Clinical trial NCT05800275: Capecitabine, Tucatinib, and Intrathecal Trastuzumab for Breast Cancer Patients with Leptomeningeal Disease
Official title: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Leptomeningeal Metastasis
Leptomeningeal Disease
HER2-positive Metastatic Breast Cancer
Keywords: Intrathecal injection
Leptomeningeal Disease
Breast Cancer Metastatic
Leptomeningeal Metastasis
Intrathecal trastuzumab
Capecitabine
Tucatinib
HER2-positive Metastatic Breast Cancer
Lead sponsor: UNICANCER
Sponsor class: OTHER
Collaborators: name: Seagen Inc.
First posted: 2023-04-05
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The goal of this clinical trial is to evaluate the efficacy of tucatinib and capecitabine in combination with intrathecal trastuzumab on overall survival rate at 12 months in HER2-positive metastatic breast cancer (MBC) patients with proven leptomeningeal evolution and requiring intrathecal therapy.


Eligibility criteria: Inclusion Criteria:

1. 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;
2. Patients ≥18 years old;
3. Histologically confirmed metastatic breast cancer;
4. 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 metastatic site; any estrogen and progesterone (ER/PR) status is allowed;
5. 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 );
6. Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0-2;
7. Life expectancy ≥2 months;
8. Stable dose of steroids for at least 5 days prior to registration;
9. If symptomatic brain or leptomeningeal metastasis, local treatment (surgery, radiation therapy) is allowed until 2 weeks before inclusion but should have been completed no more than 8 weeks before inclusion and with no clinical indication for immediate re-treatment with local therapy in the opinion of the investigator;
10. Adequate hematological function within 14 days before inclusion: Absolute neutrophil count (ANC) ≥1.5 x 10⁹/L; platelets count ≥100 x 10⁹/L; and hemoglobin ≥9.0 g/dL;
11. 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);
12. Normal renal function within 14 days before inclusion: estimated creatinine clearance ≥60 mL/min according to the Cockcroft-Gault formula;
13. 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
14. Resolution of all acute toxic effects of prior anti-cancer therapy or surgical procedures to National cancer institute-Common terminology criteria for adverse events (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);
15. Women of childbearing potential must have a negative pregnancy test (blood or urine test) within 14 days prior to inclusion;
16. 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;
17. Patients affiliated to the social security system (or equivalent);
18. 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:

1. 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;
2. Previous treatment with Tucatinib or Capecitabine;
3. Severe leukopenia, neutropenia, or thrombocytopena, severe hepatic impairment, severe renal impairment (creatinine clearance below 30mL/min)
4. Recent or concomitant treatment with brivudine ;
5. Any antiplatelet or curative anticoagulant treatment for blood coagulation disorders;
6. Severe pre-existing cerebrovascular dysfunction or pathology such as stroke and intra-cerebral hematoma or uncontrolled intracerebral hypertension induced by brain metastasis;
7. 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;
8. Known history of testing positive for HIV or known acquired immunodeficiency syndrome;
9. Carriers of Hepatitis B or Hepatitis C or have other known chronic liver disease;
10. Uncontrolled hypertension;
11. Uncontrolled infection;
12. Severe dyspnea at rest due to complications of advanced malignancy or requiring supplementary oxygen therapy;
13. Pregnant or breast-feeding women;
14. Known prior severe hypersensitivity to tucatinib or compounds chemically or/and biologically similar or any component in its formulation;
15. Hypersensitivity to trastuzumab, murine proteins, or to any of the excipients in its formulation;
16. Known prior severe hypersensitivity to capecitabine or to any of the excipients or fluorouracil;
17. Known complete dihydropyrimidine dehydrogenase (DPD) deficiency (if applicable);
18. Inability to swallow tablets or significant gastrointestinal disease which would preclude the adequate oral absorption of medications;
19. 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;
20. Person deprived of their liberty or under protective custody or guardianship;
21. Participation in another therapeutic trial within the 30 days prior to treatment initiation;
22. 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.

Primary outcomes:
measure: overall survival rate at 12 months
timeFrame: 12 months
Secondary outcomes:
measure: Clinical neurological symptoms relief
timeFrame: At baseline, every week during treatment up to 18 months then every 9 weeks up to 42 months
measure: Progression free survival (PFS)
timeFrame: From inclusion to disease progression or death, up to 42 months
measure: Overall survival (OS)
timeFrame: From inclusion to death from any cause; up to 42 months
measure: Quality of life questionnaire - Core 30 (QLQ-C30)
timeFrame: At baseline, every 3 weeks during treatment up to 18 months then every 9 weeks up to 42 months
measure: Quality of Life Questionnaire - Brain Cancer Module (QLQ-BN20)
timeFrame: At baseline, every 3 weeks during treatment up to 18 months then every 9 weeks up to 42 months
measure: Intra-cerebrospinal fluid response at 4 weeks
timeFrame: 4 weeks
measure: Duration of leptomeningeal metastases (LM) response
timeFrame: From inclusion to disease LM progression or death, up to 42 months
measure: Montreal Cognitive Assessment (MoCA)
timeFrame: At baseline, every 3 weeks during treatment up to 18 months then every 9 weeks up to 42 months
measure: Toxicity during the study
timeFrame: Throughout study completion, up to 42 months
Other outcomes:
Locations:
city: Bordeaux
country: France
facility: Institut Bergonié
city: Caen
country: France
facility: Centre François Baclesse
city: Clermont-Ferrand
country: France
facility: Centre Jean Perrin
city: Dijon
country: France
facility: Centre Georges-François Leclerc
city: Lyon
country: France
facility: Centre Léon Bérard
city: Montpellier
country: France
facility: Institut régional du Cancer de Montpellier
city: Nice
country: France
facility: Centre Antoine Lacassagne
city: Reims
country: France
facility: Institut Jean Godinot
city: Rouen
country: France
facility: Centre Henri Becquerel
city: Strasbourg
country: France
facility: Institut de cancérologie Strasbourg Europe - ICANS
city: Villejuif
country: France
facility: Gustave Roussy
Study officials:
affiliation: Centre Léon Bérard - LYON
name: Louis LARROUQUERE
role: PRINCIPAL_INVESTIGATOR
References: