"TUC-TOC": Tucatinib in combination with Oral Etoposide (VP16) - Trastuzumab in Patients with metastatic HER2+ Breast cancer after progression under Tucatinib-Capecitabine-Trastuzumab or toxicity related to capecitabine: a multicenter Phase II
- Trial ID
- 2022-500743-20-00
- Protocol
- IC 2021-06
- Sponsor
- Institut Curie
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **efficacy** of the combination of tucatinib, oral VP16, and trastuzumab by measuring the objective response rate (ORR) within the first six months of treatment in patients with metastatic HER2-positive breast cancer. This is clinically relevant as it aims to determine the potential of this combination therapy to induce a measurable response in a patient population that has progressed under previous treatments.
Secondary objectives include:
- Assessing the **tolerability** and safety profile of the combination therapy.
- Evaluating the efficacy on progression-free survival (PFS) and overall survival (OS).
- Determining the duration of response (DoR) and time to response (TTR).
- Evaluating clinical benefit rates and health-related quality of life using the EQ-5D-5L instrument.
- Comparing efficacy in terms of the proportion of patients alive and without progression at six months, PFS, and OS in predefined subgroups, including those with brain metastasis.
- Exploratory objectives include evaluating the pharmacokinetics of the combination and identifying potential biomarkers of response and resistance mechanisms through ctDNA analysis, including TOP2A and HER2 co-amplification.
Participants
The clinical trial focuses on evaluating the efficacy of a treatment regimen for **metastatic HER2+ breast cancer**. The study population comprises adult female participants, specifically those aged 18 years and older. The trial does not include male subjects or vulnerable populations. Participants were selected based on specific inclusion criteria, such as having a histologically confirmed HER2+ breast carcinoma, a life expectancy of at least three months, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Additionally, participants must have measurable disease as assessed by RECIST version 1 and be capable of swallowing capsules. The trial does not provide information on the total number of participants, as the sponsor has not disclosed this data. Lifestyle considerations, such as diet and physical activity, are not specified in the trial details. Key inclusion criteria include disease progression under specific treatments, adequate organ function, and the ability to comply with study procedures. Participants with brain metastases are eligible under certain conditions, and all participants must be covered by a health insurance plan and capable of providing informed consent.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy, safety, and tolerability of a combination therapy involving **tucatinib**, oral **etoposide** (VP16), and **trastuzumab** in patients with metastatic HER2-positive breast cancer. This is a multicenter, open-label, Phase II study. The trial employs a randomized, controlled design to ensure the reliability of the results. The primary objective is to assess the objective response rate (ORR) within the first six months of treatment. Secondary endpoints include progression-free survival, overall survival, and the incidence of adverse events.
The trial is expected to last until December 18, 2028, with recruitment starting on December 19, 2023. Participants will be involved in the study for a maximum treatment period of 52 weeks. The study includes several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor treatment response and safety, and an end-of-study visit to assess overall outcomes. The inclusion criteria require participants to have a histologically confirmed diagnosis of HER2-positive breast cancer, adequate organ function, and a life expectancy of at least three months. Participants must also be able to swallow capsules and be available for the study duration.
Participants may be terminated early from the study if they experience unacceptable toxicity, disease progression, or withdraw consent. The study will also monitor for serious adverse events and adverse events according to NCI CTCAE v5.0. The trial aims to provide valuable insights into the treatment of metastatic HER2-positive breast cancer, particularly in patients who have progressed under previous therapies or have contraindications to capecitabine.
Treatment
The clinical trial involves the administration of several experimental medications, each with specific pharmaceutical forms, dosages, and routes of administration. **Etoposide**, marketed as CELLTOP 50 mg, is provided in the form of a soft capsule. The maximum daily dose is 50 mg, with a total maximum dose of 833 mg over a treatment period of up to 52 weeks. The route of administration is oral, and the medication is chemically derived. Participant compliance with the dosing schedule will be monitored throughout the trial.
**Tucatinib** is administered in two different dosages: TUKYSA 50 mg and TUKYSA 150 mg, both in the form of film-coated tablets. The maximum daily dose for tucatinib is 600 mg, with a total maximum dose of 10,800 mg over a 52-week period. The route of administration is oral, and the substance is chemically synthesized. Compliance with the dosing regimen will be closely monitored to ensure adherence.
**Trastuzumab** is provided in two formulations. The first is Herceptin 150 mg, a powder for concentrate for solution for infusion, with a maximum daily dose of 6 mg/kg and a total maximum dose of 108 mg/kg over a 24-week period. The route of administration is via infusion. The second formulation is Herceptin 600 mg, a solution for injection in a vial, with a maximum daily dose of 600 mg and a total maximum dose of 10,800 mg over a 52-week period. This formulation is administered via subcutaneous injection. Trastuzumab is a protein-based medication, and participant compliance with the administration schedule will be monitored.
No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified in this trial. The trial aims to evaluate the efficacy of the combination of tucatinib, oral etoposide, and trastuzumab in patients with HER2-positive metastatic breast cancer. The study will assess the objective response rate within the first six months of treatment. Compliance monitoring will be an integral part of the trial to ensure accurate assessment of the treatment's efficacy.
Efficacy
The efficacy of the combination treatment of tucatinib, oral **etoposide** (VP16), and trastuzumab in patients with HER2 positive metastatic breast cancer will be assessed primarily through the **objective response rate (ORR)**. The ORR is defined as the best response, either complete or partial, occurring within the first six months of treatment, as evaluated by investigators using RECIST v1.1 criteria. Secondary endpoints include the assessment of serious adverse events (SAEs) and adverse events (AEs) according to NCI CTCAE v5.0, progression-free survival (PFS), overall survival (OS), duration of response (DoR), time to response (TTR), and clinical benefit rate (CBR) at 24 weeks. These parameters will be measured and analyzed at specified intervals throughout the trial duration.
Exploratory endpoints will involve pharmacokinetic assessments of oral VP16 and tucatinib, as well as baseline and progression changes in circulating tumor DNA (ctDNA) levels, mutation status, and expression levels of cancer-associated genes. Additionally, TOP2A and HER2 co-amplification will be evaluated using ShallowWGS on FFPE tumor tissue. The trial is designed to provide comprehensive data on the efficacy and safety of the treatment regimen, with a focus on both clinical outcomes and molecular markers.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Disease progression under tucatinib-capecitabine-trastuzumab /OR / Medical contra-indication to initiate or continue capecitabine in association with tucatinib-trastuzumab (investigator’s decision based on patient medical history, DPD deficiency and/or capecitabine grade 2 toxicity or higher).
- Age > 18 years,
- Histologically confirmed HER2+ breast carcinoma (ASCO/CAP guidelines) with archived tumor tissue available
- Have a life expectancy of at least 3 months
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- Participants must be able to swallow capsules
- Participants must be able and willing to be available for the duration of the study and are willing to follow study procedures
- Measurable disease, assessed by RECIST version 1
- Patients with brain metastases are eligible: o Unless urgent treatment is required o If time since WBRT is ≥ 21 days prior to first dose of treatment, time since SRS is ≥ 7 days prior to first dose of treatment, or time since surgical resection is ≥ 28 days
- Relevant records of any CNS treatment must be available to allow for classification of target and non-target lesions
- Left ventricular ejection fraction (LVEF) ≥ 50% (within 4 weeks before inclusion)
- Adequate organ function (obtained within 14 days prior to treatment start) as evidenced by: o Absolute neutrophil count (ANC) ≥ 1.5 X 10^9/L o Hemoglobin (Hgb) ≥ 9 g/dL o Platelet count ≥ 100 X 10^9/L o Bilirubin ≤ 1.5 X upper limit of normal (ULN), except for patients with a documented history of Gilbert’s disease (≤ 2 X ULN) o Alanine aminotransferase (ALT), and aspartate aminotransferase (AST) ≤ 2.5 X ULN (for patients with liver metastases ≤ 5 X ULN); o Alkaline phosphatase (AP) ≤ 3 X ULN (for patients with liver metastases, ≤ 5 X ULN);o Serum creatinine ≤ 1.5 mg/dL (133 μmol/L) or calculated creatinine clearance ≥ 50 mL/min (using Cockcroft-Gault formula)
- If the patient is female: Women of childbearing potential (WCBP): negative serum pregnancy test. The patient must be willing to use effective methods of contraception. Patients must be postmenopausal, surgically infertile, or willing to use a physical barrier method of contraception in addition to an intrauterine device or hormonal contraception until at least 6 months after completion of study treatment, If the patient is male: Male patients must agree to use an acceptable method of contraception (e.g., condom) during the study and for 3 months after completion of investigational treatment,
- Patients must be covered by a health insurance plan.
- Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
Exclusion Criteria
- Have previously been treated with: a. lapatinib within 12 months of starting study treatment (except in cases where lapatinib was given for ≤ 21 days and was discontinued for reasons other than disease progression or severe toxicity) b. neratinib, afatinib, or other investigational HER2/ EGFR or HER2 TKI at any time previously (excepted for patients already under tucatinib who continue without interruption)
- Patients who are pre-treated with tucatinib and who received a decreased dose of tucatinib (<300mg twice daily) are not eligible in the safety run-in phase
- Have used a strong CYP3A4 or CYP2C8 inhibitor within 5 half-lives of the inhibitor, or have used a strong CYP3A4 or CYP2C8 inducer within 5 days prior to first dose of study treatment
- Patients unable for any reason to undergo MRI of the brain
- Leptomeningeal metastases or brain metastases requiring immediate symptomatic treatment or a high dose of corticosteroid therapy (≥2mg/day dexamethasone or equivalent)
- Have poorly controlled (> 1/week) generalized or complex partial seizures, or manifest neurologic progression due to brain metastases notwithstanding CNS-directed therapy
- Any toxicity related to prior cancer therapies that has not resolved to ≤ Grade 1 at time of treatment start, with the following exceptions: a. Alopecia and neuropathy (must have resolved to ≤ Grade 2); b.Congestive Heart Failure (must have been ≤ Grade 1 in severity at the time of occurrence and must have resolved completely); c. Anemia (must have resolved to ≤ Grade 2)
- Patients who have had a last dose of IV chemotherapy within 21 days, last dose of oral cytotoxic chemotherapy, radiotherapy, biological therapy, or investigational therapy within 14 days prior to treatment start. This does not apply to patients already under tucatinib who continue without interruption.
- Patients who have had any major surgery within 28 days prior to inclusion
- Have evidence within 2 years of the start of study treatment of another malignancy that required systemic treatment. This does not apply to patients already under tucatinib who continue without interruption
- Concomitant use of other agents for the treatment of cancer or any investigational agent(s)
- Women who are either pregnant, lactating, planning to get pregnant
- Have a serious concomitant systemic disorder (eg, active infection or a gastrointestinal disorder causing clinically significant symptoms such as nausea, vomiting, diarrhea, or profound immune suppression) that, in the opinion of the investigator, would compromise the patient’s ability to adhere to the protocol, including but not limited to the following: (a) Have known human immunodeficiency virus (HIV) infection; (b) Active hepatitis B or C virus infection (screening required) or have other known chronic liver disease; (c) Severe renal impairment, interstitial lung disease (ILD), severe dyspnea at rest or requiring oxygen therapy, liver disease diagnosed with Child-Pugh A or higher cirrhosis or history of major surgical resection involving the stomach or small bowel, or preexisting Crohn’s disease or ulcerative colitis or a preexisting chronic condition resulting in clinically significant diarrhea
- Have clinically significant cardiopulmonary disease such as: - ventricular arrhythmia requiring therapy, - uncontrolled hypertension (defined as persistent systolic blood pressure > 150 mm Hg and/or diastolic blood pressure > 100 mm Hg on antihypertensive medications), or - any history of symptomatic CHF o severe dyspnea at rest (CTCAE Grade 3 or above) due to complications of advanced malignancy, - hypoxia requiring supplementary oxygen therapy except when oxygen therapy is needed only for obstructive sleep apnea, - presence of ≥ Grade 2 QTc prolongation on screening ECG, - conditions potentially resulting in drug-induced prolongation of the QT interval or torsade de pointes: 1. Congenital or acquired long QT syndrome, 2. Family history of sudden death, 3. History of previous drug induced QT prolongation, 4. Current use of medications with known and accepted associated risk of QT prolongation
- Have known myocardial infarction or unstable angina within 6 months prior to first dose of study treatment
- Require therapy with warfarin or other coumarin derivatives (non-coumarin anticoagulants are allowed)
- Have inability to swallow pills or significant gastrointestinal disease which would preclude the adequate oral absorption of medication
- Patients with altered mental status or psychiatric disorder that, in the opinion of the investigator, would preclude a valid patient informed consent.
- Person deprived of liberty or placed under a legal protection regime with representation of the person.
- Inability to comply with medical monitoring of the trial for geographic, social or psychological reasons
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Recruiting | 19 Dec 2023 | 66 |
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 | 600 | 52 | PRD8771172 |
TUKYSA 150 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL USE | 600 | 52 | PRD8771193 |
Herceptin 150 mg powder for concentrate for solution for infusion | Test | POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION | INFUSION | 6 | 24 | PRD2154035 |
CELLTOP 50 mg – Weichkapseln | Test | WEICHKAPSELN | ORAL | 50 | 52 | PRD1606599 |
Herceptin 600 mg solution for injection in vial | Test | SOLUTION FOR INJECTION IN VIAL | SUBCUTANEOUS INJECTION | 600 | 52 | PRD2154036 |