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

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

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 Overview

• Status: Withdrawn
• Conditions: Breast Cancer; HER2-positive Breast Cancer; Brain Metastases; CNS Disease
• Intervention / Treatment: Drug: Tucatinib; Drug: Pembrolizumab; Drug: Trastuzumab

• Study Type: Interventional
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90048
      • Cedars-Sinai Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: 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.

Drug: Tucatinib; 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.; Other Names: Tukysa; Drug: Pembrolizumab; 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.; Other Names: Keytruda; Drug: Trastuzumab; 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.; Other Names: Herceptin

What is the study measuring?

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.

Collaborators and Investigators

• Sponsor: Reva Basho
• Collaborators: Merck Sharp & Dohme LLC; Seagen Inc.
• Investigators: Principal Investigator: Reva Basho, MD, Cedars-Sinai Medical Center

Study record dates

Study Major Dates

• Study Start (Anticipated): June 1, 2022
• Primary Completion (Anticipated): June 1, 2024
• Study Completion (Anticipated): June 1, 2024

Study Registration Dates

• First Submitted: July 28, 2020
• First Submitted That Met QC Criteria: August 12, 2020
• First Posted (Actual): August 13, 2020

Study Record Updates

• Last Update Posted (Actual): July 1, 2022
• Last Update Submitted That Met QC Criteria: June 28, 2022
• Last Verified: June 1, 2022

More Information

Terms related to this study

• Keywords: trastuzumab; pembrolizumab; tucatinib
• Additional Relevant MeSH Terms: Pathologic Processes; Brain Diseases; Nervous System Diseases; Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Neoplastic Processes; Central Nervous System Neoplasms; Nervous System Neoplasms; Breast Neoplasms; Neoplasm Metastasis; Brain Neoplasms; Central Nervous System Diseases; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Immunological; Protein Kinase Inhibitors; Trastuzumab; Pembrolizumab; Tucatinib
• Other Study ID Numbers: IIT2019-21-Basho-TOPAZ

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No