RESOLVE: Abemaciclib + Letrozole +/- Metformin, Zotatifin, or Gedatolisib in Endometrial or Low-Grade Serous Ovarian Cancer
RESOLVE: letRozole abEmaciclib combinationS in endOmetriaL and oVarian cancEr: A Multi-Cohort Phase 2 Study of Letrozole/Abemaciclib Alone and in Combination With Metformin, Zotatifin and Gedatolisib
1 other identifier
interventional
180
1 country
3
Brief Summary
This research study is studying a combination of targeted therapies as a possible treatment for estrogen-receptor positive (ER+) endometrial cancer and low-grade serous ovarian cancer. The drugs involved in this study are:
- Abemaciclib (also known as Verzenio™)
- Letrozole (also known as Femara®)
- Metformin (also known as Glucophage®)
- Zotatifin (also known as eFT226)
- Gedatolisib (also known as PF-05212384)
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P75+ for phase_2
Started Dec 2018
Longer than P75 for phase_2
3 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
Click on a node to explore related trials.
Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
September 14, 2018
CompletedFirst Posted
Study publicly available on registry
September 18, 2018
CompletedStudy Start
First participant enrolled
December 24, 2018
CompletedPrimary Completion
Last participant's last visit for primary outcome
August 1, 2028
ExpectedStudy Completion
Last participant's last visit for all outcomes
August 1, 2031
June 15, 2025
June 1, 2025
9.6 years
September 14, 2018
June 12, 2025
Conditions
Keywords
Outcome Measures
Primary Outcomes (2)
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 Outcomes (2)
Overall Survival Rate
3 years
Treatment-related toxicities
3 years
Study Arms (8)
Cohort 1
EXPERIMENTAL* Abemaciclib is administered by mouth twice daily * LY3023414 is administered by mouth twice daily * Letrozole is administered by mouth once daily
Cohort 2
EXPERIMENTAL* Abemaciclib is administered by mouth twice daily * LY3023414 is administered by mouth twice daily
Cohort 1A
EXPERIMENTAL* Abemaciclib is administered by mouth twice daily * Letrozole is administered by mouth once daily
Cohort 3
EXPERIMENTAL* Abemaciclib is administered by mouth twice daily * Letrozole is administered by mouth once daily * Metformin is administered by mouth once daily
Cohort 4
EXPERIMENTAL* Abemaciclib is administered by mouth twice daily * Letrozole is administered by mouth once daily * Zotatifin is administered intravenously on days 1 and 8 of a 21-day cycle
Cohort 5
EXPERIMENTAL* Abemaciclib is administered by mouth twice daily * Letrozole is administered by mouth once daily * Zotatifin is administered intravenously on days 1 and 8 of a 21-day cycle
Cohort 6
EXPERIMENTAL* Abemaciclib is administered by mouth twice daily * Letrozole is administered by mouth once daily * Gedatolisib is administered intravenously on days 1, 8 and 15 of a 28-day cycle
Cohort 7
EXPERIMENTAL* Abemaciclib is administered by mouth twice daily * Letrozole is administered by mouth once daily * Gedatolisib is administered intravenously on days 1, 8 and 15 of a 28-day cycle
Interventions
Letrozole is a hormonal therapy that works by lowering the production of estrogen in the body.
Abemaciclib is a cyclin-dependent kinase (CDK) inhibitor.
LY3023414 is a potent selective inhibitor of the class I PI3K isoforms, mTOR, and DNA-PK.
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.
Zotatifin is a selective eukaryotic initiation factor 4A (eIF4A) inhibitor.
Gedatolisib is a PI3K/AKT/mTOR (PAM) pathway inhibitor.
Eligibility Criteria
You may qualify if:
- 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, 4, 6 and 7, must have histologically confirmed either i) endometrioid endometrial cancer or ii) endometrial carcinosarcoma with endometrioid epithelial component
- For Cohort 5: Participants must have histologically confirmed diagnosis of low-grade serous carcinoma of ovary, fallopian tube or peritoneum; original diagnosis of de novo low-grade serous carcinoma or original diagnosis of serous borderline tumor with subsequent diagnosis of low-grade serous carcinoma. Participants whose tumors contain both low-grade serous carcinoma and high-grade serous carcinoma are not eligible.
- 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 Cohort 5, participants are eligible regardless of ER positive or negative status.
- 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.
- For cohorts 4, 5, 6 and 7, patients must not have remaining ovarian function to be included. Women who have ovarian function are eligible but must be placed on hormonal suppression.
- 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.
- +7 more criteria
You may not qualify if:
- 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. For Cohorts 4 and 5, prior treatment with CDK4/6 inhibitors is allowed in up to 50% of participants for each cohort (≤8 participants in the first stage and ≤18 total in both stages for each cohort \[if the study goes to second stage\]). For Cohort 7, patients must have received prior treatment with CDK4/6 inhibitors.
- Participants who are currently receiving metformin therapy (if enrolling to Cohort 3).
- Participants who have impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the study drugs
- 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.
- Use of known QT-prolonging drugs during screening or expected requirement for use during study therapy.
- 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.
- +4 more criteria
Contact the study team to confirm eligibility.
Sponsors & Collaborators
- Dana-Farber Cancer Institutelead
- Eli Lilly and Companycollaborator
- Effector Therapeuticscollaborator
- Celcuity Inccollaborator
Study Sites (3)
Massachusetts General Hospital Cancer Center
Boston, Massachusetts, 02214, United States
Beth Israel Deaconess Medical Center (BIDMC)
Boston, Massachusetts, 02215, United States
Dana Farber Cancer Institute
Boston, Massachusetts, 02215, United States
Related Publications (1)
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.
PMID: 36174113DERIVED
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Study Officials
- PRINCIPAL INVESTIGATOR
Panagiotis Konstantininopoulos, MD
Dana-Farber Cancer Institute
Central Study Contacts
Study Design
- Study Type
- interventional
- Phase
- phase 2
- Allocation
- NON RANDOMIZED
- Masking
- NONE
- Purpose
- TREATMENT
- Intervention Model
- SEQUENTIAL
- Sponsor Type
- OTHER
- Responsible Party
- PRINCIPAL INVESTIGATOR
- PI Title
- Principal Investigator
Study Record Dates
First Submitted
September 14, 2018
First Posted
September 18, 2018
Study Start
December 24, 2018
Primary Completion (Estimated)
August 1, 2028
Study Completion (Estimated)
August 1, 2031
Last Updated
June 15, 2025
Record last verified: 2025-06
Data Sharing
- IPD Sharing
- Will not share