TRADE: Dose Escalation Tolerability of Abemaciclib in HR+ HER2- Early Stage Breast Cancer

The TRADE Study: A Phase 2 Trial to Assess the ToleRability of Abemaciclib Dose Escalation in Patients With Early-Stage HR-positive and HER2-negative Breast Cancer

In this research study, investigators are testing if a dose-increasing strategy for abemaciclib will have less side effects and be better tolerated than the standard dosage of abemaciclib for participants with early-stage high-risk hormone receptor positive breast cancer.

The names of the study drugs involved in this study are:

• Abemaciclib (CDK4 and CDK6 inhibitor)
• Tamoxifen (Selective estrogen receptor modulator)
• Anastrozole/Letrozole (Non-steroidal aromatase inhibitors)
• Exemestane (steroidal aromatase inhibitor)
• LHRH (Gonadotropin-releasing hormone agonist, or Luteinizing hormone-releasing hormone agonist)

Study Overview

• Status: Active, not recruiting
• Conditions: Breast Cancer; Early-stage Breast Cancer; High Risk Breast Carcinoma
• Intervention / Treatment: Drug: Abemaciclib; Drug: Tamoxifen; Drug: Anastrozole; Drug: Letrozole; Drug: Exemestane; Drug: LHRH Agonist

Detailed Description

This research study is a prospective, single-arm, open label, phase 2 study designed to evaluate if a dose-increasing strategy for abemaciclib will have less side effects and be better tolerated than the standard dosage of abemaciclib for participants with early-stage high-risk hormone receptor positive breast cancer.

This research study involves adjuvant abemaciclib plus endocrine (anti-hormone) therapy that works to target breast cancer. Adjuvant therapy is treatment given after surgery, chemotherapy, and/or radiation therapy.

The U.S. Food and Drug Administration (FDA) has approved abemaciclib as a treatment option for early-stage high-risk hormone receptor breast cancer. The FDA has also approved hormonal therapies as treatment for hormone receptor positive breast cancer.

The research study procedures include screening for eligibility, study treatment including laboratory evaluations and questionnaires, blood tests, tumor biopsies, and stool collections.

Participation in this research study is expected to last for at least 2 years and up to 5 years.

It is expected that about 90 people will take part in this research study.

Eli Lilly and Company is supporting this study by providing funding for the study and supplying the study drug, abemaciclib.

• Study Type: Interventional
• Enrollment (Estimated): 90
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Connecticut
    • Stamford, Connecticut, United States, 06904
      • Stamford Hospital
  • Maine
    • Brewer, Maine, United States, 04412
      • Eastern Maine Medical Center (Northern Light)
    • Scarborough, Maine, United States, 04074
      • New England Cancer Specialists
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Medical Center
    • Boston, Massachusetts, United States, 02215
      • Dana-Farber Cancer Institute
    • Boston, Massachusetts, United States, 02118
      • Boston Medical Center
    • Brighton, Massachusetts, United States, 02135
      • Dana-Farber Cancer Institute at Steward St. Elizabeth's
    • Foxborough, Massachusetts, United States, 02035
      • Dana-Farber Cancer Institute at Foxborough
    • Methuen, Massachusetts, United States, 01844
      • Dana-Farber Cancer Institute at Merrimack Valley
    • Milford, Massachusetts, United States, 01757
      • Dana-Farber Cancer Institute at Milford
    • South Weymouth, Massachusetts, United States, 02190
      • Dana-Farber Cancer Institute at South Shore
  • New Hampshire
    • Londonderry, New Hampshire, United States, 03053
      • Dana-Farber Cancer Insitute at Londonderry Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Stage II or III node-positive HR+/HER2- breast cancer per local laboratory assessment.
• Eligible participants must be appropriate candidates for adjuvant abemaciclib, per assessment of their treating physician.
• Participants must be candidates for adjuvant endocrine therapy, which may have started before or at time of entry onto the trial. Patient may be receiving adjuvant aromatase inhibitor or tamoxifen, +/- ovarian suppression.
• Participants must have undergone definitive surgery of the primary breast tumor(s) within 16 months of study entry.
• At least 21 days must have elapsed between last dose of chemotherapy and registration. Participants who previously 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 randomization.
• At least 14 days must have elapsed between end of radiotherapy and day 1 of treatment with abemaciclib. Participants who received prior radiotherapy must have completed and fully recovered from the acute effects of radiotherapy. No radiotherapy should be planned to occur during study therapy.
• At least 14 days must have elapsed since most recent breast surgery prior to registration and patient has recovered from side effects of prior surgery.
• Bilateral or multifocal/multicentric breast cancers that meet eligibility criteria are allowed.
• ECOG performance status 0-1
• Men and women with any menopausal status ≥18 years of age

• Adequate organ function as defined below:

  • Absolute neutrophil count (ANC) ≥ 1500 x 10^9/L
  • Platelets ≥ 100 x 10^9/L
  • Hemoglobin ≥ 8g/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 the erythrocyte transfusion.
  • Bilirubin ≤ 1.5 x ULN. For patients with Gilbert syndrome, the limit is ≤ 2 x institutional ULN AND direct bilirubin within the normal range of normality.
  • AST/ALT ≤ 3 x institutional ULN

• Premenopausal women must have a negative serum or urine pregnancy test. Pregnancy testing does not need to be pursued in female patients who are:

  • Age > 60 years; or
  • Age < 60 with intact uterus and amenorrhea for 12 consecutive months or more AND FSH/estradiol levels within postmenopausal range; or
  • Status-post bilateral oophorectomy, total hysterectomy, or bilateral tubal ligation.
• Women of child-bearing potential and men with partners of childbearing potential must be willing to employ one highly effective form of nonhormonal contraception (with the exception of hormonal IUDs) or two effective forms of nonhormonal contraception by the patient and/or partner and continue its use for the duration of the study treatment and for 3 months after the last dose of abemaciclib.
• Subject must be able to swallow and retain oral medication.
• Ability to understand and the willingness to sign a written informed consent document.
• Non-English-speaking patients are eligible but will be exempt from patient-completed questionnaires.

Exclusion Criteria:

• Prior treatment with any CDK4/6 inhibitor.
• Patients with node-negative breast cancer are not eligible for the trial.
• Concurrent therapy with other investigational agents.
• Diagnosis of inflammatory breast cancer (T4d).
• History of allergic reactions attributed to abemaciclib or similar chemical or biologic composition or excipients.

• Participants with a history of malignancy are ineligible except in the following circumstances:

  --Individuals with a history of invasive breast cancer are not eligible unless they have been disease-free for a minimum of five years.

• Individuals with a malignancy history other than invasive breast cancer are eligible if they have no active malignancy and are deemed by the investigator to be at low risk for recurrence of that malignancy.
• Individuals with the following cancer history are eligible: adequately treated non- melanoma skin cancers, curatively treated in situ cancer of the cervix, ductal carcinoma in situ (DCIS) of the breast, stage 1 grade 1 endometrial carcinoma. Other exceptions may exist following review with the sponsor-investigator
• 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, 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 uncontrolled Crohn's disease or ulcerative colitis or a preexisting chronic condition resulting in baseline Grade 2 or higher diarrhea) or other conditions that in the opinion of the investigator limit compliance with study requirements.
• 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.

• Any of the following due to teratogenic potential of the study drugs:

  • Pregnant women
  • Nursing women
  • Women of childbearing potential who are unwilling to employ adequate contraception (condoms, diaphragms, IUDS, surgical sterilization, abstinence, etc). Hormonal birth control methods are not permitted.
  • Men who are unwilling to employ adequate contraception (condoms, surgical sterilization, abstinence, etc).
• Receipt of an experimental treatment in a clinical trial within the last 30 days or 5 half-lives, whichever is longer, prior to enrollment, or is currently enrolled in any other type of medical research (for example: medical device) judged by the sponsor-investigator not to be scientifically or medically compatible with this study.
• Active systemic bacterial infection (requiring intravenous [IV] antibiotics at time of initiating study treatment) or invasive/ systemic fungal infection\
• For patients with known HIV infection, CD4 baseline count should be evaluated: patients with a CDK count ≥ 350 cells/uL can be enrolled. Participants should be on established anti-retroviral therapy (ART) for at least four weeks and have an HIV viral load less than 400 copies/mL prior to enrollment. Potential pharmacological interactions of the ART with abemaciclib and endocrine therapy must be reviewed, particularly for the effects on CYP3A4.
• Patients with active or chronic Hepatitis B or C are eligible provided they meet liver function laboratory criteria and cannot be on any medication with a known interaction with the study agents.
• Participants receiving any medications or substances that are strong inhibitors or inducers of CYP3A4, including selected herbals (e.g., hypericum) and food (e.g., grapefruit) known for pharmacological interactions, cannot be enrolled, due to interference with the dose-escalation, unless the food or supplement has been discontinued at least after an interval equivalent to 3-5 half-lives of the inhibitor.

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; Study procedures will be conducted as follows: Cycles 1 - 24Days 1 - 28 of 28-day cycle: Predetermined dose of Abemaciclib 2 x per day.Endocrine therapy 1 x per day.; In clinic visits with blood tests, questionnaires, and assessments:Day 1 of Cycles 1, 2, and 3Day 15 of Cycles 1 and 2Every three cycles after Cycle 3 Day 1.; End of treatment visit with blood tests, questionnaires, assessments, and stool sample collection.

Drug: Abemaciclib; CDK4 and CDK6 inhibitor, tablet taken orally; Drug: Tamoxifen; Selective estrogen receptor modulator, taken orally per institutional standard of care; Drug: Anastrozole; Non-steroidal aromatase inhibitor, taken orally per institutional standard of care; Drug: Letrozole; Non-steroidal aromatase inhibitor, taken orally per institutional standard of care; Drug: Exemestane; Steroidal aromatase inhibitor, taken orally per institutional standard of care; Drug: LHRH Agonist; Luteinizing hormone-releasing hormone agonist), taken orally per institutional standard of care

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Composite Adverse Rate at 3 months	The rate of the composite endpoint will be reported, including disaggregated and combined rates of treatment discontinuations and/or dose reductions at 3 months.	3 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Grade 2-4 Diarrhea	Incidence of grade 2-4 diarrhea will be reported as frequencies and absolute numbers based on CTCAE5.0.	Up to 26 weeks
Composite Rate of Abemaciclib	The composite rate will be reported, including disaggregated and combined rates of treatment discontinuations, dose reductions, dose holds, and inability to reach or maintain the target dose.	Up to 25 weeks
Incidence of Treatment-Related Adverse Events	The incidence of treatment-related adverse events will be reported as frequencies and absolute numbers based on CTCAT5.0.	Up to 25 weeks
Rate of Inability to Reach the Full Dose	Rate of inability to reach the full dose will be reported as the rate of participants who have never reached the full dose at 150mg BID.	Up to 25 weeks
Therapeutic Adherence to Oral Adjuvant Therapy	Ratio of the self-reported number of pills taken and number of pills prescribed	Up to 25 weeks
Dose Intensity of Abemaciclib	Rate of patients at full dose (150mg BID) at 12 w versus those unable to reach full dose	12 weeks

Collaborators and Investigators

• Sponsor: Dana-Farber Cancer Institute
• Collaborators: Eli Lilly and Company
• Investigators: Principal Investigator: Erica Mayer, MD, MPH, Dana-Farber Cancer Institute

Study record dates

Study Major Dates

• Study Start (Actual): October 5, 2023
• Primary Completion (Actual): January 22, 2025
• Study Completion (Estimated): January 1, 2027

Study Registration Dates

• First Submitted: August 14, 2023
• First Submitted That Met QC Criteria: August 14, 2023
• First Posted (Actual): August 21, 2023

Study Record Updates

• Last Update Posted (Estimated): January 16, 2026
• Last Update Submitted That Met QC Criteria: January 15, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Keywords: Breast Cancer; Early-stage high-risk breast cancer; Early-stage breast cancer; High risk breast carcinoma
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Skin Diseases; Breast Diseases; Skin and Connective Tissue Diseases; Breast Neoplasms; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Pituitary Hormone-Releasing Hormones; Hypothalamic Hormones; Peptide Hormones; Neuropeptides; Peptides; Amino Acids, Peptides, and Proteins; Oligopeptides; Nerve Tissue Proteins; Proteins; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Azoles; Hydrocarbons; Hydrocarbons, Cyclic; Hydrocarbons, Aromatic; Benzene Derivatives; Nitriles; Triazoles; Stilbenes; Benzylidene Compounds; Letrozole; Anastrozole; Tamoxifen; Gonadotropin-Releasing Hormone; abemaciclib; exemestane
• Other Study ID Numbers: 23-355

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The Dana-Farber / Harvard Cancer Center encourages and supports the responsible and ethical sharing of data from clinical trials. De-identified participant data from the final research dataset used in the published manuscript may only be shared under the terms of a Data Use Agreement. Requests may be directed to: [contact information for Sponsor Investigator or designee]. The protocol and statistical analysis plan will be made available on Clinicaltrials.gov only as required by federal regulation or as a condition of awards and agreements supporting the research.
• IPD Sharing Time Frame: Data can be shared no earlier than 1 year following the date of publication
• IPD Sharing Access Criteria: Contact the Belfer Office for Dana-Farber Innovations (BODFI) at innovation@dfci.harvard.edu
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

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.: Yes