherapy in the setting of Stage IV disease is permitted but the patient must be without evidence of disease at the completion of chemotherapy and have at least six months of progression-free survival since the completion of chemotherapy before detection of the recurrent cancer for which she is receiving treatment on this protocol.

   Prior immunotherapy and/or targeted therapy is allowed in addition to, in combination with, in lieu of, or subsequent to prior chemotherapy.

   Regardless of circumstances, no more than one prior chemotherapy regimen (including chemo-radiotherapy) is permitted, and no more than one additional systemic therapy is permitted. Hence, eligible patient may have received 0, 1, or 2 prior lines of systemic therapy and for women who received two prior lines of therapy, only one of them may have included chemotherapy.

   Patients who received prior chemotherapy, immunotherapy or targeted therapy must have recovered (Common Terminology Criteria for Adverse Events [CTCAE] Grade ≤1) from the acute effects of chemotherapy except for residual alopecia or Grade 2 peripheral neuropathy prior to enrollment. A washout period of at least 21 days is required between last systemic therapy dose and initiation of therapy.

   Patients who received radiotherapy must have completed and fully recovered from the acute effects of radiotherapy. A washout period of at least 14 days is required between end of radiotherapy and initiation of therapy.

5. Patient must be able to swallow oral medications.
6. Patient must have an ECOG performance status of 0 to 1.

7. Patients must have adequate organ and marrow function as defined below NOTE: Institutional/laboratory upper limit of normal = ULN Institutional/laboratory lower limit of normal = LLN

   Bone marrow function:

   • Absolute neutrophil count (ANC) greater than or equal to 1500/mcl
   • Platelets greater than or equal to 100,000 cells/mcl
   • Hemoglobin greater than or equal to 8 g/dL (Patients may receive erythrocyte transfusions to achieve this hemoglobin level at the discretion of the investigator. Initial treatment must not begin earlier than the day after erythrocyte transfusion).

   Renal function:

   • Creatinine less than or equal to 1.5 x ULN

   Hepatic function:

   • Bilirubin less than or equal to 1.5 x ULN (Patients with Gilbert's syndrome with a total bilirubin ≤2 times ULN and direct bilirubin within normal limits are permitted).
   • ALT (alanine aminotransferase) and AST (aspartate aminotransferase) less than or equal to 3 x ULN
   • Alkaline phosphatase less than or equal to 2.5 x ULN
   • Albumin greater than or equal to 2.8 g/dL
8. Patients must have signed an approved informed consent and authorization permitting release of personal health information.
9. Patients must be at least 18 years of age.
10. Patients of childbearing potential must have a negative serum pregnancy test prior to the study entry and be practicing a highly effective form of contraception during the study treatment and for 8 weeks after stopping the treatment.

Highly effective contraception methods include combination of any of the following (NOTE: Estrogen containing contraceptives are prohibited):

• Use of oral, injected, or implanted hormonal methods of contraception or;
• Placement of an intrauterine device (IUD) or intrauterine system (IUS);
• Barrier methods of contraception: condom or occlusive cap (diaphgram or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository;
• Total abstinence or;
• Male/female sterilization. Women are considered post-menopausal and not of child-bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks prior to randomization. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child-bearing potential.

Exclusion criteria

1. Patients who have previously received any CDK4/6 inhibitor.
2. Patients with clear cell, serous, carcinosarcoma, mixed histology endometrial cancers, or uterine sarcomas.
3. Known intolerance or hypersensitivity to abemaciclib or letrozole.
4. Patients who have previously received hormonal therapy for endometrial cancer.
5. Patients with concomitant invasive malignancy or a history of other invasive malignancies, with the exception of non-melanoma skin cancer, are excluded if there is any evidence of other malignancy being present within the past five years. Patients are also excluded if their previous cancer treatment contraindicates this protocol.
6. Patients receiving chronic treatment with systemic steroids or another immunosuppressive agent.
7. Patients with active systemic bacterial infection (requiring intravenous [IV] antibiotics at time of initiating study treatment, fungal infection, or detectable viral infection (such as known human immunodeficiency virus positivity or with known active hepatitis B or C [for example, hepatitis B surface antigen positive]). Screening is not required for enrollment.
8. Patients with a serious pre-existing medical condition(s) that would preclude participation in this study (for example: interstitial lung disease, severe dyspnea at rest or requiring oxygen therapy, severe renal impairment (i.e. estimated creatinine clearance <30ml/min), history of major surgical resection involving the stomach or small bowel, or preexisting Crohn's disease or ulcerative colitis or pre-existing chronic condition resulting in baseline grade 2 or higher diarrhea).

9. Patients with a known history of cardiac disease. This includes:

   • Uncontrolled hypertension, defined as systolic greater than 150mm Hg or diastolic greater than 90mm Hg despite antihypertensive medications
   • Myocardial infarction or unstable angina within 6 months prior to registration.
   • New York Heart Association (NYHA) Class II or greater congestive heart failure.
   • History of serious ventricular arrhythmia (i.e. ventricular tachycardia or ventricular fibrillation) or serious cardiac arrhythmia requiring medication, syncope of cardiovascular etiology or sudden cardiac arrest. This does not include asymptomatic atrial fibrillation with controlled ventricular rate.
   • Cerebrovascular accident (CVA, stroke), transient ischemic attack (TIA) within 6 months prior to the first date of study therapy.
10. Patients who are pregnant or breast-feeding.
11. Patients with known central nervous system metastases.
12. Patients with known human immunodeficiency virus (HIV) infection.
13. Patients with an impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of abemaciclib (i.e. ulcerative disease; uncontrolled nausea, vomiting and/or diarrhea; malabsorption syndrome; clinical signs and symptoms of gastrointestinal obstruction; and/or patients who require parenteral hydration and/or nutrition).
14. Patients who plan to receive live attenuated vaccines within 1 week of start of abemaciclib and during the study. Patients should also avoid close contact with others who have received live attenuated vaccines. Examples of live attenuated vaccines include intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines.
15. Patients with active bleeding or pathologic conditions that carry high risk of bleeding such as known bleeding disorder or coagulopathy.
16. Patients with history of unprovoked venous thrombosis unless taking anticoagulation treatment for duration of trial.
17. Patients who are currently part of or have participated in any clinical investigation with an investigational drug within 30 days prior to dosing.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Abemaciclib and Letrozole; Study treatment will consist of abemaciclib 150mg orally twice a day and letrozole 2.5mg orally once a day.	Drug: Abemaciclib; Abemaciclib 150mg orally twice a day; Drug: Letrozole; Letrozole 2.5mg orally once a day

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival	To evaluate the efficacy in terms of the probability of surviving progression free for at least 6 months (PFS at 6 mo)	From date of protocol entry to date of first documented progression up to 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Response rate	To determine the proportion responding by RECIST v1.1 in patients with advanced, persistent, or recurrent endometrioid endometrial cancer	From date of protocol entry to date of first response assessed up to 5 years
Time to disease progression or death	To estimate the time to disease progression or death (PFS and OS endpoints).	From date of protocol entry to date of progression or death assessed up to 5 years
Toxicity Assessment of Adverse Events	To describe the toxicities in patients receiving combination therapy with letrozole and abemaciclib	Every 4 weeks assessed up to 5 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Protein expression analysis of Cyclin D and E Pathway	Perform multiplexed protein expression analysis at a single cell level using imaging mass cytometry (IMC), exploring the relationship to response, and assessing for longitudinal changes upon progression/relapse. Cyclin D and E Pathway: Protein expression of CCND1, CDK4, CDK6, RB1, phospho-RB1, CDKN2A, CCNE1, CCNE2, CDK2, CCND3	At time of primary and secondary outcome analysis up to 5 years
Protein expression analysis of Immune Cell Infiltration and activity	Perform multiplexed protein expression analysis at a single cell level using imaging mass cytometry (IMC), exploring the relationship to response, and assessing for longitudinal changes upon progression/relapse. Immune cell infiltration and activity: CD45, CD3, CD8, CD4, FoxP3, PD-1, Tim-3, CTLA-4, CD25, Ki67.	At time of primary and secondary outcome analysis up to 5 years
Protein expression analysis of sex hormone/insulin/IGF pathway	Perform multiplexed protein expression analysis at a single cell level using imaging mass cytometry (IMC), exploring the relationship to response, and assessing for longitudinal changes upon progression/relapse. Sex hormone/insulin/IGF pathway: Protein expression of ER (ESR1), PR, IR, IGF1R, and phospho-IGF1R/IR	At time of primary and secondary outcome analysis up to 5 years
Cyclin D1 3'UTR mutations	Determine the frequency of Cyclin D1 3'UTR mutations and correlatioin with response.	At time of primary and secondary outcome analysis up to 5 years
Estradiol levels	Compare the pre- and post-treatment circulating estradiol levels, and association with response.	At time of primary and secondary outcome analysis up to 5 years
Insulin levels	Compare the pre- and post-treatment circulating insulin levels, and association with response.	At time of primary and secondary outcome analysis up to 5 years

Collaborators and Investigators

• Sponsor: Gynecologic Oncology Group
• Collaborators: Eli Lilly and Company
• Investigators: Study Chair: Marilyn Huang, MD, University Of Virginia

Study record dates

Study Major Dates

• Study Start (Actual): October 10, 2020
• Primary Completion (Estimated): December 1, 2024
• Study Completion (Estimated): December 1, 2025

Study Registration Dates

• First Submitted: May 11, 2020
• First Submitted That Met QC Criteria: May 13, 2020
• First Posted (Actual): May 19, 2020

Study Record Updates

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

More Information

Terms related to this study

• 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; 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
• Other Study ID Numbers: GOG-3039

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No