Multi-drug treatment for breast cancer patients with brain metastases

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

13 Dec 2021 → ongoing

Decision date (initial)

2024-03-19

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Seagen

External identifiers

EU CT number

2024-510703-11-00

EudraCT number

2020-005735-79

ClinicalTrials.gov

NCT05041842

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

To evaluate the efficacy, in terms of progression-free survival rate (RECIST v1.1), of tucatinib in combination with pertuzumab and trastuzumab in patients with isolated brain progression

Secondary objectives 3

1. Efficacy - to evaluate the efficacy of tucatinib in terms of : Overall survival; Brain progression-free survival according to Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1); Brain metastasis response in patient not in complete remission at the brain level after local treatment.
2. Safety : to evaluate the safety of the association of pertuzumab, trastuzumab and tucatinib
3. Ancillary studies : to identify predictive biomarkers

Conditions and MedDRA coding

HER2+ metastatic breast cancer with isolated brain progression

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 17

1. Male or female, Age ≥18
2. Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0-1
3. Histologically confirmed HER2 positive breast cancer, with HER2 positive defined by in situ hybridization (ISH), immunohistochemistry (IHC), or fluorescence in situ hybridization (FISH) methodology
4. Documented isolated brain progression (defined as new or progressive brain metastases with stable or responding systemic disease) under pertuzumab and trastuzumab treatment (with or without taxane) for metastatic disease (There is no limit to the number and size of brain metastasis)
5. Complete local treatment of brain progression (Surgery and/or radiation therapy) should have been completed no more than 12 weeks before inclusion and there is no clinical indication for immediate re-treatment with local therapy in the opinion of the investigator
6. Able to undergo MRI scanning of the brain
7. Normal renal function: creatinine <1.5 x upper limit of normal (ULN)
8. Adequate liver function: total bilirubin ≤1.5 ULN (unless documented Gilbert’s syndrome); AST and ALT ≤2.5 ULN (≤5 ULN in the presence of liver metastases)
9. Normal hematological function: ANC ≥1.5 x 109/L; platelets count ≥100 x 109/L; and hemoglobin ≥9.0 g/dL
10. Adequate cardiac functions, including: 12 Lead electrocardiograms (ECG) with normal tracing or non-clinically significant changes that do not require medical intervention; QT/QTcF 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) ≥50%; No history of Torsades de Pointes or other symptomatic QTc abnormality
11. Resolution of all acute toxic effects of prior anti-cancer therapy or surgical procedures to NCI CTCAE version 5.0 Grade 1 or to baseline (except alopecia or other toxicities not considered a safety risk for the patient at investigator’s discretion)
12. Stable dose of steroids at the time of enrolment
13. Women of childbearing potential must have a negative pregnancy test (blood or urine test) within 14 days prior to inclusion
14. 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
15. 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
16. Patients affiliated to the social security system (or equivalent)
17. 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 15

1. Radiologic extra-cranial progression under pertuzumab and trastuzumab treatment, at the time of enrolment. The systemic disease must be stable or responding at the time of enrolment
2. Proven leptomeningeal disease
3. Any progressive brain lesion between the brain local treatment completion and the enrolment
4. Poorly controlled seizures (more than 1/week)
5. Clinically significant cardiopulmonary disease
6. 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
7. Previous treatment with a tyrosine kinase inhibitor
8. Carriers of Hepatitis B or Hepatitis C or have other known chronic liver disease
9. Positive for human immunodeficiency virus (HIV)
10. Known prior severe hypersensitivity to tucatinib or compounds chemically or/and biologically similar or any component in its formulation
11. History of any other cancer (except non-melanoma skin cancer or carcinoma in-situ of the cervix) unless the patient has been in remission and off all other cancer therapy for at least 3 years
12. Pregnant women or women who are breast-feeding
13. Inability to swallow tablets or significant gastrointestinal disease which would preclude the adequate oral absorption of medications
14. Person deprived of their liberty or under protective custody or guardianship or unable to give informed consent
15. Participation in another therapeutic trial within the 30 days prior to tucatinib treatment initiation

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 6-month Progression-Free Survival (PFS) rate, defined as the proportion of patients with an objective tumor progression by imaging, or death from any cause, whichever occurs first at 6 months from inclusion.

Secondary endpoints 5

1. Efficacy : Overall Survival (OS) defined as the time interval between the date of inclusion in the study and the date of death (all causes). Patients not known to have died at the time of analysis will be censored at the last recorded date on which the patient was known to be alive.
2. Efficacy : Brain Progression-Free Survival (BPFS) defined as the time interval between the date of inclusion in the study and the date of documented progression of the brain metastases. Tumor progression will be evaluated according to RECIST v1.1, as determined by investigator assessment, or as the appearance of a lesion for patients in complete response (CR) at the brain level at the inclusion.
3. Efficacy : In patients who are not in CR at the brain level after local treatment: Overall brain metastasis response defined as the best overall response of the brain metastases during the study.
4. Safety : Adverse Events will be graded according to National Cancer Institute-common terminology criteria for adverse events (NCI-CTCAE) v5.0.
5. Ancillary studies : Biomarkers research will be defined by the study steering committee at the end of the trial to ensure the optimal use of update technologies and hypotheses.

Investigational products

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

Test 8

Auxiliary 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Unicancer

Sponsor organisation

Unicancer

Address

101 Rue De Tolbiac

City

Paris

Postcode

75013

Country

France

Scientific contact point

Organisation

Unicancer

Contact name

Nourredine AIT RAHMOUNE

Public contact point

Organisation

Unicancer

Contact name

Nourredine AIT RAHMOUNE

Locations

1 EU/EEA country · 16 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 15 files

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

Application history

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