A study of tucatinib versus placebo in combination with pertuzumab and trastuzumab for subjects with advanced or metastatic HER2+ breast cancer

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Seagen Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

11 Feb 2022 → ongoing

Decision date (initial)

2024-04-26

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Seagen Inc

External identifiers

EU CT number

2023-503826-37-00

EudraCT number

2021-002491-39

ClinicalTrials.gov

NCT05132582

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Others, Pharmacokinetic, Efficacy, Therapy

Compare progression-free survival (PFS) by investigator per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 between treatment arms

Secondary objectives 6

1. Compare overall survival (OS) between treatment arms
2. Evaluate PFS by blinded independent central review (BICR) per RECIST v1.1
3. Assess the change in health-related quality of life (HRQoL)
4. Evaluate PFS in the brain
5. Evaluate the safety and tolerability of tucatinib in combination with trastuzumab and Pertuzumab
6. Evaluate the pharmacokinetics (PK) of tucatinib

Conditions and MedDRA coding

Unresectable locally-advanced or metastatic HER2+ breast cancer

Study design 1 period

Regulatory references

Scientific advice from competent authorities

The Spanish Agency Of Medicines And Medical Devices, Danish Medicines Agency

Plan to share IPD

Yes

IPD plan description

Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical trials/trial data and results/data requests. URL: https://www.pfizer.com/science/clinical trials/trial data and results/data requests

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 6

1. 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
2. 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.
3. 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.
4. Known hormone receptor status (per local guidelines; may be hormone receptor positive [HR+] or negative [HR-])
5. Have Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1
6. 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 3

1. 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.
2. Unable for any reason to undergo contrast-enhanced MRI of the brain
3. 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

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 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

Secondary endpoints 10

1. OS, defined as the time from randomization to death from any cause
2. 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
3. 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)
4. - 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
5. Adverse events (AEs)
6. Clinical laboratory assessments
7. Incidence of dose holding, dose reductions, and discontinuations of tucatinib
8. Incidence of dose holding and discontinuations of trastuzumab
9. Incidence of dose holding and discontinuations of Pertuzumab
10. Plasma concentrations of tucatinib

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Placebo 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Seagen Inc.

Sponsor organisation

Seagen Inc.

Address

21823 30th Drive Southeast

City

Bothell

Postcode

98021-3907

Country

United States

Scientific contact point

Organisation

Seagen Inc.

Contact name

Clinical Medical Lead

Public contact point

Organisation

Seagen Inc.

Contact name

Clinical Medical Lead

Third parties 7

Locations

12 EU/EEA countries · 93 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 82 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

15 submissions — initial application plus substantial / non-substantial modifications