A Phase II Study of Tucatinib and Ado-trastuzumab Emtansine (T-DM1) in Patients With HER2-positive Metastatic Solid Tumors and Metastases to Brain (TUCATEMEB)
Overview
- Phase
- Phase 2
- Intervention
- Trastuzumab emtansine
- Conditions
- Metastatic Solid Tumor
- Sponsor
- M.D. Anderson Cancer Center
- Enrollment
- 30
- Locations
- 1
- Primary Endpoint
- Incidence of Adverse Events, Graded According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version (v) 5.0
- Status
- Recruiting
- Last Updated
- 3 months ago
Overview
Brief Summary
To learn if the study drugs, tucatinib and adotrastuzumab emtansine (T-DM1), can help to control solid tumors that have spread to the brain.
Detailed Description
Primary Objectives: ● To determine the intracranial antitumor activity of the tucatinib and ado-trastuzumab emtansine (T- bination per the modified Response Evaluation Criteria in Solid Tumors (mRECIST) in patients with huma Key Secondary Objectives: * To determine the intracranial antitumor activity of the tucatinib and T-DM1 combination per the Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria in patients with HER2-positive metastatic solid tumors and brain metastases. * To evaluate the duration of intracranial response of the tucatinib and T-DM1 combination in patients with HER2-positive metastatic solid tumors and brain metastases. Other Secondary Objectives: * To evaluate the safety and tolerability of the tucatinib and T-DM1 combination in patients with HER2-positive metastatic solid tumors and brain metastases. * To evaluate the systemic antitumor activity of the tucatinib and T-DM1 combination per the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 in patients with HER2-positive metastatic solid tumors and brain metastases. * To evaluate progression-free survival (PFS) in patients with HER2-positive metastatic solid tumors and brain metastases receiving the tucatinib and T-DM1 combination. * To evaluate overall survival (OS) in patients with HER2-positive metastatic solid tumors and brain metastases receiving the tucatinib and T-DM1 combination. * To evaluate the duration of response to the tucatinib and T-DM1 combination per the RECIST v1.1 in patients with HER2-positive metastatic solid tumors and brain metastases. * To evaluate the clinical benefit rate of the tucatinib and T-DM1 combination per the RECIST v1.1 in patients with HER2-positive metastatic solid tumors and brain metastases. Exploratory Objectives: * To assess the effects of the tucatinib and T-DM1 combination on cell proliferation and apoptosis. * To evaluate predictive and pharmacodynamic (PD) biomarkers of response and resistance to the tucatinib and T-DM1 combination. * To assess the effects of the tucatinib and T-DM1 combination on circulating-free DNA (cfDNA) dynamics.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Histologically confirmed HER2-positive metastatic solid tumor. HER2 positivity defined as HER2 overexpression by immunohistochemistry (IHC) 3+ or 2+ and fluorescence in situ hybridization (FISH) positive and/or HER2 amplification by in situ hybridization (ISH) or next generation sequencing (NGS) and/or activating ERBB2 mutation(s) (verified by MDACC Precision Oncology Decision Support).
- •Patients must have one of the following on the screening brain MRI:
- •Untreated brain metastases not requiring immediate local CNS therapy
- •Previously treated brain metastases with progression of previous lesions or new lesions, but not requiring immediate local CNS therapy
- •At least one measurable untreated brain lesion ≥0.5 cm and \<3.0 cm in the longest axis
- •Prior SRS radiosurgery (must be completed within 7 days of study treatment initiation) is allowed as long as the previous treatment volume does not overlap with the current targets.
- •Measurable (per the RECIST v1.1) or evaluable extracranial disease.
- •Prior treatment with HER2-targeted treatments such as trastuzumab, pertuzumab, T-DM1, neratinib, lapatinib, or tucatinib is allowed, but not required. Patients with breast and gastric cancer must have received at least 1 line of HER2 targeted treatment.
- •Age ≥18 years at the time of consent.
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 (Appendix B).
Exclusion Criteria
- •Patients must not have any of the following on the screening brain MRI:
- •Any untreated brain lesions \>3.0 cm in size
- •Any brain lesion thought to require immediate local therapy, including (but not limited to) a lesion in an anatomic site where increase in size or possible treatment-related edema may pose risk to the patient (e.g., brainstem lesions). Patients who undergo local treatment for such lesions may still be eligible for the study based on inclusion criteria #
- •Ongoing use of systemic corticosteroids for control of symptoms of brain metastases at a total daily dose of \>4 mg of dexamethasone (or equivalent).
- •Poorly controlled (\>1/week) generalized or complex partial seizures, or manifestation of neurologic progression due to brain metastases notwithstanding CNS-directed therapy.
- •History of allergic reactions to trastuzumab or compounds chemically or biologically similar to tucatinib, except for Grade 1 or 2 IRRs to trastuzumab that were successfully managed, or known allergy to any of the excipients in the study drugs.
- •Treatment with any systemic anticancer therapy or investigational agent within 5 half-lives (of the drug) or within 21 days (whichever is shorter ) prior to study treatment initiation.
- •Any toxicity related to prior cancer therapies that has not resolved to ≤ Grade 1, with the following exceptions:
- •Alopecia;
- •Neuropathy, which must have resolved to ≤ Grade 2;
Arms & Interventions
Tucatinib and Adotrastuzumab Emtansine (T-DM1)
Each study cycle is 21 days (3 weeks) Participants will take tablets of tucatinib two (2) times a day, about 8-12 hours apart. Participants will receive T-DM1 by vein over about 30 minutes on Day 1 of each cycle
Intervention: Trastuzumab emtansine
Tucatinib and Adotrastuzumab Emtansine (T-DM1)
Each study cycle is 21 days (3 weeks) Participants will take tablets of tucatinib two (2) times a day, about 8-12 hours apart. Participants will receive T-DM1 by vein over about 30 minutes on Day 1 of each cycle
Intervention: Tucatinib
Outcomes
Primary Outcomes
Incidence of Adverse Events, Graded According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version (v) 5.0
Time Frame: through study completion; an average of 1 year.