TUCATINIB for HER2-positive breast cancer (locally advanced or metastatic)

Inclusion criteria

• {"criterion_text":"- Have centrally confirmed HER2+ breast carcinoma according to the 2018 American Society of Clinical Oncologists (ASCO)-College of American Pathologists (CAP) guidelines prior to randomization (defined as a 3+ score on immunohistochemistry (IHC) and/or 2+ IHC and concurrent positive by ISH). a. Tissue blocks or tumor slides must be submitted and confirmed as HER2+ by a sponsor designated central laboratory prior to randomization"}
• {"criterion_text":"- Have unresectable locally advanced or metastatic (hereafter referred to as “advanced”) disease; if recurrent (after [neo]adjuvant therapy), there must be a minimum 6month -treatment f-ree interval from any trastuzumab and pertuzumab received in the early breast cancer setting to the diagnosis of advanced HER2+ disease. Prior standard of care therapy for early breast cancer is permitted (eg, prior ado-trastuzumab- emtansine [T-DM1]); however, Exclusion Criterion 1 should be noted."}
• {"criterion_text":"- Have received 4-8 cycles of pre-study induction therapy including only trastuzumab, pertuzumab, and taxane as first-line therapy for the treatment of advanced breast cancer prior to study enrollment. Participants are eligible provided they are without evidence of disease progression (per investigator judgement, ie, CR, PR, or SD) following completion of induction therapy. o Participants receiving <6 cycles (ie, 4-5 cycles) of taxane are only eligible if the taxane was stopped early due to intolerable toxicity (eg, documented neuropathy impacting function). o Participants are permitted to receive trastuzumab and pertuzumab for 2 additional cycles (after completion of chemotherapy) to allow completion of screening procedures. Study treatment should begin within 6 weeks (± 3 days) from the start of the last cycle of trastuzumab and pertuzumab. o Participants are permitted to receive up to 2 cycles of carboplatin during the start of induction therapy in combination with trastuzumab, pertuzumab, and taxane (eg, to obtain confirmation of metastatic breast cancer diagnosis) o Participants who received traditional medications (eg, traditional Chinese medication) and/or supplements with potential anti-cancer effects during induction therapy will remain eligible if they discontinue these treatments at least 4 weeks prior to the start of study treatment."}
• {"criterion_text":"- Known hormone receptor status (per local guidelines; may be hormone receptor positive [HR+] or negative [HR-])"}
• {"criterion_text":"- Have Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1"}
• {"criterion_text":"- CNS Inclusion – Based on screening contrast-enhanced brain magnetic resonance imaging (MRI), participants may have any of the following: o No evidence of brain metastases o Untreated brain metastases which are asymptomatic, not needing immediate local treatment and, if identified on prior brain imaging, without evidence of progression since starting first-line induction therapy with trastuzumab, pertuzumab, and taxane o Previously treated brain metastases which are asymptomatic o Brain metastases previously treated with local therapy must not have progressed since treatment o Time since whole brain radiation therapy (WBRT) is ≥ 14 days prior to first dose of study treatment, time since stereotactic radiosurgery (SRS) is ≥7 days prior to first dose of study treatment, or time since surgical resection is ≥28 days prior to first dose of study treatment o Relevant records of any CNS treatment must be available to allow for classification of target and non-target lesions"}

Exclusion criteria

• {"criterion_text":"- Have previously been treated with any tyrosine kinase inhibitor targeting HER2 and/or epidermal growth factor receptor (EGFR) including pyrotinib, lapatinib, tucatinib, neratinib, and afatinib (except neratinib if given in the extended adjuvant setting and at least 12 months have elapsed from the last neratinib dose to the start of study intervention) or are currently participating in another interventional clinical trial."}
• {"criterion_text":"- Unable for any reason to undergo contrast-enhanced MRI of the brain"}
• {"criterion_text":"- CNS Exclusion – Based on screening brain MRI and clinical assessment, participants must not have any of the following: o Symptomatic brain metastasis after CNS-directed local therapy o Progression of brain metastases since starting first-line trastuzumab, pertuzumab, and taxane o Ongoing use of systemic corticosteroids at a total daily dose of >2 mg of dexamethasone (or equivalent). For participants requiring systemic steroids for control of comorbidities (eg, asthma or autoimmune diseases), daily dose must not exceed 2 mg dexamethasone (or equivalent). o Any untreated brain lesion in an anatomic site which may pose risk to participant (eg, brain stem lesions). Participants who successfully undergo local treatment for such lesions may be permitted to rescreen, if otherwise eligible, after discussion with, and approval by, the medical monitor. o Known or suspected leptomeningeal disease (LMD) as documented by the investigator a. Poorly controlled (>1/week) seizures, or other persistent neurologic symptoms despite CNS directed therapy for brain metastasis"}

Primary endpoints

• {"endpoint_text":"- PFS, defined as the time from randomization to investigator-assessed documented disease progression per RECIST v1.1, or death from any cause, whichever occurs first","definition_or_measurement_approach":"Time from randomization to investigator-assessed documented disease progression per RECIST v1.1, or death from any cause"}

Secondary endpoints

• {"endpoint_text":"- OS, defined as the time from randomization to death from any cause","definition_or_measurement_approach":"Time from randomization to death from any cause"}
• {"endpoint_text":"- PFS, defined as the time from randomization to documented disease progression (as determined by BICR per RECIST v1.1), or death from any cause, whichever occurs first","definition_or_measurement_approach":"Time from randomization to documented disease progression determined by blinded independent central review (BICR) per RECIST v1.1, or death"}
• {"endpoint_text":"- Time to deterioration of HRQoL, defined as time to 10-point decrease in the global health status/QoL scale of the European Organization for Research and Treatment of Cancer (EORTC) quality-of-life questionnaire (QLQ-C30)","definition_or_measurement_approach":"Time to a 10-point decrease in the global health status/QoL scale of the EORTC QLQ-C30"}
• {"endpoint_text":"- Central nervous system (CNS)-PFS, defined as the time from randomization to investigator-assessed disease progression in brain (RECIST v1.1), or death from any cause, whichever occurs first","definition_or_measurement_approach":"Time from randomization to investigator-assessed progression in brain per RECIST v1.1, or death"}
• {"endpoint_text":"- Adverse events (AEs)","definition_or_measurement_approach":"Standard collection and reporting of adverse events"}
• {"endpoint_text":"- Clinical laboratory assessments","definition_or_measurement_approach":"Routine clinical laboratory testing per protocol schedule"}
• {"endpoint_text":"- Incidence of dose holding, dose reductions, and discontinuations of tucatinib","definition_or_measurement_approach":"Protocol-defined recording of dose holds, reductions, and discontinuations for tucatinib"}
• {"endpoint_text":"- Incidence of dose holding and discontinuations of trastuzumab","definition_or_measurement_approach":"Protocol-defined recording of dose holds and discontinuations for trastuzumab"}
• {"endpoint_text":"- Incidence of dose holding and discontinuations of Pertuzumab","definition_or_measurement_approach":"Protocol-defined recording of dose holds and discontinuations for pertuzumab"}
• {"endpoint_text":"- Plasma concentrations of tucatinib","definition_or_measurement_approach":"Pharmacokinetic sampling and measurement of plasma tucatinib concentrations"}

Belgium

Earliest CTIS Part Ii Submission Date

03-04-2024

Latest Decision Or Authorization Date

24-01-2025

Processing Time Days

296

Number Of Participants

5

Finland

Earliest CTIS Part Ii Submission Date

03-04-2024

Latest Decision Or Authorization Date

27-01-2025

Processing Time Days

299

Number Of Participants

2

Netherlands

Earliest CTIS Part Ii Submission Date

03-04-2024

Latest Decision Or Authorization Date

27-01-2025

Processing Time Days

299

Number Of Participants

4

Italy

Earliest CTIS Part Ii Submission Date

03-04-2024

Latest Decision Or Authorization Date

28-01-2025

Processing Time Days

300

Number Of Participants

24

Greece

Earliest CTIS Part Ii Submission Date

03-04-2024

Latest Decision Or Authorization Date

28-01-2025

Processing Time Days

300

Number Of Participants

8

Poland

Earliest CTIS Part Ii Submission Date

03-04-2024

Latest Decision Or Authorization Date

28-01-2025

Processing Time Days

300

Number Of Participants

9

Austria

Earliest CTIS Part Ii Submission Date

03-04-2024

Latest Decision Or Authorization Date

29-01-2025

Processing Time Days

301

Number Of Participants

5

Spain

Earliest CTIS Part Ii Submission Date

03-04-2024

Latest Decision Or Authorization Date

09-07-2025

Processing Time Days

462

Number Of Participants

50

Germany

Earliest CTIS Part Ii Submission Date

03-04-2024

Latest Decision Or Authorization Date

12-11-2025

Processing Time Days

588

Number Of Participants

40

France

Earliest CTIS Part Ii Submission Date

03-04-2024

Latest Decision Or Authorization Date

07-01-2026

Processing Time Days

644

Number Of Participants

79

Czechia

Earliest CTIS Part Ii Submission Date

03-04-2024

Latest Decision Or Authorization Date

08-01-2026

Processing Time Days

645

Number Of Participants

17

Portugal

Earliest CTIS Part Ii Submission Date

03-04-2024

Latest Decision Or Authorization Date

13-04-2026

Processing Time Days

740

Number Of Participants

6

Primary sponsor

Full Name

Seagen Inc.

Organisation Type

Pharmaceutical company

Country Of Registered Address

United States

Contract research organisations

Name

Icon Clinical Research Limited

Responsibilities

Central data entry for local laboratory results (iRIS Services)

Name

PPD Global Central Labs

Responsibilities

Kit build, sample management and storage

Name

4g Clinical LLC

Responsibilities

Randomization and Trial Supply Management

Name

Medidata Solutions Inc.

Responsibilities

Operational/support services (e.g., data capture/management)

Third parties

• {"country":"United States","full_name":"Alturas Analytics Inc.","duties_or_roles":"Tucatinib PK","organisation_type":"Pharmaceutical company"}
• {"country":"Belgium","full_name":"PPD Global Central Labs","duties_or_roles":"Kit build, sample management and storage","organisation_type":"Pharmaceutical company"}
• {"country":"Ireland","full_name":"Icon Clinical Research Limited","duties_or_roles":"Central data entry for local laboratory results (iRIS Services)","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Clario","duties_or_roles":"Medical image analysis/ review - X-ray, MRI, ultrasound, etc, Primary/ surrogate endpoint test","organisation_type":"Health care"}
• {"country":"United States","full_name":"Medidata Solutions Inc.","duties_or_roles":"Operational/support services (code 7)","organisation_type":"Non-Pharmaceutical company"}
• {"country":"Germany","full_name":"Discovery Life Sciences Biomarker Services GmbH","duties_or_roles":"HER2 status - including by IHC and FISH/ISH","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"4g Clinical LLC","duties_or_roles":"Randomization and Trial Supply Management","organisation_type":"Non-Pharmaceutical company"}