Treatment for breast cancer patients with meninges invaded by tumor cells

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Unicancer

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

22 Feb 2024 → ongoing

Decision date (initial)

2023-09-21

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Seattle Genetics

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy, Pharmacokinetic, Pharmacogenomic

To evaluate the efficacy of tucatinib and capecitabine in combination with intra-cerebrospinal fluid (CSF) trastuzumab on overall survival rate at 12 months in HER2-positive metastatic breast cancer
(MBC) patients with proven leptomeningeal evolution.

Secondary objectives 11

1. Efficay_To evaluate clinical neurological symptoms relief and the duration of clinical response
2. Efficacy_To evaluate progression-free survival (PFS), BM-PFS and LM-PFS
3. Efficacy_To evaluate overall survival (OS)
4. Efficacy_To assess the quality of life
5. Efficacy_CSF response at 4 weeks
6. Efficacy_Duration of leptomeningeal metastases (LM) response
7. Safety_To evaluate the safety and toxicity profile of tucatinib, capecitabine and intra-CSF trastuzumab
8. Safety_Cognitive toxicity
9. Ancillary studies_Pharmacokinetic studies
10. Ancillary studies_Pharmacogenomic studies
11. Ancillary studies_Circulating biomarkers for ctDNA monitoring (HER2 amplification) and Circulating Tumor Cells (CTC) analysis in CSF and blood

Conditions and MedDRA coding

Patients having a HER2-amplified metastatic breast cancer with evolutive leptomeningeal metastases (LM) requiring intrathecal therapy

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 19

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 at a 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. Evaluable disease according to RANO-LM and RECIST v1.1 (if applicable);
7. Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0-2;
8. Life expectancy ≥2 months;
9. Stable dose of steroids for at least 5 days prior to inclusion;
10. 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;
11. 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;
12. 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);
13. Normal renal function within 14 days before inclusion: estimated creatinine clearance ≥60 mL/min according to the Cockcroft-Gault formula
14. 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
15. 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);
16. Women of childbearing potential must have a negative pregnancy test (blood or urine test) within 14 days prior to inclusion;
17. 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;
18. Patients affiliated to the social security system (or equivalent);
19. 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 20

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

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Efficacy of combination will be evaluated in terms of overall survival rate 12 months (12m-OS) after treatment by tucatinib, capecitabine, and intra-CSF trastuzumab. 12m-OS will be defined as the proportion of patients alive 12 months after treatment initiation.

Secondary endpoints 11

1. Efficay_Clinical neurological symptoms relief will be defined as complete or partial regression of symptoms associated to LM using NANO scale.
2. Efficacy_Progression-free survivals (PFS, PFS-brain metastases [BM] and PFS-LM) will be defined as the time from treatment initiation (C1D1) to the date of the first documented progression (RECIST v1.1 or RANO-LM for LM and BM) or death due to any cause. Patients who have not progressed at the time of analysis will be censored at the time of their last evaluable assessment._
3. Efficacy_Overall Survival (OS) will be defined as the time between treatment initiation (C1D1) and death from any cause.
4. Efficay_Quality of life will be assessed using the QLQ-C30 and BN20 questionnaires.
5. Efficacy_CSF response at 4 weeks will be defined by absence of tumor cells in CSF evaluated by the cytologist on minimal 10mL of CSF, fixed within 1h after sampling.
6. Efficacy_Duration of LM response will be defined in responding patients as the delay between first intracranial objective response and progression, using PFS-LM definition.
7. Safety_Tolerance will be assessed using the NCI-CTCAE v5.0 grading scale.
8. Safety_Cognitive troubles will be evaluated using the MOCA (Le Montreal Cognitive Assessment)
9. Ancillary studies_Venous blood samples and cerebrospinal fluid (CSF) (approximately 5 mL) will be collected before intra-CSF traztuzumab injection, from week 2 to week 10, and at week 18 to determine the concentrations of experimental treatment. Concentration will be determine using high performance liquid chromatography (HPLC).
10. Ancillary studies_Genomic alteration will be assessed using tumors cells from collected CSF sample. DNA will be extracted from cell to perform array-based comparative genomic hybridization (CGH) and next-generation sequencing (NGS; homemade Illumina pipeline).
11. Ancillary studies_Droplet digital PCR and CellSearch® will be performed on CSF sample and blood samples for the analysis of HER2 amplification and Circulating Tumor Cells (CTC)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 5

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Unicancer

Sponsor organisation

Unicancer

Address

101 Rue De Tolbiac

City

Paris Cedex 13

Postcode

75654

Country

France

Scientific contact point

Organisation

Unicancer

Contact name

Telma ROQUE

Public contact point

Organisation

Unicancer

Contact name

Telma ROQUE

Locations

1 EU/EEA country · 13 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 17 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications