| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| HER2-positive metastatic breast cancer with isolated brain progression (defined as new or progressive brain metastases with stable or responding systemic disease) after complete local treatment. |
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| E.1.1.1 | Medical condition in easily understood language |
| HER2-positive metastatic breast cancer with isolated brain progression after complete local treatment. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 23.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10065430 |
| E.1.2 | Term | HER2 positive breast cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10055113 |
| E.1.2 | Term | Breast cancer metastatic |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10006128 |
| E.1.2 | Term | Brain metastases |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| 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. |
|
| E.2.2 | Secondary objectives of the trial |
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
Safety:
• To evaluate the safety of the association of pertuzumab, trastuzumab, and tucatinib
Ancillary studies:
• To identify predictive biomarkers
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
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
• QTc interval ≤480 msec (mean of replicate values, correction per institutional standard)
• Left ventricular ejection fraction (LVEF) ≥50%
• No history of Torsades de Pointes or other symptomatic QTc abnormality
11. Stable dose of steroids at the time of enrolment;
12. Women of childbearing potential must have a negative pregnancy test (blood or urine test) within 14 days prior to inclusion;
13. 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 (association of trastuzumab, pertuzumab +/- tucatinib). Hormonal contraceptives such as birth control pills, patches, implants, or injections are not allowed in patients who are hormone receptor positive;
14. 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;
15. Patients affiliated to the social security system (or equivalent);
16. 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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|
| E.4 | Principal exclusion criteria |
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.
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| 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. Progression will be determined locally by the investigator through the use of RECIST v1.1 in case of lesions identified at baseline. For patients without any evidence of disease at inclusion, the progression will be defined as an appearance of a new lesion (measurable or not measurable). |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
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.
• 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. Patients who have not progressed at the time of analysis will be censored at the time of the latest date of assessment by imaging.
• 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. Brain metastases response will be evaluated according to RECIST v1.1, as determined by investigator assessment.
Safety:
• Adverse Events will be graded according to National Cancer Institute-common terminology criteria for adverse events (NCI-CTCAE) v5.0.
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.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 31 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 42 |
| E.8.9.1 | In the Member State concerned days | |
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