Tucatinib, Trastuzumab, and Capecitabine for the Treatment of HER2+ LMD

NCT03501979 | Terminated Phase 2 Results DMC FDA Drug

• 1 other identifier: UAB 1794
• Study Type: interventional
• Target: 17
• Locations: 1 country
• Sites: 9

Brief Summary

A phase 2 non-randomized study to assess the safety and efficacy of the combination of tucatinib and trastuzumab with capecitabine for the treatment of leptomeningeal metastases in HER2-neu positive breast cancer.

Conditions

Metastatic Breast Cancer; Leptomeningeal Disease

Keywords

HER2+; metastatic breast cancer; leptomeningeal disease; tucatinib; trastuzumab; capecitabine

Outcome Measures

Primary Outcomes (1)

• Length of Subject Survival After Starting Study Treatment

  Number of participants alive. A Gehan-like trial design with an interim futility analysis will be used.

  Through study completions, an average of 2 years

Secondary Outcomes (8)

• Number of Adverse Events

  up to 28 months

• Progression Free Survival

  up to 12 months

• Duration of Response in the Central Nervous System (CNS)

  up to 28 months

• Clinical Benefit Rate (CBR) in CNS

  Baseline up to 28 months

• Duration of Response in Extra-CNS Disease

  up to 28 months

Study Arms (1)

Tucatinib + Trastuzumab + Capecitabine

EXPERIMENTAL

Tucatinib will be taken orally at 300 mg twice a day starting with Cycle 1, Day 1. A cycle consists of 21 days. Capecitabine will be taken orally at 1000 mg/m2 twice a day on Days 1-14 starting with cycle 1. Trastuzumab is given intravenously as a loading dose of 8 mg/kg on Cycle 1, Day 1 and then at 6 mg/kg for all subsequent cycles.

Drug: Tucatinib; Drug: Trastuzumab; Drug: Capecitabine

Interventions

Tucatinib DRUG

Tucatinib study drug is given in tablet form and taken daily.

Also known as: ONT-380

Tucatinib + Trastuzumab + Capecitabine

Trastuzumab DRUG

Trastuzumab is approved by the FDA and is available commercially. Trastuzumab must be prepared and is administered intravenously.

Tucatinib + Trastuzumab + Capecitabine

Capecitabine DRUG

Capecitabine is approved by the FDA and is available commercially as an oral drug.

Tucatinib + Trastuzumab + Capecitabine

Eligibility Criteria

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

You may qualify if:

• Men and women, age ≥18 years at time of consent
• Histologically proven metastatic infiltrating carcinoma of the breast that is HER2 positive - Immunohistochemistry (IHC) 3+ and/or Fluorescence in situ hybridization (FISH) ratio \>2.0, or average HER2 copy number \>6.0 signals per cell or per current ASCO-CAP (American Society of Clinical Oncology - College of American Pathologists) or NCCN (National Comprehensive Cancer Network) guidelines. (NOTE: HER2 testing may be performed on primary and/or metastatic site; Any estrogen and progesterone \[ER/PR\] status is allowed.)
• Evidence of leptomeningeal disease (LMD) as diagnosed by a) presence of malignant cells in CSF (+CSF cytology) and/or b) Magnetic Resonance Imaging (MRI) evidence of LMD, plus clinical signs and/or symptoms. NOTE: Measurable extra-CNS disease is not required. Note: Patients who have MRI evidence of focal LMD with negative cytology and no symptoms are not eligible for enrollment.
• Karnofsky Performance Status ≥ 50 or Eastern Cooperative Oncology Group (ECOG) ≤ 3
• Patient is able and willing to undergo study-required testing including:
• Contrast-enhanced MRI Note: If patient has implants in place that are MRI incompatible, these must be removed prior to enrollment.
• Placement of an Ommaya reservoir (ventricular access device). Note: This is mandatory for the first 15 patients enrolled onto the protocol (first stage). In the second stage, this is strongly recommended per protocol. If a patient cannot or chooses not to undergo Ommaya placement in the second stage, the patient will be allowed to enroll.
• Evaluation by medical oncologist at baseline and at every cycle (required)
• Evaluation by neurologist/neuro-oncologist at baseline and at every cycle (strongly recommended); if this is not possible at a site, a medical oncologist may per perform the protocol specified evaluations at each visit.
• Patients who are on steroids due to CNS disease or LMD diagnosis should be on a stable dose for at least 5 days prior to registration.
• Prior treatment allowances are as follows:
• \>14 days since last dose of any previous endocrine therapy, chemotherapy, trastuzumab or other antibody-based therapy. NOTE: If patients have been previously receiving trastuzumab on a weekly basis (at a dose of 2mg/kg), only a 7 day washout will be required.
• \>14 days or five half-lives since previous treatment with any experimental agent, whichever is greater
• Cumulative dose of doxorubicin \>360 mg/m2 or previous treatment with another anthracycline with cumulative dose equivalent to \>360 mg/m2 doxorubicin is not allowed.
• Patients must not have received any therapy specifically directed at LMD, including prior systemic or intrathecal therapy for LMD.

You may not qualify if:

• Medical, social, or psychosocial factors that, in the opinion of the Investigator, could impact safety or compliance with study procedures.
• Patient is pregnant or is breastfeeding. Note: If female and of child-bearing potential (females who are not surgically sterile or who have had a period in the last 12 months), has negative pregnancy test within 21 days prior to treatment. If a sexually active male or a sexually active female of child- bearing potential, agrees to use dual (two concurrent) forms of medically accepted contraception from the time of consent until 6 months after the last dose.
• History of allergic reactions to compounds of similar chemical or biological composition to capecitabine (Group A only), trastuzumab or tucatinib, except for a history of Grade 1 or Grade 2 infusion related reaction to trastuzumab, that has been successfully managed.
• Known to be HIV positive, or a carrier for Hepatitis B and/or Hepatitis C (whether active disease or not)
• Known liver disease, autoimmune hepatitis, or sclerosing cholangitis
• Inability to swallow pills or any significant gastrointestinal diseases, which would preclude adequate absorption of oral medications
• Use of a strong CYP2C8/CYP3A4 inducer or inhibitor within three elimination half-lives of the inducer or inhibitor prior to the start of study treatment.
• Known impaired cardiac function or clinically significant cardiac disease such as ventricular arrhythmia requiring therapy or congestive heart failure. Note: Patients with hypertension must have controlled disease defined as systolic blood pressure \>150 mmHg and/or diastolic blood pressure \>100 mmHg on antihypertensive medications.
• Myocardial infarction or unstable angina within 6 months prior to the first dose of study drug.
• Patient with known dihydropyrimidine dehydrogenase deficiency
• Previous treatment with tucatinib
• Previous treatment with capecitabine within 12 months prior to study registration
• Prior history of other cancer (except non melanoma skin, cervical intraepithelial neoplasia) with evidence of disease within the last 5 years.

Sponsors & Collaborators

• University of Alabama at Birmingham: lead
• Translational Breast Cancer Research Consortium: collaborator
• Johns Hopkins University: collaborator
• Seagen Inc.: collaborator
• University of Michigan: collaborator
• Georgetown University: collaborator
• University of California, San Francisco: collaborator
• University of Chicago: collaborator
• Indiana University: collaborator
• University of Washington: collaborator
• University of Texas: collaborator

Study Sites (9)

University of Alabama at Birmingham

Birmingham, Alabama, 35294, United States

Location

UCSF-Mission Bay

San Francisco, California, 94158, United States

Location

MedStar Georgetown University-Lombardi CCC

Washington D.C., District of Columbia, 20007, United States

Location

University of Chicago

Chicago, Illinois, 60637-1470, United States

Location

Indiana University-Melvin and Bren Simon cancer center

Indianapolis, Indiana, 46202, United States

Location

Dana Farber/Harvard Cancer Center-

Boston, Massachusetts, 02215, United States

Location

University of Michigan-

Ann Arbor, Michigan, 48109, United States

Location

University of Texas MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

University of Washington Medical Center-Montlake

Seattle, Washington, 98109, United States

Location

MeSH Terms

Conditions

Breast Neoplasms; Meningeal Neoplasms

Interventions

tucatinib; Trastuzumab; Capecitabine

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases; Central Nervous System Neoplasms; Nervous System Neoplasms; Nervous System Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Fluorouracil; Uracil; Pyrimidinones; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides

Limitations and Caveats

The study only remains open to monitor patients for overall survival per the primary endpoint after FDA approval was granted for tucatinib in advanced stage HER2+ breast cancer in April 2020.

Results Point of Contact

• Title: Dr. Erica Stringer-Reasor
• Organization: University of Alabama at Birmingham

esreasor@uabmc.edu

205-975-2914

Study Officials

• Erica M Stringer-Reasor, MD

  University of Alabama at Birmingham

  PRINCIPAL INVESTIGATOR

• Rashmi K Murthy, MD, MBE

  M.D. Anderson Cancer Center

  STUDY CHAIR

• Barbara J O'Brien, MD

  M.D. Anderson Cancer Center

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

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: Assistant Professor

Model Details: Subjects will receive combination treatment with tucatinib + trastuzumab + capecitabine every 21 days, which is one cycle. Evaluation will be done every two cycles with an MRI of the brain and spine. Cycles 3 and beyond will be at the discretion of the physician. A scan will be done every four cycles.

Study Record Dates

• First Submitted: April 8, 2018
• First Posted: April 18, 2018
• Study Start: February 20, 2019
• Primary Completion: June 22, 2021
• Study Completion: June 22, 2021
• Last Updated: August 29, 2025
• Results First Posted: February 8, 2023

Record last verified: 2025-08

Data Sharing

• IPD Sharing: Will not share

Locations

US (9)