ALPINE: Maintenance Letrozole/Abemaciclib

NCT06366347 | Recruiting Phase 2 DMC FDA Drug

• 1 other identifier: 23-695
• Study Type: interventional
• Target: 32
• Locations: 1 country
• Sites: 6

Brief Summary

The purpose of this research study is to see if the study drugs abemaciclib and letrozole are effective and safe for participants with estrogen-receptor positive (ER+), mismatch repair proficient, tumor protein p53 (TP53) wild-type endometrial cancer. The names of the study drugs involved in this study are:

• Abemaciclib (a type of cyclin-dependent kinase (CDK) inhibitor)
• Letrozole (a type of aromatase inhibitor)

Conditions

Endometrial Cancer; TP53; Recurrent Endometrial Cancer

Keywords

TP53 wild-type endometrial cancer; Endometrial Cancer; Recurrent endometrial cancer

Outcome Measures

Primary Outcomes (1)

• Median Progression Free Survival (PFS)

  PFS is defined as the time from the date the participant was registered to the date of documented progressive disease (PD) by RECIST version 1.1 or death (regardless of cause) in the absence of progression, regardless of whether the participant withdraws from study drug or receives another anti-cancer therapy prior to progression. Participants alive without disease progression are censored at date of last disease evaluation. A participant who dies without progression, and the death is \>12 weeks after the last evaluable tumor assessment, is censored for PFS at the date of last disease evaluation. A participant who has no baseline or no post treatment tumor assessment is censored at 0 days for PFS, unless she dies \< 12 weeks from randomization, in which case the PFS event date is the death date. Per RECIST 1.1 for target lesions: PD is at least a 20% increase in sum, taking as reference the smallest sum on study with at least 5 mm absolute increase.

  Up to 2 years

Secondary Outcomes (3)

• Grade 3-5 Adverse Events (AE) Rate

  Up to 2 years and 1 month

• Median Overall Survival (OS)

  Up to 5 years

• Objective Response Rate (ORR)

  Up to 2 years

Study Arms (1)

Arm 1: Abemaciclib + Letrozole

EXPERIMENTAL

Participants will be stratified by Primary Stage IVb (4b) vs. Primary Measurable Stage III (3)/IVa (4a) vs. Recurrent Endometrial Cancer and will complete study procedures as follows: * Baseline visit with X-ray, CT, MRI, or PET scan. * Cycles 1 through 3: --Days 1 through 21 of 21 day cycle: Predetermined dose of Abemaciclib 2x per day. Predetermined dose of Letrozole 1x per day. * Cycle 4 and every 2 cycles thereafter: --Days 1 through 21 of 21 day cycle: Predetermined dose of Abemaciclib 2x per day. Predetermined dose of Letrozole 1x per day. * X-ray, CT, MRI, or PET scan every 9 weeks for first 9 months, then every 12 months. * End of Treatment visit with assessments and X-ray, CT, MRI, or PET scan. * Follow up for up to 3 years.

Drug: Abemaciclib; Drug: Letrozole; Drug: Pembrolizumab

Interventions

Abemaciclib DRUG

CDK inhibitor, tablet taken orally per protocol.

Also known as: Verzenio, LY2835219, C27H32F2N8

Arm 1: Abemaciclib + Letrozole

Letrozole DRUG

Aromatase inhibitor, tablet taken orally per protocol.

Also known as: Femara, C17H11N5

Arm 1: Abemaciclib + Letrozole

Pembrolizumab DRUG

Humanized immunoglobulin G4 monoclonal antibody, 4mL (milliliter) single-dose vial, via intravenous (into the vein) infusion per institutional standard of care.

Also known as: Keytruda, MK-3475, Humanized X PD-1-mAB (monoclonal antibody) (H409A11) IgG4 (immunoglobulin G4), C6504H10004N1716O2036S46

Arm 1: Abemaciclib + Letrozole

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Participants 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 (Clinical Laboratory Improvement Amendments)-certified laboratory.
• Tumor must be TP53 wild-type as determined by immunohistochemistry (IHC) or via CLIA-certified targeted Next-Generation Sequencing (NGS); IHC assessment of p53 status is included in the NCCN guidelines of uterine neoplasms for the molecular analysis of endometrial carcinoma.
• Participants must have mismatch repair proficient (MMRP) endometrial cancer as determined by immunohistochemistry (IHC) or polymerase chain reaction (PCR) or any CLIA-certified next generation sequencing assay.
• No known tumor mutational burden ≥ 10 mutations/megabase (Mb).
• No known RB1 mutations or two-copy RB1 deletion.
• Participants must have just completed a minimum of 4 cycles and a maximum of 10 cycles of a combination of carboplatin and taxane or a combination of taxane and anti-PD-(L)1 inhibitor therapy (e.g., pembrolizumab, or dostarlimab, or durvalumab).
• Participants must have had measurable stage III, measurable stage IVA, stage IVB (with or without measurable disease) or recurrent (with or without measurable disease) endometrial cancer.
• Participants are permitted to have received:
• a. Prior adjuvant chemotherapy (e.g., paclitaxel/carboplatin alone or as a component of concurrent chemotherapy and radiation therapy \[with or without cisplatin\])
• b. Prior radiation therapy for treatment of endometrial cancer. Prior radiation therapy may have included pelvic radiation therapy, extended field pelvic/paraaortic radiation therapy, intravaginal brachytherapy, and/or palliative radiation therapy. All radiation therapy must have been completed at least 4 weeks prior to registration.
• c. Prior hormonal therapy for treatment of endometrial cancer.
• Must be able to initiate study drug between 3 to 8 weeks (or 21 to 56 days) after completion of their final dose of chemotherapy and anti-PD-(L)1 blockade (if they were receiving anti-PD-(L)1 blockade).
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 (see Appendix A)
• Age ≥ 18 years

You may not qualify if:

• Participants who have received previous treatment with CDK4/6 inhibitors, including but not limited to previous abemaciclib therapy.
• Any gastrointestinal dysfunctions that could interfere with the absorption of study drugs (e.g., bowel obstruction, inability to swallow tablets, malabsorption syndrome, unresolved nausea, vomiting, diarrhea CTCAE v 5.0 \> grade 1).
• Patients who received chemotherapy 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 starting study treatment.
• The patient has 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.
• Major injuries or surgery within 14 days prior to start of study treatment and/or planned major surgery during the on-treatment study period. 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 starting study treatment.
• Other malignant disease with disease-free ≤ 3 years except: curatively treated carcinoma in situ of the cervix, basal cell carcinoma of the skin, or ductal carcinoma in situ (DCIS) of the breast or any other cancer deemed by the investigator to be at low risk for recurrence of that malignancy.
• Active brain metastases (e.g., stable for \< 8 weeks, no adequate previous treatment with radiotherapy and/or surgery, symptomatic, requiring treatment with anti-convulsant therapy. Corticoid therapy is allowed if administered as stable dose for at least 1 month before starting study treatment).
• Females who are pregnant or lactating. 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.
• The patient has serious and/or uncontrolled preexisting medical condition(s) that, in the judgment of the investigator, would preclude participation in this study (for example, interstitial lung disease/pneumonitis, severe dyspnea at rest or requiring oxygen therapy, severe renal impairment \[e.g. estimated creatinine clearance \<30ml/min\], history of major surgical resection involving the stomach or small bowel, or preexisting Crohn's disease or ulcerative colitis or a preexisting chronic condition resulting in baseline Grade 2 or higher diarrhea).
• Participants who at the time of study enrollment are known to require concomitant therapy with 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.
• Participants with personal history of any of the following conditions: syncope of cardiovascular etiology, ventricular arrhythmia of pathological origin (including, but not limited to, ventricular tachycardia and ventricular fibrillation), or sudden cardiac arrest.
• 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 3 years prior to study enrollment, or individuals who are deemed by the treating investigator to be at low risk for disease recurrence.

Sponsors & Collaborators

• Dana-Farber Cancer Institute: lead
• Eli Lilly and Company: collaborator

Study Sites (6)

Beth Israel Deaconess Medical Center

Boston, Massachusetts, 02215, United States

RECRUITING

Brigham and Women's Hospital

Boston, Massachusetts, 02215, United States

RECRUITING

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215, United States

RECRUITING

Dana-Farber Cancer Institute at Foxborough

Foxborough, Massachusetts, 02035, United States

WITHDRAWN

Dana-Farber Cancer Institute at Milford

Milford, Massachusetts, 01757, United States

WITHDRAWN

Dana-Farber Cancer Institute at South Shore Hospital

Weymouth, Massachusetts, 02190, United States

RECRUITING

MeSH Terms

Conditions

Endometrial Neoplasms

Interventions

abemaciclib; Letrozole; pembrolizumab; Antibodies, Monoclonal; Immunoglobulin G

Condition Hierarchy (Ancestors)

Uterine Neoplasms; Genital Neoplasms, Female; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Uterine Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases

Intervention Hierarchy (Ancestors)

Nitriles; Organic Chemicals; Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Immunoglobulin Isotypes

Study Officials

• Panagiotis Konstantinopoulos, MD, PhD

  Dana-Farber Cancer Institute

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Panagiotis Konstantinopoulos, MD, PhD

CONTACT

617-632-2334; Panagiotis_Konstantinopoulos@DFCI.HARVARD.EDU

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principle Investigator

Study Record Dates

• First Submitted: April 8, 2024
• First Posted: April 15, 2024
• Study Start: September 25, 2024
• Primary Completion (Estimated): September 1, 2027
• Study Completion (Estimated): March 1, 2029
• Last Updated: February 11, 2026

Record last verified: 2025-08

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: Data can be shared no earlier than 1 year following the date of publication
• Access Criteria: Contact the Belfer Office for Dana-Farber Innovations (BODFI) at innovation@dfci.harvard.edu

Locations

US (6)