| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Treatment in patients with advanced, HER2-positive breast cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| HER2 Positive Breast Cancer. |
|
| 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 | 14.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10065430 |
| E.1.2 | Term | HER-2 positive breast cancer |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10027475 |
| E.1.2 | Term | Metastatic breast cancer |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 |
| Feasibility Part: To evaluate the safety and tolerability profile of the combination docetaxel with T-DM1in patients with HER2+, inoperable, locally advanced or mBC. To evaluate the safety and tolerability of the combination of docetaxel and T-DM1 in patients with newly diagnosed HER2+ LABC and thereafter the safety and tolerability of the addition of pertuzumab to the combination trastuzumab emtansine with docetaxel. The dose of trastuzumab emtansine and docetaxel found to be feasible in MBC feasibility will be the starting dose for the LABC feasibility. Extension Part: In 2nd and 1st line MBC patients: To validate the safety and efficacy of the recommended T-DM1 dose in combination with docetaxel q3w as determined in the MBC feasibility part. In newly diagnosed LABC patients: To validate the safety and efficacy of the recommended TDM1 dose in combination with docetaxel and in combination with docetaxel and pertuzumab q3w, as determined in the LABC Feasibility Part of the study. |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate the:
• Toxicity profile of study drugs
• Progression Free Survival (PFS).
• Overall Response Rate (ORR).
• Clinical Benefit Rate (CR, PR or SD for at least 6 months).
• Duration of Response (DR).
• Time to treatment failure (TTF).
• Pharmacokinetic (PK) characteristics of T-DM1 when combined with docetaxel. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Signed written informed consent.
2. Age ≥ 18 years.
3. ECOG PS of 0 or 1.
4. Life expectancy of ≥ 12 weeks.
5. Histologically or cytologically confirmed breast cancer, which is documented to be metastatic or inoperable, locally advanced without meeting the LABC criteria, and amenable for treatment with docetaxel.
6. Evaluable (Feasibility Part only) or measurable (Extension Part) disease (as defined by RECIST 1.0).
7. HER2-positive disease locally confirmed by HER2 protein over expression.
8. History of progression within 3 months prior to study entry.
for LABC Patients
9. Histologically or cytologically confirmed newly diagnosed locally advanced breast cancer defined as stage IIIa to stage IIIC disease according to the American Joint Committee on Cancer (AJCC) staging system [62]:
• T2 to T4d tumor
• Any N
• M0
10. HER2-positive breast cancer as defined by IHC 3+ and/or FISH positive, prospectively confirmed by a Sponsor designated central laboratory prior to enrollment
11. Locally advanced breast cancer amenable for treatment with neoadjuvant docetaxel based chemotherapy
12. Patient agreement to undergo mastectomy or lumpectomy after neoadjuvant treatment
Amenable to investigational therapy with the combination of T-DM1 and docetaxel prior to the initiation of standard of care. |
|
| E.4 | Principal exclusion criteria |
1. Pregnant or lactating females.
2. Women of childbearing potential unless surgically sterile or using adequate measures of contraception (intra-uterine device or barrier method of contraception in conjunction with spermicidal jelly).
3. Patients must not have received radiotherapy for the treatment of metastatic or locally recurrent/advanced disease other than for the relief of the pain in progressing metastatic bone lesions (limited to < 30% of marrow bearing bone) and/or brain metastasis. Patients must have recovered from their radiotherapy-related toxicities.
4. Significant cardiac disease including but not confined to:
- Inadequate left ventricular ejection function (LVEF) at baseline, as defined as LVEF ≤50% by either echocardiogram or MUGA.
- New York Health Association (NYHA) Class ≥I congestive heart failure.
- Current unstable angina or serious cardiac arrhythmia despite adequate medication.
- Myocardial infarction or clinically significant valvular heart disease within the last 6 months prior to enrollment in the study.
- History of exposure to high doses of anthracyclines.
5. Patients with a history of uncontrolled seizures, central nervous system disorders or psychiatric disability, which could affect ability to give informed consent, or compliance with study drugs.
6. Brain metastases that are untreated, symptomatic or require therapy to control symptoms; or any radiation, surgery, or other therapy to control symptoms from brain metastasis within 2 months of the first study treatment. CT or MRI scan of the brain is mandatory within 28 days of first treatment.
7. Treatment with any investigational drug within 30 days prior to commencing treatment with study drug.
8. Inadequate organ function of the a) Liver b) Kidney c) Bone marrow d) Peripheral nervous system:Peripheral neuropathy of ≥Grade 2 per NCI CTC for AE Version 3.0.
9. Patients with serious, uncontrolled, intercurrent illness including infections (bacterial or viral) and poorly controlled diabetes mellitus.
10. Patients with severe dyspnoea at rest due to complications of advanced malignancy or requiring supplementary oxygen.
11. Incomplete wound healing following major surgical procedure, open biopsy or significant traumatic injury or anticipation of the need for major surgery during the course of the study treatment.
10. Evidence of any other disease, metabolic or psychological dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug, or that may affect patient compliance with study routines, or places the patient at high risk from treatment related complications.
11. Known hypersensitivity to any of the study drugs, trastuzumab, murine proteins or excipients.
12. Inability to comply with the protocol.
13. Patients unable or unwilling to participate in the study.
for MBC Patients:
14. Patients must not have received radiotherapy for the treatment of metastatic or locally recurrent/advanced disease other than for the relief of the pain in progressing
metastatic bone lesions (limited to < 30% of marrowbearing bone) and/or brain metastasis. Patients must have recovered from their radiotherapy-related toxicities.
15. Brain metastases that are untreated, symptomatic or require therapy to control symptoms; or any radiation, surgery, or other therapy to control symptoms from brain metastasis within 2 months of the first study treatment. CT or MRI scan of the brain is mandatory within 28 of first treatment.
for LABC Patients:
16. Clinically or radiologically detectable metastasis (M1 disease).
17. Patient for whom surgery as primary intent procedure is the best option to treat their disease.
18. Patients must not have received any systemic or loco regional anti cancer therapy for the treatment of locally advanced disease. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. safety and tolerability of increased docetaxel in combination with T-DM1, assessed by adverse events or dose limiting toxicity\n
2. safety and tolerability, dose limiting toxicity |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. every 3 weeks throughout treatment phase
2. every 3 weeks throughout the study and in follow-up phase at day 28, months 3 and 3monthly thereafter
|
|
| E.5.2 | Secondary end point(s) |
1. Progression Free Survival (PFS)
2. response rate and clinical benefit rate according to tumor assessment
3. toxicity profile |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. after cycles 2,4,6 and 8, and 12weekly thereafter
2. after cycles 2,4,6 and 8, and 12weekly thereafter throughout treatment phase
3. throughout the combination treatment period of the study, every 3 weeks
|
|
| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| 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) | Yes |
| 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 | No |
| 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 8 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| France |
| Spain |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| 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
|
The end of the study is defined as the date of the last visit of the last patient participating in this trial. The last visit is defined as the safety follow up visit for the last MBC patient if not participating in the global extension study (TDM4529g/BO25430) or the safety
follow up visit for the last LABC patient, whatever comes last. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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