Phase II Evaluation of Trastuzumab, Tucatinib, and Vinorelbine in HER2-Positive Non-Resectable Locally Advanced or Metastatic Breast Cancer
- Trial ID
- 2024-512590-27-00
- Protocol
- GEICAM/2020-08
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **efficacy** of the combination of tucatinib, vinorelbine, and trastuzumab in patients with non-resectable locally advanced or metastatic HER2-positive breast cancer. This is clinically relevant as it aims to determine the potential of this combination therapy to improve treatment outcomes in a population with limited therapeutic options.
Secondary objectives include:
- Evaluating other efficacy objectives in all patients.
- Assessing other efficacy objectives specifically in patients with brain metastasis at baseline.
- Evaluating the **safety** of the combination of tucatinib, vinorelbine, and trastuzumab.
- Assessing the tolerability of this combination therapy.
- Evaluating the effect on the **Quality of Life (QoL)** of patients, as measured by the EORTC QLQ-C30.
Participants
The clinical trial involves participants diagnosed with **non-resectable locally advanced or metastatic HER2-positive breast cancer**. The study population includes both male and female subjects who are at least 18 years of age. Participants are required to have a documented HER2-positive status and must have undergone at least two prior anti-HER2 treatment regimens. The trial does not include a vulnerable population. Participants are expected to have a life expectancy of at least 12 weeks and an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. The sponsor has not provided the total number of participants. The selection criteria emphasize adequate organ and marrow function, and participants must have measurable disease according to RECIST 1.1 criteria. Lifestyle considerations such as diet and physical activity are not specified in the available data. The trial does not focus on any specific lifestyle habits, and the sponsor has not disclosed additional information regarding the selection process or specific lifestyle considerations.
Plans and Procedures
The clinical trial is designed as a **single-arm phase II study** to evaluate the efficacy and safety of a combination therapy involving **trastuzumab**, **tucatinib**, and **vinorelbine** in patients with **HER2-positive non-resectable locally advanced or metastatic breast cancer**. The trial is expected to run from March 2023 to August 2026. Participants will be involved in the study for the duration necessary to assess the primary and secondary endpoints, which include objective response rate, progression-free survival, and overall survival, among others. The trial will involve multiple study visits, starting with an inclusion visit where eligibility is confirmed through criteria such as documented HER2-positive status, adequate organ function, and previous therapy with at least two anti-HER2 regimens.
Following the inclusion visit, participants will undergo regular follow-up visits to monitor treatment response and safety. These visits will include assessments such as imaging studies, laboratory tests, and evaluations of adverse events. The end-of-study visit will occur after the completion of the treatment regimen or upon early termination. Conditions that may lead to early termination include significant adverse events, disease progression, or withdrawal of consent. The trial employs a rigorous methodology to ensure the reliability of the results, with endpoints assessed using established criteria such as RECIST version 1.1 for response evaluation.
Treatment
The clinical trial involves the administration of **Tucatinib**, marketed under the name **TUKYSA**, which is provided in two different dosages: 50 mg and 150 mg film-coated tablets. The pharmaceutical form of both dosages is a film-coated tablet, and the route of administration is oral. The medication is manufactured by SEAGEN B.V. and is stored in bottles that must be kept at a temperature between 2°C and 8°C. The tablets are to be taken as part of a combination therapy for patients with HER2-positive non-resectable locally advanced or metastatic breast cancer. The specific dosing schedule and frequency of administration are determined by the study protocol, which is not detailed in the provided data.
In addition to **Tucatinib**, the study involves the use of **Trastuzumab** and **Vinorelbine** as part of the combination therapy. **Trastuzumab** is a monoclonal antibody used as a standard-of-care therapy for HER2-positive breast cancer, while **Vinorelbine** is a chemotherapy agent. The combination aims to evaluate the efficacy and safety of these agents in conjunction with **Tucatinib**. The administration routes and dosing schedules for **Trastuzumab** and **Vinorelbine** are not specified in the provided data, but they are typically administered intravenously in clinical settings. Participant compliance with the medication regimen is monitored throughout the study to ensure adherence to the treatment protocol.
Efficacy
The efficacy of the combination of **tucatinib**, vinorelbine, and trastuzumab in patients with HER2-positive non-resectable locally advanced or metastatic breast cancer will be assessed through several primary and secondary endpoints. The primary endpoint is the Objective Response Rate (ORR), which is defined as the rate of complete response (CR) plus partial response (PR) based on the investigator's assessment using the Response Evaluation Criteria for Solid Tumors (RECIST) version 1.1. This will be evaluated in patients who have received at least one dose of the treatment.
Secondary endpoints include the ORR in patients with brain metastasis at baseline, as well as other efficacy measures such as Progression-Free Survival (PFS), Duration of Response (DOR), Disease Control Rate (DCR), Clinical Benefit Rate (CBR), and Overall Survival (OS). Safety will be monitored by assessing the incidence and severity of adverse events (AEs) and clinical laboratory abnormalities, with AE grades defined by the NCI-CTCAE version 5.0 and terms coded according to the MedDRA dictionary.
Quality of Life (QoL) will be evaluated using the EORTC QLQ-C30 questionnaire, focusing on changes from baseline in the global health status score and each scale of the questionnaire. Time to deterioration in QoL will be defined as the time from enrollment to the first detection of a deterioration event, characterized by an increase or decrease of at least the minimally important difference (MID) from baseline for the symptom and functional scales, respectively.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Written and signed informed consent obtained prior to any study-specific procedure
- Male or female patients at least 18 years of age
- Documented HER2-positive status by local laboratory determination, preferably on the most recent available FFPE tumor sample, according to the American Society of Clinical Oncology (ASCO)/Collegue of American Pathologists (CAP) international guidelines valid at the time of the assay
- Previous therapy with at least two prior anti-HER2 treatment regimens (either in early stage or advanced disease). Prior taxanes and trastuzumab are mandatory. Prior treatment with pertuzumab, T-DM1, trastuzumab-deruxtecan and anti-HER2 TKI agents is allowed
- Measurable disease according to RECIST 1.1 criteria, defined as at least 1 extra-osseous lesion that can be accurately measured in at least 1 dimension
- Mandatory contrast brain magnetic resonance imaging (MRI) must be performed at baseline and patients must have at least one of the following: a. No evidence of brain metastases. b. Untreated brain metastases not needing immediate local therapy. c. Previously treated brain metastases. • Brain metastases previously treated with local therapy may either be stable since treatment or may have progressed since prior local central nervous system (CNS) therapy, provided that there is no clinical indication for immediate re-treatment with local therapy. • Subjects treated with CNS local therapy for newly identified lesions may be eligible to enroll if all of the following criteria are met: Time since stereotactic radiosurgery (SRS) is at least 1 week prior to first dose of study treatment, time since whole brain radiation therapy (WBRT) is at least 3 weeks prior to first dose, or time since surgical resection is at least 4 weeks. Other sites of evaluable disease are present. • Relevant records of any CNS treatment must be available to allow for classification of target and non-target lesions.
- Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 1.
- Life expectancy ≥ 12 weeks
- Adequate organ and marrow function defined as follows: a. Absolute Neutrophil Count (ANC) ≥ 1,500/mm3 (1.5x109/L). b. Platelet count ≥ 100,000/mm3 (100x109/L). c. Hemoglobin ≥ 9g/dL (90g/L). d. Serum creatinine ≤ 1,5x upper limit of the normal range (ULN) or estimated creatinine clearance ≥ 60 mL/min as calculated using the standard method for the institution. e. Total serum bilirubin ≤ 1,5xULN (≤ 3.0xULN if Gilbert´s disease). f. Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT ≤ 3.0xULN (≤5.0xULN if liver metastases are present). g. Alkaline phosphatase ≤ 2.5xULN (≤5.0xULN if bone or liver metastases are present).
- Left ventricular ejection fraction (LVEF) ≥ 50% measured by multiple-gated acquisition scan (MUGA) or echocardiogram (ECHO).
- Negative urine or serum pregnancy test for females of childbearing potential.
Exclusion Criteria
- Have received more than 4 lines of systemic therapy for locally advanced or MBC
- Have received prior treatment with tucatinib, vinorelbine for locally advanced or MBC or anti-HER2 TKI agents if administered less than 12 months prior to study entry
- Have used a strong CYP3A4 or CYP2C8 inhibitor or CYP3A substrate within 2 weeks, or a strong CYP3A4 or CYP2C8 inducer within 5 days prior to the first dose of study treatment (see Protocol Attachment 2 for more information).
- Patients who received before inclusion: a. Any investigational agent within 4 weeks. b. Chemotherapy within a period of time that is shorter than the cycle duration used for that treatment (e.g. < 3 weeks for fluorouracil, doxorubicine, epirubicine or < 1 week for weekly chemotherapy). c. Biologic therapy (e.g., antibodies): up to 4 weeks prior to starting study treatment. d. Endocrine therapy: tamoxifen or aromatase inhibitor (AI) within 2 weeks prior to starting study treatment. e. Radiotherapy within 2 weeks (3 weeks if WBRT) prior to starting study treatment (all acute toxic effects must be resolved to NCI-CTCAE version 5.0 grade <1, except toxicities not considered a safety risk for the patient at investigator´s discretion). Patients who received prior radiotherapy to >25% of bone marrow are not eligible regardless of when it was administered. f. Major surgery or other anti-cancer therapy not previously specified within 4 weeks prior to starting study treatment, Resolution of all acute toxic effects of prior anti-cancer therapy or surgical procedures to NCI-CTCAE version 5.0 grade ≤ 1 (except alopecia or other toxicities not considered a safety risk for the patient at investigator´s discretion) is mandatory
- Are unable for any reason to undergo MRI of the brain
- Have any of the following with regards to CNS disease: a. Any untreated brain lesions >2 cm in size. b. Any brain lesion thought to require immediate local therapy, including (but not limited to) a lesion in an anatomic site where increase in size or possible treatment-related edema may pose risk to patient (e.g., brain stem lesions). Patients who undergo local treatment for such lesions identified by screening contrast brain MRI may still be eligible for the study based on criteria described under CNS inclusion criteria 6c. c. Known or concurrent leptomeningeal disease as documented by the investigator. d. Ongoing use of corticosteroids for control of symptoms of brain metastases at a total daily dose of >2 mg of dexamethasone (or equivalent). e. Poorly controlled (> 1/week) generalized or complex partial seizures or manifest neurologic progression due to brain metastases notwithstanding CNS-directed therapy.
- Have clinically significant, uncontrolled heart disease and/or recent cardiac events including any of the following: a. Ventricular arrhythmia requiring therapy. b. Myocardial infarction or unstable angina within 6 months prior to first dose of study treatment. c. Uncontrolled hypertension (defined as persistent systolic blood pressure > 150 mm Hg and/or diastolic blood pressure > 100 mm Hg on antihypertensive medications). d. Any history of symptomatic congestive heart failure (CHF). e. History of LVEF decline below 50% during or after prior trastuzumab therapy or other cardiac toxicity during previous trastuzumab treatment that necessitated discontinuation of trastuzumab.
- Have a diagnosis of any other malignancy within 3 years prior to inclusion, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the cervix or colorectal.
- Have history of allergic reactions to trastuzumab, vinorelbine, or tucatinib (or compounds chemically or biologically similar), except for Grade 1 or 2 infusion related reactions to trastuzumab or vinorelbine that were successfully managed.
- Have difficulties to swallow tablets, malabsorption syndrome, disease significantly affecting gastrointestinal function, resection of the stomach or small bowel, or active inflammatory bowel disease (e.g., ulcerative diseases).
- Have positive serology for Human Immunodeficiency Virus (HIV), or active infection for hepatitis B, hepatitis C or have other known chronic liver disease.
- Other severe acute or chronic medical (such as neuropathy grade 3-4) or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study treatment administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study.
- Are pregnant, breastfeeding, or planning a pregnancy. Women of child-bearing potential or partners of women of child-bearing potential, unless agreement to remain abstinent or use of single or combined non-hormonal contraceptive methods that result in a failure rate of < 1% per year during the treatment period and for at least 7 months after the last dose of study treatment. a. Abstinence is only acceptable if it is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post-ovulation methods) and withdrawal are not acceptable methods of contraception. b. Examples of non-hormonal contraceptive methods with a failure rate of < 1% per year include tubal ligation, male sterilization (only if he is the sole partner and have been performed at least 6 months prior to screening), and certain intrauterine devices. c. Alternatively, two methods (e.g., two barrier methods such as a condom and a cervical cap) may be combined to achieve a failure rate of < 1% per year. Barrier methods must always be supplemented with the use of a spermicide. d. Male participants must not donate sperm during study and up to the time period specified above.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Spain | Not Recruiting | 01 Mar 2023 | 49 |
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 |
|---|---|---|---|---|---|---|
TUKYSA 50 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL | — | — | PRD8771172 |
TUKYSA 150 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL | — | — | PRD8771193 |