TOPAZ: Tucatinib in COmbination With Pembrolizumab And TrastuZumab in Patients With HER2-Positive Breast Cancer Brain Metastases

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Breast Cancer, Brain Metastases, HER2-positive Breast Cancer, CNS Disease

Intervention / Treatment
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* Drug: Tucatinib
* Drug: Pembrolizumab
* Drug: Trastuzumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥18 years. ECOG performance status of 0-2. 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tucatinib + Pembrolizumab + Trastuzumab<br>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. | Drug: Tucatinib<br>* Initial dosage of trial treatment for tucatinib will be given as 300 mg (dispensed as 2 x 150 mg tablets) orally twice a day for Days 1 - 21 of each 3-week cycle during the treatment period.<br>* Other names: Tukysa;Drug: Pembrolizumab<br>* Initial dosage of trial treatment for pembrolizumab will be given as 200 mg by intravenous infusion every 3 weeks on Day 1 of each 3-week cycle during the treatment period. Pembrolizumab will be administered for a maximum of 35 doses.<br>* Other names: Keytruda;Drug: Trastuzumab<br>* Initial dosage of trial treatment for trastuzumab will be given as 8 mg/kg by intravenous (IV) infusion once on Day 1 of Cycle 1, and 6 mg/kg by IV every 3 weeks on Day 1 of each 3-week cycle starting on Cycle 2 during the treatment period.<br>* Other names: Herceptin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 24-week CNS disease control rate (DCR) | 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. | 24 weeks | 
| Recommended dose of tucatinib in combination with pembrolizumab and trastuzumab |  | 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CNS objective response rate (ORR) | Proportion of participants with confirmed CR or PR per RANO-BM Criteria | From baseline until the date of first documented progression or study discontinuation. Assessed up to 2 years. | 
| Systemic ORR | Proportion of participants with confirmed CR or PR per RECIST v.1.1 | From baseline until the date of first documented progression or study discontinuation. Assessed up to 2 years. | 
| Progression-free survival (PFS) | From date of registration to date of first documentation of true progression or symptomatic deterioration (as defined above), or death due to any cause. Patients last known to be alive and progression free are censored at date of last assessment. PFS will be assessed in the CNS and systemically. | 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 date of registration to date of death due to any cause. Patient's last known to be alive are censored at date of last contact. | From baseline until death or 3 years, whichever occurs first. | 
| Toxicity profile of tucatinib, pembrolizumab, and trastuzumab co-administration | Number of adverse events as assessed per CTCAE v.5. | From first dose of study treatment until 30 days after the last dose of study treatment. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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tucatinib, pembrolizumab, trastuzumab