Clinical Trials /

A Phase 2 Study of LY3023414 and Abemaciclib With or Without Letrozole in Endometrial Cancer

NCT03675893

Description:

This research study is studying a combination of targeted therapies as a possible treatment for endometrial cancer. The drugs involved in this study are: - Abemaciclib (also known as Verzenio™) - LY3023414 - Letrozole (also known as Femara®)

Related Conditions:
  • Endometrial Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Phase 2 Study of LY3023414 and Abemaciclib With or Without Letrozole in Endometrial Cancer
  • Official Title: A Phase 2 Two-Group Study of LY3023414 and Abemaciclib With or Without Letrozole in Recurrent or Persistent Endometrial Cancer

Clinical Trial IDs

  • ORG STUDY ID: 18-301
  • NCT ID: NCT03675893

Conditions

  • Endometrial Cancer

Interventions

DrugSynonymsArms
LetrozoleFemaraCohort 1
LY3023414Cohort 1
AbemaciclibVerzenioCohort 1

Purpose

This research study is studying a combination of targeted therapies as a possible treatment for endometrial cancer. The drugs involved in this study are: - Abemaciclib (also known as Verzenio™) - LY3023414 - Letrozole (also known as Femara®)

Detailed Description

      This is a Phase II clinical trial with a safety lead-in.The safety lead-in will test the
      safety of a combination of investigational drugs and also try to define the appropriate dose
      of the combination to use for further studies. "Investigational" means that the drugs are
      being studied.

      The FDA (the U.S. Food and Drug Administration) has not approved LY3023414 as a treatment for
      any disease. The FDA has not approved abemaciclib or letrozole for this specific disease, but
      both drugs have been approved for other uses.

      Abemaciclib is a cyclin-dependent kinase (CDK) inhibitor and LY3023414 is a phosphoinositide
      3-kinase (PI3K) inhibitor. Both PI3K and 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 LY3023414, abemaciclib, and letrozole is
      effective at slowing or stopping endometrial cancer cell growth.
    

Trial Arms

NameTypeDescriptionInterventions
Cohort 1ExperimentalAbemaciclib is administered by mouth twice daily LY3023414 is administered by mouth twice daily Letrozole is administered by mouth once daily
  • Letrozole
  • LY3023414
  • Abemaciclib
Cohort 2ExperimentalAbemaciclib is administered by mouth twice daily LY3023414 is administered by mouth twice daily
  • LY3023414
  • Abemaciclib

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.

          -  For enrollment to Cohort 1: 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.

          -  For enrollment to 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.

          -  For enrollment to 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 CT scan, MRI, or calipers by clinical exam. See
             Section 11 for the evaluation of measurable disease.

          -  Age ≥ 18 years

          -  ECOG performance status of 0 or 1(see Appendix A)

          -  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 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 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression Free Survival Rate
Time Frame:6 months
Safety Issue:
Description:Number of patients alive and disease progression-free per RECIST 1.1 criteria.

Secondary Outcome Measures

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

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Dana-Farber Cancer Institute

Trial Keywords

  • Endometrial Cancer
  • PI3K
  • CDK4/6
  • PIK3CA
  • PIK3R1
  • PTEN

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