Phase 3 Randomized, Double-Blind Study of Tucatinib with Trastuzumab and Pertuzumab in Maintenance Therapy for Metastatic HER2-Positive Breast Cancer
- Trial ID
- 2023-503826-37-00
- Protocol
- SGNTUC-028
- Sponsor
- Seagen Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to compare **progression-free survival (PFS)** by investigator assessment using the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 between treatment arms in patients with unresectable locally-advanced or metastatic HER2-positive breast cancer. This objective is clinically relevant as it aims to determine the efficacy of tucatinib in combination with trastuzumab and pertuzumab as maintenance therapy, potentially offering a new therapeutic option for this patient population.
Secondary objectives include:
- Comparing overall survival (OS) between treatment arms, which is crucial for understanding the long-term benefits of the treatment.
- Evaluating PFS by blinded independent central review (BICR) per RECIST v1.1, providing an objective assessment of treatment efficacy.
- Assessing the change in health-related quality of life (HRQoL), which is important for understanding the impact of treatment on patients' daily lives.
- Evaluating PFS in the brain, which is significant for patients with brain metastases.
- Evaluating the safety and tolerability of tucatinib in combination with trastuzumab and pertuzumab, ensuring the treatment's risk-benefit profile is acceptable.
- Evaluating the pharmacokinetics (PK) of tucatinib, which is essential for understanding the drug's behavior in the body.
Participants
The clinical trial involves a total of **443 participants** diagnosed with **unresectable locally-advanced or metastatic HER2+ breast cancer**. The study population includes both male and female subjects, with an age range that encompasses adults and older adults. Participants were selected based on specific inclusion criteria, such as having centrally confirmed HER2+ breast carcinoma and having received prior standard of care therapy for early breast cancer. The trial population includes individuals with a known hormone receptor status and an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1, indicating they are in relatively good health. Lifestyle considerations such as diet and physical activity are not specified. The trial also includes a vulnerable population, and participants may have brain metastases under certain conditions. The selection process ensures that participants have not shown disease progression following pre-study induction therapy. The sponsor has not provided additional information regarding specific lifestyle factors or other demographic details.
Plans and Procedures
The clinical trial is a **randomized, double-blind, controlled** study designed to evaluate the efficacy and safety of **tucatinib** in combination with **trastuzumab** and **pertuzumab** versus placebo in combination with trastuzumab and pertuzumab for patients with unresectable locally-advanced or metastatic **HER2 positive breast cancer**. The primary objective is to compare progression-free survival (PFS) between the treatment arms, assessed by investigators using the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. The trial is expected to run from December 2021 to September 2027, with an estimated duration of 66 weeks for each participant.
Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on criteria such as centrally confirmed HER2+ breast carcinoma and prior treatment history. Following successful screening, participants will be randomized to receive either the investigational treatment or placebo. The study includes multiple follow-up visits to monitor safety, efficacy, and any adverse events. These visits will involve clinical assessments, laboratory tests, and imaging studies as per protocol requirements. The end-of-study visit will occur after the completion of the treatment period or upon early termination.
Participant involvement is expected to last approximately 66 weeks, with conditions for early termination including disease progression, unacceptable toxicity, or withdrawal of consent. The trial will also assess secondary endpoints such as overall survival (OS), time to deterioration of health-related quality of life (HRQoL), and central nervous system progression-free survival (CNS-PFS). Safety assessments will include monitoring adverse events, clinical laboratory evaluations, and the incidence of dose modifications. The trial is conducted under strict adherence to ethical guidelines and regulatory requirements to ensure participant safety and data integrity.
Treatment
The clinical trial involves the administration of several treatments, including both experimental and non-experimental medications. **TUKYSA** (tucatinib) is an experimental medication used in this study. It is available in two dosages: 50 mg and 150 mg film-coated tablets. The active substance is **tucatinib**, a chemical compound. The maximum daily dose is 600 mg, with a total maximum dose of 1,204,500 mg over a treatment period of 66 weeks. The tablets are administered orally. The clinical formulation is stored in HDPE bottles, with specific storage conditions of 2-8°C and a shelf-life of 36 months. The commercial product differs in packaging and storage conditions, with a 24-month shelf-life and no special storage requirements.
**Phesgo** is another treatment used in the trial, consisting of a 600 mg/600 mg solution for injection. It contains the active substances **trastuzumab** and **pertuzumab**, which are recombinant humanized IgG1 monoclonal antibodies. The solution is administered via injection, with a maximum daily dose of 600 mg and a total maximum dose of 57,357 mg over the same 66-week treatment period. This medication is authorized for use in the European Union and is provided by Roche Registration GmbH.
Placebo treatments are also utilized in this study to maintain the double-blind design. **Tucatinib 150 mg placebo tablets** and **Tucatinib 50 mg placebo tablets** are administered to participants. These placebo tablets are designed to mimic the appearance and administration route of the active tucatinib tablets, ensuring that neither the participants nor the investigators can distinguish between the active and placebo treatments. The placebo tablets are administered orally, following the same dosing schedule as the active tucatinib tablets.
Efficacy
The efficacy of the clinical trial will be assessed primarily through the evaluation of **progression-free survival (PFS)**, as determined by the investigator using the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. PFS is defined as the time from randomization to documented disease progression or death from any cause, whichever occurs first. This primary endpoint will provide a direct measure of the treatment's impact on delaying disease progression in patients with metastatic HER2-positive breast cancer.
Secondary endpoints include overall survival (OS), which is the time from randomization to death from any cause, and PFS as determined by blinded independent central review (BICR) per RECIST v1.1. Additional secondary endpoints involve the time to deterioration of health-related quality of life (HRQoL), specifically a 10-point decrease in the global health status/quality of life scale of the European Organization for Research and Treatment of Cancer (EORTC) quality-of-life questionnaire (QLQ-C30). Central nervous system (CNS)-PFS, adverse events (AEs), clinical laboratory assessments, and the incidence of dose modifications for tucatinib, trastuzumab, and pertuzumab will also be evaluated. Plasma concentrations of tucatinib will be measured to assess pharmacokinetics.
The trial is designed to compare the efficacy of tucatinib in combination with trastuzumab and pertuzumab against a placebo in combination with trastuzumab and pertuzumab. The study will follow a randomized, double-blind, phase 3 design, with efficacy assessments conducted at specified intervals throughout the trial duration, which is estimated to conclude by September 2027. The trial aims to provide comprehensive data on the efficacy and safety of the treatment regimen in the specified patient population.
Inclusion and Exclusion Criteria
Inclusion Criteria
- 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
- 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.
- 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.
- Known hormone receptor status (per local guidelines; may be hormone receptor positive [HR+] or negative [HR-])
- Have Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1
- 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
- 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.
- Unable for any reason to undergo contrast-enhanced MRI of the brain
- 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
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Not Recruiting | 01 Dec 2021 | 5 |
 Belgium | Not Recruiting | 01 Dec 2021 | 5 |
 Czechia | Not Recruiting | 01 Dec 2021 | 17 |
 Finland | Not Recruiting | 01 Dec 2021 | 2 |
 France | Not Recruiting | 01 Dec 2021 | 79 |
 Germany | Not Recruiting | 01 Dec 2021 | 40 |
 Greece | Not Recruiting | 01 Dec 2021 | 8 |
 Italy | Not Recruiting | 01 Dec 2021 | 24 |
 The Netherlands | Not Recruiting | 01 Dec 2021 | — |
 Poland | Not Recruiting | 01 Dec 2021 | 9 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Tucatinib 150mg placebo tablets | Placebo | N/A | — | — | — | N/A |
Tucatinib 50mg placebo tablets | Placebo | N/A | — | — | — | N/A |
TUKYSA 150 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL USE | 600 | 66 | PRD8771193 |
TUKYSA 50 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL USE | 600 | 66 | PRD8771172 |
Phesgo 600 mg/600 mg solution for injection | Test | SOLUTION FOR INJECTION | SOLUTION FOR INJECTION | 600 | 66 | PRD8601831 |