Tucatinib With Brain and/or Spinal XRT in Patients With HER2+ Metastatic Breast Cancer and LMD

Phase 2

Recruiting

• Conditions: HER2-positive Breast Cancer; LMD
• Interventions: Drug: Tucatinib 150 MG; Drug: Trastuzumab; Drug: Capecitabine; Radiation: Brain & Spinal Radiation

• Registration Number: NCT06016387
• Lead Sponsor: Sunnybrook Health Sciences Centre

Brief Summary

The proposed study will evaluate the safety and efficacy of XRT followed by systemic therapy among patients with HER2+ metastatic breast cancer and LMD

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.

Study Timeline

• Study First Submitted: 2023-08-18
• Study First Submitted QC: 2023-08-24
• Study First Posted: 2023-08-29
• Study Start: 2023-11-25
• Status Verified: 2025-01
• Last Update Submitted: 2025-01-27
• Last Update Posted: 2025-01-29
• Primary Completion: 2025-10-05
• Study Completion: 2028-10-05

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 30

Inclusion Criteria

Phase 1

1. Men or women with HER2+ metastatic breast cancer.
2. Evidence of LMD in the brain and/or spine
3. Age 18+ at time of consent;
4. ECOG ≤ 2;
5. If applicable, the last dose of prior chemotherapy, immunotherapy, endocrine therapy therapy must have been completed 14 days prior to study enrollment.
6. More than 14 days or 5 half-lives from the last dose of any experimental agent is required, whichever is greater;
7. 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

Exclusion Criteria

Phase 1

1. Prior WBRT for brain metastases
2. Prior therapy specifically directed at LMD
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.
5. Presently known dihydropyrimidine dehydrogenase deficiency;
6. Diagnosed with Hereditary fructose intolerance;
7. Diagnosed with Gilbert's disease;
8. Prior history of other cancer with evidence of disease within the last 5 years;
9. Prior use of tucatinib at any time prior to enrollment.

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
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 & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Tucatinib, Transtuzumab, Capecitabine	Brain & Spinal Radiation	Tucatinib, Trastuzumab and Capecitabine With Brain and/or Spinal Radiotherapy (XRT) in Patients With HER2+ Metastatic Breast Cancer and Leptomeningeal Disease.
Tucatinib, Transtuzumab, Capecitabine	Tucatinib 150 MG	Tucatinib, Trastuzumab and Capecitabine With Brain and/or Spinal Radiotherapy (XRT) in Patients With HER2+ Metastatic Breast Cancer and Leptomeningeal Disease.
Tucatinib, Transtuzumab, Capecitabine	Capecitabine	Tucatinib, Trastuzumab and Capecitabine With Brain and/or Spinal Radiotherapy (XRT) in Patients With HER2+ Metastatic Breast Cancer and Leptomeningeal Disease.
Tucatinib, Transtuzumab, Capecitabine	Trastuzumab	Tucatinib, Trastuzumab and Capecitabine With Brain and/or Spinal Radiotherapy (XRT) in Patients With HER2+ Metastatic Breast Cancer and Leptomeningeal Disease.

Primary Outcome Measures

Name	Time	Method
Survival status from the start of XRT • Survival status 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	To assess overall survival (OS) from the start of XRT.

Secondary Outcome Measures

Name	Time	Method
Neurologic-specific QoL (FACT-BR version 4)	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).
Extracranial objective response (RECIST v1.1)	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).
Overall QoL (EORTC QLQ-C30 version 3)	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).
Time to CNS progression 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	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).
Safety and tolerability (CTCAE v.5.0)	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).
Progression free survival 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	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).
CNS specific objective response (RANO-BM)	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).

Trial Locations

Locations (2)

The Ottawa Hospital; 🇨🇦 Ottawa, Ontario, Canada

Sunnybrook Health Sciences Centre; 🇨🇦 Toronto, Ontario, Canada