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
Sunnybrook Health Sciences Centre
30 participants
Nov 25, 2023
INTERVENTIONAL
Conditions
Summary
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
Eligibility
Inclusion Criteria16
- 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.
- 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;
- Age 18+ at time of consent;
- ECOG ≤ 2;
- More than 14 days or 5 half-lives from the last dose of any experimental agent is required, whichever is greater;
- 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.
- 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;
- Adequate hematologic, liver, and renal function within 2 weeks prior to phase 2 enrollment, as follows:
- Hemoglobin ≥ 9 g/dL
- ANC ≥ 1 x109/L
- Platelets ≥ 100 x109/L
- Total bilirubin ≤ 1.5 X upper limit of normal (ULN)
- AST and ALT ≤ 2.5X ULN
- International normalized ratio (INR) and activated partial thromboplastin time (aPTT) ≤ 1.5 X ULN
- Creatinine clearance (CrCL) ≥ 50 mL/min
- 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 Criteria14
- Prior WBRT for brain metastases (prior stereotactic radiosurgery for parenchymal CNS metastases received \<7 days prior to consent );
- Prior therapy specifically directed at LMD, including prior radiotherapy or systemic therapy;
- Inability to comply with MRI-based surveillance of CNS disease;
- 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;
- Diagnosed with Hereditary fructose intolerance;
- Diagnosed with Gilbert's disease;
- Prior history of other cancer (except non melanoma skin, cervical intraepithelial neoplasia) with evidence of disease within the last 5 years;
- Prior use of tucatinib at any time prior to enrollment.
- Hypersensitivity to any of the active substances in tucatinib, trastuzumab, or capecitabine.
- Phase 2:
- Currently pregnant or breastfeeding;
- 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);
- Myocardial infarction or unstable angina within 6 months prior to the first dose of systemic therapy.
- Blood product transfusions in order to meet eligibility criteria
Interventions
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.
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.
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.
Brain \& Spinal XRT is a treatment for patients with HER2+ metastatic breast cancer and leptomeningeal disease,
Locations(2)
View Full Details on ClinicalTrials.gov
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NCT06016387