Evaluation of Tucatinib, Pertuzumab, and Trastuzumab in HER2-Positive Metastatic Breast Cancer with Isolated Brain Progression
- Trial ID
- 2024-510703-11-00
- Protocol
- UC-BCG-2011
- Sponsor
- Unicancer
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **efficacy** of tucatinib in combination with pertuzumab and trastuzumab in patients with HER2-positive metastatic breast cancer with isolated brain progression. This is assessed in terms of progression-free survival rate according to the Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1). This objective is clinically relevant as it aims to determine the potential of this combination therapy to delay disease progression in a challenging patient population with limited treatment options.
Secondary objectives include: - Evaluating the efficacy of tucatinib in terms of overall survival, brain progression-free survival, and brain metastasis response in patients not in complete remission at the brain level after local treatment. - Assessing the safety of the combination of pertuzumab, trastuzumab, and tucatinib. - Identifying predictive biomarkers through ancillary studies. These objectives are crucial for understanding the broader impact of the treatment on patient outcomes and identifying potential markers for treatment response.
Participants
The clinical trial involves participants diagnosed with **HER2+ metastatic breast cancer** with isolated brain progression. The study population includes both male and female subjects aged 18 years and older. Participants are required to have adequate cardiac, renal, liver, and hematological functions, as well as a stable dose of steroids at the time of enrollment. The trial population was selected based on specific inclusion criteria, including a histologically confirmed diagnosis of HER2 positive breast cancer and documented isolated brain progression under pertuzumab and trastuzumab treatment. Participants must have completed local treatment of brain progression no more than 12 weeks before inclusion and should be able to undergo MRI scanning of the brain. The trial does not specify the total number of participants, as this information was not provided by the sponsor. Lifestyle considerations such as diet and physical activity are not detailed in the available data. The study includes a vulnerable population, and participants must be affiliated with a social security system or equivalent and willing to comply with the trial protocol.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy of **tucatinib** in combination with **pertuzumab** and **trastuzumab** in patients with HER2-positive metastatic breast cancer with isolated brain progression. This study is a randomized, double-blind, controlled trial with an estimated duration from December 2021 to March 2026. The trial aims to assess the progression-free survival rate at six months as the primary endpoint, with secondary endpoints including overall survival, brain progression-free survival, and overall brain metastasis response. Safety will be monitored through adverse events graded according to NCI-CTCAE v5.0.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, cardiac function, and previous treatment history. Follow-up visits will be scheduled to monitor treatment response and safety, with assessments including imaging studies and laboratory tests. The end-of-study visit will conclude the participant's involvement, with data collected for final analysis. The expected length of participant involvement is up to 21 days of treatment, with conditions for early termination including significant adverse events or disease progression.
Participants will receive **tucatinib** orally, with a maximum daily dose of 600 mg, while **pertuzumab** and **trastuzumab** will be administered as solutions for infusion. The trial will ensure compliance with protocol requirements, including scheduled visits and treatment plans. Participants must agree to use adequate contraception during the trial and for a specified period after treatment. The trial is not categorized as low intervention and is classified as a Phase II study. The study will not include pediatric formulations, and all substances used are chemically or protein-derived. The trial's success will be determined by the progression-free survival rate and other efficacy measures, with ancillary studies on biomarkers conducted post-trial.
Treatment
The clinical trial involves the administration of several treatments, including both experimental and non-experimental medications. The primary experimental medication is **Tucatinib**, marketed under the name TUKYSA, available in two dosages: 150 mg and 50 mg film-coated tablets. Tucatinib is a chemical substance administered orally. The maximum daily dose is 600 mg, with a total maximum dose of 12,600 mg over a treatment period of 21 days. The tablets are stored in HDPE bottles for clinical use and blister packs for commercial use, with specific storage conditions of 2 to 8 °C for clinical settings and no special conditions for commercial settings.
**Pertuzumab** is used as a comparator treatment in the trial. It is available as a solution for infusion and a concentrate for solution for infusion. Pertuzumab is a protein-based substance administered via infusion. The maximum daily dose varies between 600 mg and 1,200 mg, depending on the formulation, with a total maximum dose ranging from 1,800 mg to 3,600 mg. The treatment period is limited to one cycle.
**Trastuzumab** is another comparator treatment, provided as a solution for injection and infusion. It is a protein-based substance with a maximum daily dose of 600 mg and a total maximum dose of 1,800 mg, administered over a single treatment cycle.
**Fulvestrant** is included as an auxiliary treatment, available as a solution for injection. It is a chemical substance with a maximum daily and total dose of 500 mg, administered over a treatment period of four cycles.
**Letrozole** is also used as an auxiliary treatment, provided in coated tablet form. It is administered orally with a maximum daily and total dose of 2.5 mg over a single treatment cycle.
**Exemestane** is another auxiliary treatment, available as a coated tablet. It is a chemical substance administered orally with a maximum daily and total dose of 25 mg over one cycle.
**Anastrozole** is included as an auxiliary treatment, provided in coated tablet form. It is a chemical substance administered orally with a maximum daily and total dose of 1 mg over a single treatment cycle.
Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed treatment regimens. The trial aims to evaluate the efficacy of the combination of tucatinib, pertuzumab, and trastuzumab in patients with HER2-positive metastatic breast cancer with isolated brain progression.
Efficacy
The efficacy of the clinical trial will be assessed primarily through the measurement of the 6-month **Progression-Free Survival (PFS)** rate. This is defined as the proportion of patients who do not experience objective tumor progression, as determined by imaging, or death from any cause within six months from inclusion in the study. Secondary efficacy endpoints include **Overall Survival (OS)**, which is the time interval from the date of inclusion in the study to the date of death from any cause. Patients who are alive at the time of analysis will be censored at the last recorded date they were known to be alive.
Additional secondary endpoints involve **Brain Progression-Free Survival (BPFS)**, defined as the time from inclusion to documented progression of brain metastases, evaluated according to RECIST v1.1 criteria. For patients not in complete response at the brain level after local treatment, the overall brain metastasis response will be assessed as the best overall response of the brain metastases during the study. Safety will be monitored through the grading of adverse events according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. Ancillary studies will include biomarker research, which will be defined by the study steering committee at the end of the trial to ensure the optimal use of updated technologies and hypotheses.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Male or female, Age ≥18
- Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0-1
- Histologically confirmed HER2 positive breast cancer, with HER2 positive defined by in situ hybridization (ISH), immunohistochemistry (IHC), or fluorescence in situ hybridization (FISH) methodology
- Documented isolated brain progression (defined as new or progressive brain metastases with stable or responding systemic disease) under pertuzumab and trastuzumab treatment (with or without taxane) for metastatic disease (There is no limit to the number and size of brain metastasis)
- Complete local treatment of brain progression (Surgery and/or radiation therapy) should have been completed no more than 12 weeks before inclusion and there is no clinical indication for immediate re-treatment with local therapy in the opinion of the investigator
- Able to undergo MRI scanning of the brain
- Normal renal function: creatinine <1.5 x upper limit of normal (ULN)
- Adequate liver function: total bilirubin ≤1.5 ULN (unless documented Gilbert’s syndrome); AST and ALT ≤2.5 ULN (≤5 ULN in the presence of liver metastases)
- Normal hematological function: ANC ≥1.5 x 109/L; platelets count ≥100 x 109/L; and hemoglobin ≥9.0 g/dL
- Adequate cardiac functions, including: 12 Lead electrocardiograms (ECG) with normal tracing or non-clinically significant changes that do not require medical intervention; QT/QTcF interval ≤470 msec for woman and ≤450 msec for men (mean of replicate values, correction per institutional standard) on the ECG at the screening visit and a normal kaliemia; Left ventricular ejection fraction (LVEF) ≥50%; No history of Torsades de Pointes or other symptomatic QTc abnormality
- Resolution of all acute toxic effects of prior anti-cancer therapy or surgical procedures to NCI CTCAE version 5.0 Grade 1 or to baseline (except alopecia or other toxicities not considered a safety risk for the patient at investigator’s discretion)
- Stable dose of steroids at the time of enrolment
- Women of childbearing potential must have a negative pregnancy test (blood or urine test) within 14 days prior to inclusion
- Woman of childbearing potential and male patients must agree to use adequate contraception for the duration of trial participation and up to 7 months after completing treatment/therapy. Hormonal contraceptives such as birth control pills, patches, implants, or injections are not allowed in patients who are hormone receptor positive
- Patient must have signed a written informed consent form prior to any trial specific procedures. When the patient is physically unable to give their written consent, a trusted person of their choice, independent from the investigator or the sponsor, can confirm in writing the patient’s consent
- Patients affiliated to the social security system (or equivalent)
- Patient must be willing and able to comply with the protocol for the duration of the trial including scheduled visits, treatment plan, laboratory tests, and examinations including follow-up
Exclusion Criteria
- Radiologic extra-cranial progression under pertuzumab and trastuzumab treatment, at the time of enrolment. The systemic disease must be stable or responding at the time of enrolment
- Proven leptomeningeal disease
- Any progressive brain lesion between the brain local treatment completion and the enrolment
- Poorly controlled seizures (more than 1/week)
- Clinically significant cardiopulmonary disease
- Used of a strong cytochrome P450 (CYP)2C8 inhibitor within 5 half-lives of the inhibitor, or use of a strong CYP3A4 or CYP2C8 inducer within 5 days prior to first dose of study treatment. Use of sensitive CYP3A substrates should be avoided one week before enrollment and during study treatment
- Previous treatment with a tyrosine kinase inhibitor
- Carriers of Hepatitis B or Hepatitis C or have other known chronic liver disease
- Positive for human immunodeficiency virus (HIV)
- Known prior severe hypersensitivity to tucatinib or compounds chemically or/and biologically similar or any component in its formulation
- History of any other cancer (except non-melanoma skin cancer or carcinoma in-situ of the cervix) unless the patient has been in remission and off all other cancer therapy for at least 3 years
- Pregnant women or women who are breast-feeding
- Inability to swallow tablets or significant gastrointestinal disease which would preclude the adequate oral absorption of medications
- Person deprived of their liberty or under protective custody or guardianship or unable to give informed consent
- Participation in another therapeutic trial within the 30 days prior to tucatinib treatment initiation
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Not Recruiting | 13 Dec 2021 | 55 |
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 |
|---|---|---|---|---|---|---|
TRASTUZUMAB | Test | — | SOLUTION FOR INFUSION | 600 | 1 | SUB12612MIG |
FULVESTRANT | Other | — | SOLUTION FOR INFUSION | 500 | 4 | SUB13933MIG |
EXEMESTANE | Other | — | ORAL | 25 | 1 | SUB07492MIG |
PERTUZUMAB | Test | — | CONCENTRATE FOR SOLUTION FOR INFUSION | 840 | 1 | SUB16455MIG |
PERTUZUMAB | Test | — | SOLUTION FOR INFUSION | 1200 | 1 | SUB16455MIG |
TRASTUZUMAB | Test | — | SOLUTION FOR INFUSION | 600 | 1 | SUB12612MIG |
PERTUZUMAB | Test | — | SOLUTION FOR INFUSION | 600 | 1 | SUB16455MIG |
TUKYSA 150 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL | 600 | 21 | PRD8771193 |
LETROZOLE | Other | — | ORAL | 2.5 | 1 | SUB08444MIG |
TUKYSA 50 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL | 600 | 21 | PRD8771172 |