Tucatinib combined with radiation for HER2-positive breast cancer with leptomeningeal disease

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

This study is testing if combining radiation with a new treatment for HER2-positive breast cancer can help patients with brain involvement live longer and feel better.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 30 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Sunnybrook Health Sciences Centre (Academic / other)
• Drugs / interventions: trastuzumab, tucatinib, chemotherapy, immunotherapy
• Locations: 2 sites (Ottawa, Ontario and 1 other locations)
• Trial ID: NCT06016387 on ClinicalTrials.gov

What this trial studies

This study evaluates the safety and efficacy of combining radiation therapy with systemic treatment using Tucatinib, Trastuzumab, and Capecitabine in patients with HER2-positive metastatic breast cancer who also have leptomeningeal disease. The approach aims to improve survival outcomes for patients who typically face a poor prognosis due to central nervous system involvement. The study will assess the impact of this combination therapy on overall survival and quality of life. Participants will undergo radiation therapy followed by the systemic treatment regimen.

Who should consider this trial

Good fit: Ideal candidates for this study are adults aged 18 and older with HER2-positive metastatic breast cancer and confirmed leptomeningeal disease.

Not a fit: Patients without HER2-positive metastatic breast cancer or those without evidence of leptomeningeal disease may not benefit from this study.

Why it matters

Potential benefit: If successful, this treatment could significantly extend survival and improve quality of life for patients with HER2-positive metastatic breast cancer and leptomeningeal disease.

How similar studies have performed: Previous studies have shown that combining radiation therapy with systemic treatments can improve survival in patients with leptomeningeal disease, indicating potential for success in this approach.

Eligibility criteria

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

Where this trial is running

Ottawa, Ontario and 1 other locations

• The Ottawa Hospital — Ottawa, Ontario, Canada (Recruiting)
• Sunnybrook Health Sciences Centre — Toronto, Ontario, Canada (Recruiting)

Study contacts

• Study coordinator: CLIMB-LMD Project Manager

Conditions HER2-positive Breast Cancer; LMD; HER2+; Breast Cancer; Leptomeningeal disease; Tucanitib; CLIMB-LMD; HER2 CLIMB LMD