ETIC-LM_Multicentric single arm phase II study evaluating the Efficacy of association of Tucatinib, capecitabine and Intra-CSF trastuzumab in HER2 amplified breast cancer patients with Leptomeningeal Metastases.

Trial ID: 2022-502351-60-00
Sponsor: Unicancer

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Diseases & Conditions

Breast cancer

Objectives

The primary objective of this study is to evaluate the **efficacy** of a combination therapy involving tucatinib, capecitabine, and intra-cerebrospinal fluid (CSF) trastuzumab on the overall survival rate at 12 months in patients with HER2-positive metastatic breast cancer (MBC) exhibiting leptomeningeal metastases. This is clinically relevant as leptomeningeal metastases represent a severe complication in breast cancer, often associated with poor prognosis and limited treatment options. The study aims to determine if this combination therapy can improve survival outcomes in this patient population.

Secondary objectives include:

Evaluating clinical neurological symptoms relief and the duration of clinical response.
Assessing progression-free survival (PFS), brain metastases progression-free survival (BM-PFS), and leptomeningeal metastases progression-free survival (LM-PFS).
Evaluating overall survival (OS).
Assessing the quality of life.
Determining CSF response at 4 weeks.
Evaluating the duration of leptomeningeal metastases response.
Evaluating the safety and toxicity profile of tucatinib, capecitabine, and intra-CSF trastuzumab.
Assessing cognitive toxicity.
Conducting pharmacokinetic and pharmacogenomic studies.
Analyzing circulating biomarkers for ctDNA monitoring (HER2 amplification) and circulating tumor cells (CTC) analysis in CSF and blood.

Participants

The clinical trial involves participants diagnosed with **HER2-amplified metastatic breast cancer** exhibiting evolutive leptomeningeal metastases requiring intrathecal therapy. The study population includes both male and female subjects aged 18 years and older. Participants are required to have a histologically confirmed diagnosis of HER2-positive breast cancer, with HER2 positivity determined through in situ hybridization, immunohistochemistry, or fluorescence in situ hybridization. The trial does not specifically target a vulnerable population. Participants must have an Eastern Cooperative Oncology Group Performance Status of 0-2 and a life expectancy of at least two months. They should also have adequate hematological, liver, renal, and cardiac function, as well as a stable dose of steroids for at least five days prior to inclusion. The sponsor has not provided information regarding the total number of participants in the trial. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data.

Plans and Procedures

The clinical trial is designed as a **single-arm, phase II study** to evaluate the efficacy of a combination therapy involving **tucatinib**, **capecitabine**, and intra-cerebrospinal fluid (CSF) **trastuzumab** in patients with HER2-amplified metastatic breast cancer with leptomeningeal metastases. The primary objective is to assess the overall survival rate at 12 months post-treatment initiation. The trial is expected to commence on September 15, 2023, and conclude by March 15, 2027, with the estimated duration of participant involvement being up to 12 months.

Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on specific inclusion criteria, such as adequate hematological, liver, and cardiac function, and a confirmed diagnosis of HER2-positive breast cancer with leptomeningeal progression. Following successful screening, participants will enter the treatment phase, receiving the investigational combination therapy. Regular follow-up visits will be scheduled to monitor treatment efficacy and safety, assess neurological symptoms, and evaluate quality of life using standardized questionnaires. The end-of-study visit will occur at the conclusion of the treatment period or upon early termination.

Early termination from the study may occur if participants experience unacceptable toxicity, disease progression, or withdrawal of consent. Additionally, participants must adhere to protocol requirements, including scheduled visits and laboratory tests, to remain in the study. The trial will employ rigorous monitoring to ensure participant safety and data integrity, with ancillary studies conducted to explore treatment concentrations and genomic alterations in tumor cells. The study's findings will contribute to understanding the therapeutic potential of this combination regimen in a challenging patient population.

Treatment

The clinical trial involves the administration of **Tucatinib**, marketed as TUKYSA, in two different dosages: 50 mg and 150 mg film-coated tablets. Tucatinib is a chemical compound provided by SEAGEN B.V. The pharmaceutical form is a film-coated tablet, and the route of administration is oral. The maximum daily dose is 300 mg, with a total dose not exceeding 300 mg per day. The treatment period is limited to one day. Compliance with the dosing schedule is monitored to ensure adherence to the protocol.

**Trastuzumab**, marketed as Herceptin, is used in the form of a 150 mg powder for concentrate for solution for infusion. This protein-based medication is provided by ROCHE REGISTRATION GMBH. The pharmaceutical form is a solution for infusion, and the route of administration is intrathecal. The maximum daily dose is 150 mg, with a total dose not exceeding 150 mg per day. The treatment period is limited to one day. Participant compliance is monitored to ensure proper administration.

**Capecitabine**, marketed as Xeloda, is administered in two dosages: 150 mg and 500 mg film-coated tablets. This chemical compound is provided by CHEPLAPHARM ARZNEIMITTEL GMBH. The pharmaceutical form is a film-coated tablet, and the route of administration is oral. The maximum daily dose is 2000 mg/m², with a total dose not exceeding 32.2 g. The treatment period is limited to two days. Compliance with the dosing schedule is monitored to ensure adherence to the protocol.

Throughout the trial, participant compliance with the dosing schedules is closely monitored to ensure adherence to the protocol. The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatment. The focus is on evaluating the efficacy of the combination of tucatinib, capecitabine, and intra-cerebrospinal fluid trastuzumab in patients with HER2-positive metastatic breast cancer with leptomeningeal metastases.

Efficacy

The efficacy of the treatment regimen in this clinical trial will be assessed primarily through the **overall survival rate** at 12 months (12m-OS) following treatment initiation with tucatinib, capecitabine, and intra-cerebrospinal fluid (CSF) trastuzumab in patients with HER2-positive metastatic breast cancer and leptomeningeal metastases. The 12m-OS is defined as the proportion of patients who are alive 12 months after the start of treatment.

Secondary efficacy endpoints include the relief of clinical neurological symptoms, which will be measured using the NANO scale to determine complete or partial regression of symptoms associated with leptomeningeal metastases. Progression-free survival (PFS) will be evaluated, including PFS for brain metastases and leptomeningeal metastases, defined as the time from treatment initiation to the first documented progression or death. Overall survival (OS) will also be assessed as the time from treatment initiation to death from any cause. Quality of life will be evaluated using the QLQ-C30 and BN20 questionnaires.

Additional efficacy assessments involve the CSF response at 4 weeks, defined by the absence of tumor cells in CSF, and the duration of leptomeningeal response, measured from the first intracranial objective response to progression. Ancillary studies will include the collection of venous blood and CSF samples to determine treatment concentrations using high-performance liquid chromatography (HPLC), genomic alterations using array-based comparative genomic hybridization (CGH) and next-generation sequencing (NGS), and analysis of HER2 amplification and circulating tumor cells (CTC) using droplet digital PCR and CellSearch®.

Inclusion and Exclusion Criteria

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Inclusion Criteria

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 ≥18 years old;
Histologically confirmed metastatic breast cancer
Histologically confirmed HER2 positive breast cancer, with HER2 positive defined by in situ hybridization (ISH), immunohistochemistry (IHC), or fluorescence in situ hybridization (FISH) methodology; Note: HER2 testing should be performed preferably at a metastatic site; any estrogen and progesterone (ER/PR) status is allowed
Proven leptomeningeal progression defined by linear leptomeningeal metastases on magnetic resonance imaging (MRI) or the presence of breast cancer cells in CSF (obtained within 28 days before inclusion);
Evaluable disease according to RANO-LM and RECIST v1.1 (if applicable);
Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0-2;
Life expectancy ≥2 months;
Stable dose of steroids for at least 5 days prior to inclusion;
If symptomatic brain or leptomeningeal metastasis, local treatment (surgery, radiation therapy) is allowed until 2 weeks before inclusion and with no clinical indication for immediate re-treatment with local therapy in the opinion of the investigator;
Adequate hematological function within 14 days before inclusion: ANC ≥1.5 x 109/L; platelets count ≥100 x 109/L; and hemoglobin ≥9.0 g/dL;
Adequate liver function within 14 days before inclusion: 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 renal function within 14 days before inclusion: estimated creatinine clearance ≥60 mL/min according to the Cockcroft-Gault formula
Adequate cardiac function:  12-lead electrocardiograms (ECG) with normal tracing or non-clinically significant changes that do not require medical intervention  QT/QTc 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) ≥55%  No history of Torsades de Pointes or other symptomatic QTc abnormality
Resolution of all toxic effects of prior anti-cancer therapy or surgical procedures to NCI CTCAE version 5.0 grade 1 or 0 to baseline (except alopecia or other toxicities not considered a safety risk for the patient at investigator’s discretion);
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;
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.

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Exclusion Criteria

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 Tucatinib or Capecitabine;
Any antiplatelet or curative anticoagulant treatment for blood coagulation disorders;
Severe pre-existing cerebrovascular dysfunction or pathology such as stroke and intracerebral hematoma or uncontrolled intracerebral hypertension induced by brain metastasis;
Ventriculoperitoneal or atrial shunt, except if the valve is equipped with an on-off device and that the patient's condition allows for to remain in the off position for 6 hours after each injection of trastuzumab;
Known history of testing positive for HIV or known acquired immunodeficiency syndrome.
Carriers of Hepatitis B or Hepatitis C or have other known chronic liver disease;
Uncontrolled hypertension;
Uncontrolled infection;
Severe dyspnea at rest due to complications of advanced malignancy or requiring supplementary oxygen therapy.
Pregnant or breast-feeding women;
Known prior severe hypersensitivity to tucatinib or compounds chemically or/and biologically similar or any component in its formulation;
Hypersensitivity to trastuzumab, murine proteins, or to any of the excipients in its formulation;
Known prior severe hypersensitivity to capecitabine or to any of the excipients or fluorouracil.
Known complete dihydropyrimidine dehydrogenase (DPD) deficiency (if applicable)
Inability to swallow tablets or significant gastrointestinal disease which would preclude the adequate oral absorption of medications;
Prior history of other malignancies other than study disease (except for basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix) unless the patient has been free of the disease for at least 5 years;
Person deprived of their liberty or under protective custody or guardianship;
Participation in another therapeutic trial within the 30 days prior to treatment initiation.
Patients with any other disease or illness, which requires hospitalization or is incompatible with the trial treatment, are not eligible. Patients unwilling or unable to comply with trial obligations for geographic, social, or physical reasons, or who are unable to understand the purpose and procedures of the trial.

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
France	Recruiting	15 Sept 2023	30

Sites & Investigators

Research sites

Centre Regional Lutte Contre Le Cancer Centre Francois Baclesse Centre Hospitalier Universitaire Amiens Picardie Centre Leon Berard

Investigators

Isabelle D.Jean-Christophe T.Aurelie M.George E.

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 150 mg film-coated tablets	Test	FILM-COATED TABLETS	ORAL USE	300	1	PRD8771193
TUKYSA 50 mg film-coated tablets	Test	FILM-COATED TABLETS	ORAL USE	300	1	PRD8771172
Xeloda 500 mg film-coated tablets	Test	FILM-COATED TABLETS	ORAL USE	2000	2	PRD9863934
Xeloda 150 mg film-coated tablets	Test	FILM-COATED TABLETS	ORAL USE	2000	2	PRD9863933
Herceptin 150 mg powder for concentrate for solution for infusion	Test	POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION	INTRATHECAL	150	1	PRD2154035