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

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ClinicalTrials.gov Identifier: NCT04512261
Recruitment Status : Not yet recruiting
First Posted : August 13, 2020
Last Update Posted : November 16, 2020
Sponsor:
Collaborators:
Merck Sharp & Dohme Corp.
Seagen Inc.
Information provided by (Responsible Party):
Reva Basho, Cedars-Sinai Medical Center

Study Description
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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.

Condition or disease Intervention/treatment Phase
Breast Cancer Brain Metastases HER2-positive Breast Cancer CNS Disease Drug: Tucatinib Drug: Pembrolizumab Drug: Trastuzumab Phase 1 Phase 2

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 33 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Estimated Study Start Date : January 1, 2021
Estimated Primary Completion Date : July 1, 2023
Estimated Study Completion Date : July 1, 2023

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Arms and Interventions
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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 Name: 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 Name: 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 Name: Herceptin


Outcome Measures
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Primary Outcome Measures :
  1. 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.

  2. Recommended dose of tucatinib in combination with pembrolizumab and trastuzumab [ Time Frame: 24 weeks ]

Secondary Outcome Measures :
  1. CNS objective response rate (ORR) [ Time Frame: 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

  2. Systemic ORR [ Time Frame: 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

  3. Progression-free survival (PFS) [ Time Frame: 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.

  4. Overall Survival (OS) [ Time Frame: 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.

  5. Toxicity profile of tucatinib, pembrolizumab, and trastuzumab co-administration [ Time Frame: 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.


Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04512261


Contacts
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Contact: Parisa Mirzadehgan, MPH, MHDS 310-967-4387 Parisa.Mirzadehgan@cshs.org

Locations
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United States, California
Cedars-Sinai Medical Center
Los Angeles, California, United States, 90048
Contact: Parisa Mirzadehgan, MS, MHDS    310-967-4387    Parisa.Mirzadehgan@cshs.org   
Principal Investigator: Reva Basho, MD         
Sub-Investigator: Heather McArthur, MD, MPH         
Sub-Investigator: Alain Mita, MD         
Sub-Investigator: Philomena McAndrew, MD         
Sub-Investigator: Dorothy Park, MD         
Sub-Investigator: Mary El-Masry, MD         
Sub-Investigator: Jethro Hu, MD         
Sub-Investigator: Surasak Phuphanich, MD         
Sub-Investigator: Jeremy Rudnick, MD         
Sub-Investigator: Stephen Shiao, MD         
Sub-Investigator: Michele Burnison, MD         
Sub-Investigator: Amin Mirhadi, MD         
Sponsors and Collaborators
Reva Basho
Merck Sharp & Dohme Corp.
Seagen Inc.
Investigators
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Principal Investigator: Reva Basho, MD Cedars-Sinai Medical Center
More Information
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Responsible Party: Reva Basho, Assistant Professor of Medicine, Cedars-Sinai Medical Center
ClinicalTrials.gov Identifier: NCT04512261    
Other Study ID Numbers: IIT2019-21-Basho-TOPAZ
First Posted: August 13, 2020    Key Record Dates
Last Update Posted: November 16, 2020
Last Verified: November 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Reva Basho, Cedars-Sinai Medical Center:
tucatinib
pembrolizumab
trastuzumab
Additional relevant MeSH terms:
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Breast Neoplasms
Neoplasm Metastasis
Brain Neoplasms
Central Nervous System Diseases
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Neoplastic Processes
 Pathologic Processes
Central Nervous System Neoplasms
Nervous System Neoplasms
Brain Diseases
Nervous System Diseases
Pembrolizumab
Trastuzumab
Antineoplastic Agents, Immunological
Antineoplastic Agents