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

• ClinicalTrials.gov Identifier: NCT06001762
• Recruitment Status: Recruiting
• First Posted: August 21, 2023
• Last Update Posted: March 26, 2024
• Sponsor: Dana-Farber Cancer Institute
• Collaborator: Eli Lilly and Company
• Information provided by (Responsible Party): Erica Mayer, MD, MPH, Dana-Farber Cancer Institute

Study Description

Brief Summary:

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)

Condition or disease	Intervention/treatment	Phase
Breast Cancer; Early-stage Breast Cancer; High Risk Breast Carcinoma	Drug: Abemaciclib; Drug: Tamoxifen; Drug: Anastrozole; Drug: Letrozole; Drug: Exemestane; Drug: LHRH Agonist	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 90 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: October 5, 2023
• Estimated Primary Completion Date: January 1, 2026
• Estimated Study Completion Date: January 1, 2027

Arms and Interventions

Arm

Intervention/treatment

Experimental: Abemaciclib; Study procedures will be conducted as follows: Cycles 1 - 24 Days 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 3 Day 15 of Cycles 1 and 2 Every 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

Outcome Measures

Primary Outcome Measures :

1. Composite Adverse Rate at 3 months [ Time Frame: 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.

Secondary Outcome Measures :

1. Incidence of Grade 2-4 Diarrhea [ Time Frame: Up to 26 weeks ]
   Incidence of grade 2-4 diarrhea will be reported as frequencies and absolute numbers based on CTCAE5.0.
2. Composite Rate of Abemaciclib [ Time Frame: Up to 25 weeks ]
   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.
3. Incidence of Treatment-Related Adverse Events [ Time Frame: Up to 25 weeks ]
   The incidence of treatment-related adverse events will be reported as frequencies and absolute numbers based on CTCAT5.0.
4. Rate of Inability to Reach the Full Dose [ Time Frame: Up to 25 weeks ]
   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.
5. Therapeutic Adherence to Oral Adjuvant Therapy [ Time Frame: Up to 25 weeks ]
   Ratio of the self-reported number of pills taken and number of pills prescribed
6. Dose Intensity of Abemaciclib [ Time Frame: 12 weeks ]
   Rate of patients at full dose (150mg BID) at 12 w versus those unable to reach full dose

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: Female
• Gender Based Eligibility: Yes
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Contacts

Contact: Erica Mayer, MD, MPH; (617) 632-3800; EMAYER@PARTNERS.ORG

Locations

United States, Connecticut

Stamford Hospital; Recruiting

Stamford, Connecticut, United States, 06904

Contact: K.M. Steve Lo, MD slo@stamhealth.org

Principal Investigator: K.M. Steve Lo, MD

United States, Maine

New England Cancer Specialists; Recruiting

Scarborough, Maine, United States, 04074

Contact: Chiara Battelli, MD research@newecs.org

Principal Investigator: Chiara Battelli, MD

United States, Massachusetts

Beth Israel Deaconess Medical Center; Recruiting

Boston, Massachusetts, United States, 02215

Contact: Shana Berwick, MD 617-667-2100 sberwick@bidmc.harvard.edu

Principal Investigator: Shana Berwick, MD

Dana-Farber Cancer Institute; Recruiting

Boston, Massachusetts, United States, 02215

Contact: Erica Mayer, MD, MPH 617-632-3800 emayer@partners.org

Principal Investigator: Erica Mayer, MD, MPH

Dana-Farber Cancer Institute at Steward St. Elizabeth's; Recruiting

Brighton, Massachusetts, United States, 02135

Contact: Alys Malcolm, MD 617-632-4595 alys_malcolm@dfci.harvard.edu

Principal Investigator: Alys Malcolm, MD

Dana-Farber Cancer Institute at Foxborough; Recruiting

Foxboro, Massachusetts, United States, 02035

Contact: Natalie Sinclair, MD 508-543-1700 natalie_sinclair@dfci.harvard.edu

Principal Investigator: Natalie Sinclair, MD

Dana-Farber Cancer Institute at Merrimack Valley; Recruiting

Methuen, Massachusetts, United States, 01844

Contact: Pedro Sanz-Altamira, MD pedro_sanz-altamira@dfci.harvard.edu

Principal Investigator: Pedro Sanz-Altamira, MD

Dana-Farber Cancer Institute at Milford; Recruiting

Milford, Massachusetts, United States, 01757

Contact: Natalie Sinclair, MD 508-543-1700 natalie_sinclair@dfci.harvard.edu

Principal Investigator: Natalie Sinclaire, MD

Dana-Farber Cancer Institute at South Shore; Recruiting

South Weymouth, Massachusetts, United States, 02190

Contact: Meredith Faggen, MD 781-624-4800 Meredith_Faggen@dfci.harvard.edu

Principal Investigator: Meredith Faggeen, MD

United States, New Hampshire

Dana-Farber Cancer Insitute at Londonderry Hospital; Recruiting

Londonderry, New Hampshire, United States, 03053

Contact: Jeanna Walsh, MD 603-552-9100 jeanna_walsh@dfci.harvard.edu

Principal Investigator: Jeanna Walsh, MD

Sponsors and Collaborators

Dana-Farber Cancer Institute

Eli Lilly and Company

Investigators

• Principal Investigator: Erica Mayer, MD, MPH; Dana-Farber Cancer Institute

More Information

• Responsible Party: Erica Mayer, MD, MPH, Principle Investigator, Dana-Farber Cancer Institute
• ClinicalTrials.gov Identifier: NCT06001762
• Other Study ID Numbers: 23-355
• First Posted: August 21, 2023
• Last Update Posted: March 26, 2024
• Last Verified: March 2024

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• 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.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (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

• 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

Keywords provided by Erica Mayer, MD, MPH, Dana-Farber Cancer Institute:

Breast Cancer; Early-stage high-risk breast cancer; Early-stage breast cancer; High risk breast carcinoma

Additional relevant MeSH terms:

Breast Neoplasms; Neoplasms; Neoplasms by Site; Breast Diseases; Skin Diseases; Tamoxifen; Letrozole; Anastrozole; Exemestane; Antineoplastic Agents; Aromatase Inhibitors; Steroid Synthesis Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Estrogen Antagonists; Hormone Antagonists; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs; Antineoplastic Agents, Hormonal; Selective Estrogen Receptor Modulators; Estrogen Receptor Modulators; Bone Density Conservation Agents