TOPAZ: Single Arm, Open Label Phase 1b/2 Study of Tucatinib in COmbination With Pembrolizumab And TrastuZumab in Patients With HER2-Positive Breast Cancer Brain Metastases
Trial Snapshot
- Phase
- Phase 1
- Status
- Withdrawn
- Sponsor
- Locations
- 1
- Primary Endpoint
- 24-week CNS disease control rate (DCR)
Study Overview
Brief Summary
This is a single arm, open label trial to assess the safety and efficacy of tucatinib in combination with pembrolizumab and trastuzumab for the treatment of HER2+ breast cancer brain metastases (BCBM). A total of 33 patients with untreated or previously treated and progressing HER2+ BCBM not requiring urgent central nervous system (CNS)-directed therapy will be enrolled. The study will determine the recommended dose of tucatinib in this combination and assess the efficacy of this combination in controlling CNS disease in patients with HER2+ BCBM.
Study Design
- Study Type
- Interventional
- Allocation
- Na
- Intervention Model
- Single Group
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Age ≥18 years.
- •ECOG performance status of 0-
- •HER2+ (as defined by ASCO/CAP clinical practice guideline) metastatic breast cancer.
- •Untreated or previously treated and progressing CNS disease.
- •Measurable CNS metastases.
- •Must be able to undergo MRI of the brain.
- •Adequate organ function.
Exclusion Criteria
- •Any indication for immediate CNS-directed therapy.
- •History of generalized or complex partial seizures.
- •Any other manifestation of neurologic progression that in the opinion of the treating physician is due to brain metastases.
- •Leptomeningeal disease.
- •Prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor.
- •Prior therapy with tucatinib.
- •Active autoimmune disease that has required systemic treatment in excess of prednisone 10mg daily or equivalent in the past 2 years.
- •Complete inclusion/exclusion criteria are detailed in the protocol.
Arms & Interventions
Tucatinib + Pembrolizumab + Trastuzumab
Patients will receive a combination therapy of tucatinib with pembrolizumab and trastuzumab during the treatment period until progression, treatment intolerance, or patient withdrawal from study. Tucatinib and pembrolizumab are administered as experimental use while trastuzumab is administered per standard use. Patients are expected to be on treatment for at least 12 weeks.
Intervention: Tucatinib (Drug)
Tucatinib + Pembrolizumab + Trastuzumab
Patients will receive a combination therapy of tucatinib with pembrolizumab and trastuzumab during the treatment period until progression, treatment intolerance, or patient withdrawal from study. Tucatinib and pembrolizumab are administered as experimental use while trastuzumab is administered per standard use. Patients are expected to be on treatment for at least 12 weeks.
Intervention: Pembrolizumab (Drug)
Tucatinib + Pembrolizumab + Trastuzumab
Patients will receive a combination therapy of tucatinib with pembrolizumab and trastuzumab during the treatment period until progression, treatment intolerance, or patient withdrawal from study. Tucatinib and pembrolizumab are administered as experimental use while trastuzumab is administered per standard use. Patients are expected to be on treatment for at least 12 weeks.
Intervention: Trastuzumab (Drug)
Outcomes
Primary Outcomes
24-week CNS disease control rate (DCR)
Time Frame: 24 weeks
Percentage of patients who experience objective tumor response \[ partial response (PR) or complete response (CR) \] or stable disease as assessed by investigator per RANO-BM reads on protocol-specified MRIs of the brain.
Recommended dose of tucatinib in combination with pembrolizumab and trastuzumab
Time Frame: 24 weeks
Secondary Outcomes
- Systemic ORR(From baseline until the date of first documented progression or study discontinuation. Assessed up to 2 years.)
- CNS objective response rate (ORR)(From baseline until the date of first documented progression or study discontinuation. Assessed up to 2 years.)
- Progression-free survival (PFS)(From baseline to first documentation of true progression or symptomatic deterioration, or death due to any cause. Assessed up to 2 years.)
- Overall Survival (OS)(From baseline until death or 3 years, whichever occurs first.)
- Toxicity profile of tucatinib, pembrolizumab, and trastuzumab co-administration(From first dose of study treatment until 30 days after the last dose of study treatment.)
Investigators
Reva Basho
Assistant Professor of Medicine
Cedars-Sinai Medical Center