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Endometrial CancerPhase 2NCT03675893

RESOLVE: Abemaciclib + Letrozole +/- Metformin or Gedatolisib in Endometrial Cancer

A Phase 2 study testing Letrozole, Abemaciclib and LY3023414 in people with Endometrial Cancer, run by Dana-Farber Cancer Institute at 3 sites in United States.

Recruiting

Looking for participants now. Contact the study team or a site below to ask about taking part.

Sites and contacts
Official record
Search all trials

Trial 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®) Metformin (also known as Glucophage®) Gedatolisib (also… Read more about this study

Who is it for?
Ages 18 years and older, women only
Conditions the study is for
Endometrial Cancer
What is being tested?
Letrozole, Abemaciclib and LY3023414
Could I receive a placebo?
No, everyone receives an active treatment
How many people
110 participants
Where
3 sitesUnited States
Study dates
24 Dec 2018to 1 Aug 2031
Phase
Phase 2
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • Women only
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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, 6 and 7, 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:
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  • 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 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.
  • Ability to understand and the willingness to sign a written informed consent document.
  • Ability to swallow and retain oral medication.
  • Participants can have received an unlimited number of prior therapies.
  • 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
  • For Cohorts 6 and 7, participants must have HbA1c ≤6.4% and fasting plasma glucose (FPG) ≤140 mg/dL.
  • For Cohort 6 and 7, patients must have wildtype TP53 as assessed either by immunohistochemistry or any CLIA-certified next-generation sequencing assay.
  • For Cohort 7, patients must have received prior CDK4/6 inhibitor therapy and developed disease progression as deemed by the investigator. Patients who have stopped CDK4/6 inhibitor therapy because of intolerance are ineligible.

Who cannot join

  • 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 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
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  • 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.
  • Participants with a history of uncontrolled hypertension despite optimal medical management, defined as systolic blood pressure > 150 mmHg or diastolic blood pressure > 90 mmHg.
  • For Cohorts 6 and 7: Inability to determine the corrected QT interval using Fridericia's formula (QTcF) on the ECG (i.e., unreadable or not interpretable) or QTcF>480 msec (determined by mean of triplicate ECGs at screening).
  • For Cohorts 6 and 7, participants with type 1 diabetes or uncontrolled type 2 diabetes.
  • For Cohorts 6 and 7, participants who have previously received any PI3K pathway inhibitors are ineligible. Up to 10 patients in Cohort 6 and up to 10 patients in Cohort 7 may have received prior mTOR inhibitor therapy such as everolimus.

Trial locations and contacts

3 sites in 1 country. Contact the study team or a site near you to ask about taking part.

Panagiotis Konstantinopoulos, MD contact

877-338-7425

PanagiotisA_Konstantinopoulos@DFCI.HARVARD.EDU

United States3 sites, 3 recruiting

  • Massachusetts General Hospital Cancer Center

    Boston, Massachusetts, 02214

    Cesar Castro, MD, 617-724-4000

    Cesar Castro, MD

    Recruiting

  • Beth Israel Deaconess Medical Center (BIDMC)

    Boston, Massachusetts, 02215

    Page Widick, MD, (617) 667-5661

    Page Widick, MD

    Recruiting

  • Dana Farber Cancer Institute

    Boston, Massachusetts, 02215

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

    Panagiotis Konstantinopoulos, MD

    Recruiting

Other trials in United States

About this study

Official title: RESOLVE: A Multi-Cohort Phase 2 Study of Letrozole/Abemaciclib Alone and in Combination With Metformin and Gedatolisib

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®)
  • Gedatolisib (also known as PF-05212384)
Read the 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.

The FDA has not approved gedatolisib as a treatment for any disease.

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. Gedatolisib is a PI3K/AKT/mTOR (PAM) pathway inhibitor. PAM inhibitors work to stop cancer cell growth. PAM inhibition has been shown to enhance CDK inhibitors and hormonal therapy, like abemaciclib and letrozole.

In this research study, we are hoping to learn whether the combinations of abemaciclib and letrozole alone, or with metformin or gedatolisib are effective at slowing or stopping endometrial cancer cell growth.

Being tested
Letrozole, Abemaciclib, LY3023414, Metformin, Gedatolisib
Keywords
Endometrial Cancer, CDK4/6, ER+, Estrogen Receptor, PI3K, PAM
Medical subject headings
Endometrial Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • LetrozoleDrug

    Also called Femara

    Letrozole is a hormonal therapy that works by lowering the production of estrogen in the body.

  • AbemaciclibDrug

    Also called Verzenio

    Abemaciclib is a cyclin-dependent kinase (CDK) inhibitor.

  • LY3023414Drug

    LY3023414 is a potent selective inhibitor of the class I PI3K isoforms, mTOR, and DNA-PK.

  • MetforminDrug

    Also called Glucophage

    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.

  • GedatolisibDrug

    Also called PF-05212384

    Gedatolisib is a PI3K/AKT/mTOR (PAM) pathway inhibitor.

Study groups in NCT03675893
Study groupRoleWhat they receive
Cohort 1Experimental* Abemaciclib is administered by mouth twice daily * LY3023414 is administered by mouth twice daily * Letrozole is administered by mouth once daily
Receives: Drug: Letrozole; Drug: Abemaciclib; Drug: LY3023414
Cohort 2Experimental* Abemaciclib is administered by mouth twice daily * LY3023414 is administered by mouth twice daily
Receives: Drug: Abemaciclib; Drug: LY3023414
Cohort 1AExperimental* Abemaciclib is administered by mouth twice daily * Letrozole is administered by mouth once daily
Receives: Drug: Letrozole; Drug: Abemaciclib
Cohort 3Experimental* Abemaciclib is administered by mouth twice daily * Letrozole is administered by mouth once daily * Metformin is administered by mouth once daily
Receives: Drug: Letrozole; Drug: Abemaciclib; Drug: Metformin
Cohort 6Experimental* 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
Receives: Drug: Letrozole; Drug: Abemaciclib; Drug: Gedatolisib
Cohort 7Experimental* 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
Receives: Drug: Letrozole; Drug: Abemaciclib; Drug: Gedatolisib

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Progression Free Survival Rate

    Number of patients alive and disease progression-free per RECIST 1.1 criteria.

    Measured: 6 months

  2. Objective Tumor Response Rate

    Number of patients who experience objective tumor responses per RECIST 1.1 criteria.

    Measured: 6 months

Secondary outcomes (2)

  1. Overall Survival Rate

    Length of time from study enrollment to death from any cause.

    Measured: 3 years

  2. Treatment-related toxicities

    Toxicities measured by CTCAE version 5.0 criteria.

    Measured: 3 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted18 Sep 2018
  2. Study start24 Dec 2018
  3. Primary completion1 Aug 2028 (estimated)
  4. Study completion1 Aug 2031 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Sequential
Masking
None (open label)
Enrolment
110 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03675893
Sponsor's protocol ID
18-301
Status last verified
Jun 2026
First submitted
14 Sep 2018
Last updated
22 Jun 2026
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Publications

  • Konstantinopoulos PA, Zhou N, Penson RT, Le TV, Campos S, Krasner C, Wright AA, Porter R, Horowitz N, Bouberhan S, Liu JF, Hindenach S, Sawyer H, Koppermann L, Hayes M, Polak M, Shea M, Widick P, Cheng SC, Castro C, Beumer JH, Matulonis UA, Lee EK. Letrozole, abemaciclib and metformin in endometrial cancer: a non-randomized phase 2 trial. Nat Commun. 2025 Dec 3;17(1):395. doi: 10.1038/s41467-025-67087-8.

    PubMed 41339350

  • 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.

    PubMed 36174113

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Letrozole, Abemaciclib and LY3023414 in people with Endometrial Cancer, run by Dana-Farber Cancer Institute at 3 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 21 inclusion and 19 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: looking for participants now, as of the sponsor's last update on 22 Jun 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 3 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

Contact Panagiotis Konstantinopoulos, MD (877-338-7425, PanagiotisA_Konstantinopoulos@DFCI.HARVARD.EDU), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Progression Free Survival Rate (time frame: 6 months). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03675893, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 22 Jun 2026.

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