Tucatinib, Trastuzumab and Capecitabine With Brain and/or Spinal Radiotherapy (XRT) in Patients With HER2+, HER2 Mutated and/or HER2-amplified Metastatic Breast Cancer and Leptomeningeal Disease: A Multi-centre Phase II, Single Arm Feasibility Study

February 19, 2026 updated by: Sunnybrook Health Sciences Centre
The proposed study will evaluate the safety and efficacy of XRT followed by systemic therapy among patients with HER2+, HER2 mutated and/or HER2-amplified metastatic breast cancer and LMD

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

Breast cancer is the most common cancer among women worldwide, and the second leading cause of brain metastases (BrM). Despite recent treatment advances, the prognosis of patients with breast cancer BrM remains poor, and the prognosis among those with leptomeningeal disease (LMD) is particularly dire with a median survival of only 2-4 months.

Patients with HER2+ metastatic breast cancer have a high life-time risk of central nervous system (CNS) metastases, with an approximately 50% lifetime risk. Although the cause of death among patients with breast cancer BrM is challenging to ascertain, approximately 50% of patients with HER2+ BrM are thought to die from central nervous system (CNS) disease involvement. Among patients with LMD specifically, the cause of death is most commonly related to CNS disease.

In an analysis of 430 patients (96 of whom had breast cancer) treated for LMD in the National Cancer Database between 2005 and 2014, those patients treated with chemotherapy plus radiotherapy had a longer median overall survival of 5 months (3.5 - 6.5 months) compared to patients treated with XRT or chemotherapy alone. In addition, a majority (n=18/26, 69%) of observational studies irrespective of primary tumor site have shown an "improvement or likely improvement" in survival with the use of XRT for LMD, either alone or in combination with systemic therapy. Hence, this proposed study will evaluate the safety and efficacy of XRT followed by systemic therapy (which is considered standard of care) among patients with HER2+ metastatic breast cancer and LMD.

In addition to enrolling patients with established HER2+ metastatic breast cancer, those with HER2 mutations and/or HER2-amplifications in their blood and/or CSF are also eligible to enroll. This is on the basis that the HER2 status is known to "flip" in a relatively high proportion of patients from HER2-negative to HER2-positive at the time that CNS metastases develop51, 52, 53. Given that HER2 status of CNS metastases is not easy to obtain (most patients with CNS metastases do not have surgical resection or biopsy to obtain tissue due to the invasive nature of this surgical approach), patients with fluid samples suggestive of a HER2-driven malignancy (HER2 mutations and/or amplifications) in the blood and/or CSF will be permitted to enrol. Most patients with HER2 amplified tumors would be considered to have HER2-positive disease on tissue samples, but ASCO/CAP guidelines for HER2-positive status only apply to tissue; hence, a separate inclusion criterion for these patients has been established.

Study Type

Interventional

Enrollment (Estimated)

30

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria: Phase 1

  1. Men or women with HER2+, HER2 mutated and/or HER2-amplified metastatic breast cancer. HER2+ status will be defined in accordance with ASCO-CAP 2018 guidelines, and can be diagnosed at any time prior to enrolment. HER2 mutations and/or HER2-amplifications can be identified in the blood and/or cerebrospinal fluid (CSF) at any time prior to enrolment; testing blood and/or CSF is not part of the study protocol and must be evaluated using a clinically validated test.
  2. Evidence of LMD* in the brain and/or spine (either positive cerebral spinal fluid cytology and/or magnetic resonance imaging evidence of LMD). Measurable disease in the central nervous system is not required. * The diagnosis of LMD can occur at any time prior to enrolment;
  3. Age 18+ at time of consent;
  4. ECOG ≤ 2;
  5. More than 14 days or 5 half-lives from the last dose of any experimental agent is required, whichever is greater;
  6. All toxicity related to prior cancer therapies must have resolved to ≤ Grade 1 prior to enrollment, except for alopecia; neuropathy, must have resolved to ≤ Grade 2.

Phase 2: Inclusion Criteria

  1. Left ventricular ejection fraction (LVEF) must be within institutional limits of normal as assessed by ECHO or MUGA documented within 2 weeks prior to starting systemic therapy on the study;

  2. Adequate hematologic, liver, and renal function within 2 weeks prior to phase 2 enrollment, as follows:

    1. Hemoglobin ≥ 9 g/dL
    2. ANC ≥ 1 x109/L
    3. Platelets ≥ 100 x109/L
    4. Total bilirubin ≤ 1.5 X upper limit of normal (ULN)
    5. AST and ALT ≤ 2.5X ULN
    6. International normalized ratio (INR) and activated partial thromboplastin time (aPTT) ≤ 1.5 X ULN
    7. Creatinine clearance (CrCL) ≥ 50 mL/min
  3. The last dose of prior therapy must have been completed 14 days prior to study enrollment. Prior chemotherapy, immunotherapy, endocrine therapy, targeted therapy and experimental agents are allowed (including prior use of trastuzumab or other antibody-based therapy). Prior use of capecitabine either alone or in combination with other HER2-targeted therapies (including other tyrosine kinase inhibitors) is permitted;

Exclusion Criteria: Phase 1

  1. Prior WBRT for brain metastases (prior stereotactic radiosurgery for parenchymal CNS metastases received <7 days prior to consent );
  2. Prior therapy specifically directed at LMD, including prior radiotherapy or systemic therapy;
  3. Inability to comply with MRI-based surveillance of CNS disease;
  4. Inability to swallow pills or any significant gastrointestinal diseases such as inflammatory bowel disease who suffer from uncontrolled diarrhea (based on the investigator's assessment),, which would preclude adequate absorption of oral medications;
  5. Diagnosed with Hereditary fructose intolerance;
  6. Diagnosed with Gilbert's disease;
  7. Prior history of other cancer (except non melanoma skin, cervical intraepithelial neoplasia) with evidence of disease within the last 5 years;
  8. Prior use of tucatinib at any time prior to enrollment.
  9. Hypersensitivity to any of the active substances in tucatinib, trastuzumab, or capecitabine.

Phase 2:

  1. Currently pregnant or breastfeeding;
  2. Use of a strong cytochrome P450 (CYP)2C8 inhibitor within 5 half-lives of the inhibitor or use of a strong CYP3A4 or CYP2C8 inducer within 5 days prior to the first dose of systemic therapy (see Appendix C and D);
  3. Myocardial infarction or unstable angina within 6 months prior to the first dose of systemic therapy.
  4. Blood product transfusions in order to meet eligibility criteria

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Tucatinib, Transtuzumab, Capecitabine
Tucatinib, Trastuzumab and Capecitabine With Brain and/or Spinal Radiotherapy (XRT) in Patients With HER2+, HER2 mutated and/or HER2-amplified Metastatic Breast Cancer and Leptomeningeal Disease.
Drug: Tucatinib 150 MG
Tucatinib is a potent, selective, adenosine triphosphate-competitive small-molecule inhibitor of the receptor tyrosine kinase HER2. The molecular formula for tubatinib is C26H24N8O2 and it has a molecular weight of 480.52 g/mol.
Other Names:
  • Tukysa
Drug: Trastuzumab

MYL-1401O contains the active substance trastuzumab, which is an IgG1 monoclonal antibody. The molecular size of the intact molecule is around 148 kDa.

Each vial of MYL-1401O contains 150 mg of lyophilized proposed active biosimilar substance trastuzumab as well as 3.36 mg L-Histidine Hydrochloride, 2.16 mg L-Histidine, 115.2 mg sorbitol and 33.6 mg PEG-3350 (Macrogol 3350). Sorbitol and PEG-3350 substitute the α- trehalose dehydrate and polysorbate-20, which are used as excipients in the EU-approved and US-licensed Herceptin formulations.

Drug: Capecitabine
Capecitabine is a tumour-activated antineoplastic agent (antimetabolite). The molecular formula for capecitabine is C15H22FN3O6 and has a molecular weight of 359.35 g/mol.
Radiation: Brain & Spinal Radiation
Brain & Spinal XRT is a treatment for patients with HER2+ metastatic breast cancer and leptomeningeal disease,
Other Names:
  • Brain & Spinal XRT

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Survival status from the start of XRT
Time Frame: From date of baseline until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months
To assess overall survival (OS) in the intention to treat population from the start of XRT.
From date of baseline until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Time to CNS progression from the start of XRT
Time Frame: From date of baseline until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months

To determine the time for CNS symptoms progresses from start of XRT in the proposed patient population after completion of brain and/or spinal XRT.

To determine the efficacy of tucatinib plus trastuzumab and capecitabine for the treatment of patients with HER2+ breast cancer and leptomeningeal metastases (LMD).
From date of baseline until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months
Safety and tolerability (CTCAE v.5.0)
Time Frame: From date of baseline until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 36 months

To determine the safety & tolerability of systemic therapy (tucatinib, trastuzumab and capecitabine) in the proposed patient population after completion of brain and/or spinal XRT.

To determine the efficacy of tucatinib plus trastuzumab and capecitabine for the treatment of patients with HER2+ breast cancer and leptomeningeal metastases (LMD).
From date of baseline until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 36 months
Progression free survival from the start of XRT
Time Frame: From date of baseline until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months

To determine progression from the start of XRT in the proposed patient population after completion of brain and/or spinal XRT.

To determine the efficacy of tucatinib plus trastuzumab and capecitabine for the treatment of patients with HER2+ breast cancer and leptomeningeal metastases (LMD).
From date of baseline until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months
CNS specific objective response (RANO-BM)
Time Frame: Every 6 weeks through study completion, an average of 5 years

To determine the CNS objective response in the proposed patient population after completion of brain and/or spinal XRT.

To determine the efficacy of tucatinib plus trastuzumab and capecitabine for the treatment of patients with HER2+ breast cancer and leptomeningeal metastases (LMD).
Every 6 weeks through study completion, an average of 5 years
Extracranial objective response (RECIST v1.1)
Time Frame: Every 6 weeks through study completion, an average of 5 years

To determine the extracranial objective response in the proposed patient population after completion of brain and/or spinal XRT.

To determine the efficacy of tucatinib plus trastuzumab and capecitabine for the treatment of patients with HER2+ breast cancer and leptomeningeal metastases (LMD).
Every 6 weeks through study completion, an average of 5 years
Neurologic-specific QoL (FACT-BR version 4)
Time Frame: Pre-treatment, at the start of Cycle 3 (Cycle 3 Day 1, +/- 7 days) and at the Safety Visit

To determine the neurologic-specific QoL's in the proposed patient population after completion of brain and/or spinal XRT.

To determine the efficacy of tucatinib plus trastuzumab and capecitabine for the treatment of patients with HER2+ breast cancer and leptomeningeal metastases (LMD).
Pre-treatment, at the start of Cycle 3 (Cycle 3 Day 1, +/- 7 days) and at the Safety Visit
Overall QoL (EORTC QLQ-C30 version 3)
Time Frame: Pre-treatment, at the start of Cycle 3 (Cycle 3 Day 1, +/- 7 days) and at the Safety Visit

To determine the Overall QoL in the proposed patient population after completion of brain and/or spinal XRT.

To determine the efficacy of tucatinib plus trastuzumab and capecitabine for the treatment of patients with HER2+ breast cancer and leptomeningeal metastases (LMD).
Pre-treatment, at the start of Cycle 3 (Cycle 3 Day 1, +/- 7 days) and at the Safety Visit

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sunnybrook Health Sciences Centre

Collaborators

Pfizer
Biocon Biologics

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

November 25, 2023

Primary Completion (Estimated)

December 31, 2026

Study Completion (Estimated)

October 5, 2028

Study Registration Dates

First Submitted

August 18, 2023

First Submitted That Met QC Criteria

August 24, 2023

First Posted (Actual)

August 29, 2023

Study Record Updates

Last Update Posted (Actual)

February 23, 2026

Last Update Submitted That Met QC Criteria

February 19, 2026

Last Verified

February 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • CLIMB-LMD

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

IPD Plan Description

The Aggregate data will be presented and/or published. The IPD will not be available keeping patients privacy in mind.

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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