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

Phase 1

Withdrawn

• Conditions: Brain Metastases; HER2-positive Breast Cancer; Breast Cancer; CNS Disease
• Interventions: Drug: Tucatinib; Drug: Pembrolizumab; Drug: Trastuzumab

• Registration Number: NCT04512261
• Lead Sponsor: Reva Basho

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2020-07-28
• Study First Submitted QC: 2020-08-12
• Study First Posted: 2020-08-13
• Status Verified: 2022-06
• Study Start: 2022-06-01
• Last Update Submitted: 2022-06-28
• Last Update Posted: 2022-07-01
• Primary Completion: 2024-06-01
• Study Completion: 2024-06-01

Recruitment & Eligibility

• Status: WITHDRAWN
• Sex: All
• Target Recruitment: Not specified

Inclusion Criteria

1. Age ≥18 years.
2. ECOG performance status of 0-2.
3. HER2+ (as defined by ASCO/CAP clinical practice guideline) metastatic breast cancer.
4. Untreated or previously treated and progressing CNS disease.
5. Measurable CNS metastases.
6. Must be able to undergo MRI of the brain.
7. Adequate organ function.

Exclusion Criteria

1. Any indication for immediate CNS-directed therapy.
2. History of generalized or complex partial seizures.
3. Any other manifestation of neurologic progression that in the opinion of the treating physician is due to brain metastases.
4. Leptomeningeal disease.
5. 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.
6. Prior therapy with tucatinib.
7. 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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Tucatinib + Pembrolizumab + Trastuzumab	Tucatinib	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.
Tucatinib + Pembrolizumab + Trastuzumab	Pembrolizumab	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.
Tucatinib + Pembrolizumab + Trastuzumab	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.

Primary Outcome Measures

Name	Time	Method
24-week CNS disease control rate (DCR)	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	24 weeks

Secondary Outcome Measures

Name	Time	Method
CNS objective response rate (ORR)	From baseline until the date of first documented progression or study discontinuation. Assessed up to 2 years.	Proportion of participants with confirmed CR or PR per RANO-BM Criteria
Systemic ORR	From baseline until the date of first documented progression or study discontinuation. Assessed up to 2 years.	Proportion of participants with confirmed CR or PR per RECIST v.1.1
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.	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.
Overall Survival (OS)	From baseline until death or 3 years, whichever occurs first.	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.
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.	Number of adverse events as assessed per CTCAE v.5.

Trial Locations

Locations (1)

Cedars-Sinai Medical Center; 🇺🇸 Los Angeles, California, United States