A randomized, 3 arm, multicentre, phase III study to evaluate the efficacy and the safety of T-DM1 combined with pertuzumab or T-DM1 combined with pertuzumab-placebo (blinded for pertuzumab), versus the combination of trastuzumab plus taxane, as first line treatment in HER2- positive progressive or recurrent locally advanced or metastatic breast cancer (MBC).

• Register: EUCTR
• Last refreshed on: 12 December 2016
• Main ID: EUCTR2009-017905-13-GR
• Date of registration: 18/01/2011
• Prospective Registration: No
• Primary sponsor: F. Hoffmann-La Roche Ltd
• Public title: A randomized, 3 arm, multicentre, phase III study to evaluate the efficacy and the safety of T-DM1 combined with pertuzumab or T-DM1 combined with pertuzumab-placebo (blinded for pertuzumab), versus the combination of trastuzumab plus taxane, as first line treatment in HER2- positive progressive or recurrent locally advanced or metastatic breast cancer (MBC).
• Scientific title: A randomized, 3 arm, multicentre, phase III study to evaluate the efficacy and the safety of T-DM1 combined with pertuzumab or T-DM1 combined with pertuzumab-placebo (blinded for pertuzumab), versus the combination of trastuzumab plus taxane, as first line treatment in HER2- positive progressive or recurrent locally advanced or metastatic breast cancer (MBC).
• Date of first enrolment: 17/12/2010
• Target sample size: 1092
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2009-017905-13
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: yes Placebo: yes Other: no
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Austria, Belgium, Czech Republic, Denmark, France, Germany, Greece, Hungary, Italy, Portugal, Spain, Sweden, United Kingdom

Key inclusion & exclusion criteria

Inclusion criteria:
a) Disease specific inclusion criteria:
1. HER2-positive breast cancer as defined by IHC 3+ and /or ISH positive, prospectively confirmed by a Sponsor designated central laboratory prior to enrollment. Archival tumor samples obtained from primary or metastatic sites are acceptable.
2. Histologically or cytologically confirmed adenocarcinoma of the breast with locally recurrent or metastatic disease, and be a candidate for chemotherapy. Patients with locally advanced disease must have recurrent or progressive disease, which must not be amenable to resection with curative intent. Patients with standard curative options available to them will be excluded from the trial.
3. Patients may have measurable and/or non-measurable disease which must be evaluable per RECIST 1.1.
b) General inclusion criteria:
4. Signed written informed consent approved by the institution’s Independent Ethical Committee (IEC).
5. Age = 18 years.
6. ECOG Performance Status 0 or 1.
7. Adequate organ function as determined by the following laboratory results, within approximately 14 days prior to randomization:
8. For women of childbearing potential and men with partners of childbearing potential, agreement to use one highly effective form of non-hormonal contraception or two effective forms of non-hormonal contraception by the patient and/or partner and to continue its use for the duration of study treatment and for 6 months after the last dose of study treatment. Male patients whose partners are pregnant must use condoms for the duration of the study treatment and for 6 months after the last dose of study treatment. Specific country and/or local requirements for contraception will be followed.
9. A negative pregnancy test must be available for premenopausal women and for women less than 12 months after the onset of menopause.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range

Exclusion criteria:
a) Disease related Exclusion Criteria:
History of systemic anti-cancer therapy after the diagnosis of MBC cancer.
1. An interval of < 6 months from the last dose of vincaalkaloid or taxane cytotoxic chemotherapy in the neoadjuvant or adjuvant setting until the time of metastatic
diagnosis.
2. Hormone therapy < 7 days prior to randomization.
3. Trastuzumab (neoadjuvant/adjuvant setting) < 21 days prior to randomization.
4. Prior T-DM1 or pertuzumab therapy.
5. Treatment with any anti-cancer investigational drug within 28 days prior to commencing study treatment.
6. History of other malignancy within the last 5 years except for appropriately treated carcinoma in situ of the cervix, nonmelanoma skin carcinoma, Stage I uterine cancer, or other malignancies with an expected curative outcome.
7. Brain metastases that are either untreated, progressive or require any type of therapy (e.g., radiation, surgery, or steroids) to control symptoms from brain metastases within 60 days prior to the first study treatment dose.
8. Radiotherapy for the treatment of locally advanced disease or for metastatic sites of disease performed within 14 days prior to study enrollment, and/or radiation of > 30% of marrowbearing bone.
9. Symptomatic hypercalcemia requiring use of bisphosphonate therapy within 21 days prior to the first study treatment. Patients who receive bisphosphonate therapy specifically to prevent skeletal events and who do not have a history of
clinically significant hypercalcemia are eligible.
10. Current peripheral neuropathy Grade = 2 per NCI-CTCAE version 4.0.
11. History of exposure to the following cumulative doses of anthracyclines as specified below.
o Doxorubicin > 500 mg/m2
o Liposomal doxorubicin > 900 mg/m2
o Epirubucin > 720 mg/m2
o Mitoxantrone > 120 mg/m2
o Idarubicin > 90 mg/m2
If another anthracycline or more than one anthracycline has been used, then the cumulative dose must not exceed the equivalent of 500 mg/m2 doxorubicin.
13. Cardiopulmonary dysfunction b) General exclusion criteria:
14. Current severe, uncontrolled systemic disease (e.g. clinically significant cardiovascular, pulmonary or metabolic disease; wound healing disorders; ulcers; bone fractures).
15. Current pregnancy and lactation.
16. Major surgical procedure or significant traumatic injury within approximately 28 days prior to randomization or anticipation of the need for major surgery during the course of study treatment.
17. Concurrent, serious, uncontrolled infections or current known infection with HIV, active hepatitis B and/or hepatitis C.
18. Current chronic daily treatment with corticosteroids (dose of > 10 mg/day methylprednisone equivalent).
19. History of intolerance, including Grade 3-4 infusion reaction or hypersensitivity to trastuzumab, murine proteins or docetaxel/paclitaxel.
20. Known hypersensitivity to any of the study drugs, including excipients, of any drugs formulated in polysorbate 80.
21. Assessment by the investigator to be unable or unwilling to comply with the requirements of the protocol.


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

First line treatment in HER2 positive progressive or recurrent locally advanced or metastatic breast cancer (MBC)
MedDRA version: 12.1 Level: LLT Classification code 10027475 Term: Metastatic breast cancer
MedDRA version: 12.1 Level: LLT Classification code 10065430 Term: HER-2 positive breast cancer
MedDRA version: 12.1 Level: LLT Classification code 10006198 Term: Breast cancer recurrent

Intervention(s)

Product Name: trastuzumab-MCC-DM1 (TDM-1)
Product Code: RO5304020/F02
Pharmaceutical Form: Powder for concentrate for solution for infusion
INN or Proposed INN: n/a
CAS Number: 1018448-65-1
Current Sponsor code: RO5304020
Other descriptive name: T-DM1
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 160-

Trade Name: Herceptin®
Pharmaceutical Form: Powder for concentrate for solution for infusion
INN or Proposed INN: TRASTUZUMAB
CAS Number: 180288-69-1
Current Sponsor code: RO0452371
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 150-

Product Name: pertuzumab (rhuMAb 2C4)
Product Code: RO4368451/F01
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: pertuzumab
CAS Number: 380610-27-5
Current Sponsor code: RO4368451
Other descriptive name: ruhMAb 2C4
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 420/14-
Pharmaceutical form of the placebo: Concentrate for solution for infusion
Route of administration of the placebo: Intravenous use

Trade Name: TAXOL®
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: PACLITAXEL
CAS Number: 33069-62-4
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 6-

Trade Name: TAXOTERE®
Pharmaceutical Form: Powder and solvent for solution for infusion
INN or Proposed INN: DOCETAXEL
CAS Number: 114977-28-5
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 80-

Primary Outcome(s)

Secondary Objective: Compare the combination of T-DM1 plus pertuzumab and T-DM1 plus
pertuzumab-placebo versus trastuzumab plus docetaxel/paclitaxel with respect to:
• Overall Response Rate (ORR) by IRF assessment
• Overall Survival Rate (OS)
• 1-year Survival Rate
• PFS and ORR based on investigator tumor assessment
• Clinical Benefit Rate (CBR: CR+PR + [SD = 6 months]) based on IRF and investigator tumor assessment
• Time to Treatment Failure (TTF) by IRF assessment
• Duration of Response (DR) based on IRF assessment
• Safety and tolerability
• Quality of Life (QoL), Productivity and Health Resource
• ORR and PFS as assessed by IRF for patient subsets defined by having low or high HER2 mRNA expression
• Pharmacokinetics of T-DM1 in the presence and absence of pertuzumab and
pharmacokinetics of pertuzumab in the presence of T-DM1

Primary end point(s): •Progression Free Survival (PFS): to compare the efficacy of he combination of T-DM1 plus pertuzumab and/or T-DM1 plus pertuzumab-placebo versus trastuzumab plus
docetaxel/paclitaxel in patients with HER2 positive progressive or recurrent locally advanced breast cancer or previously untreated metastatic breast cancer patients, based on tumor assessments reviewed by an independent review facility (IRF).
• To compare the safety of the combination of T-DM1 plus pertuzumab and T-DM1 plus pertuzumab-placebo versus trastuzumab plus docetaxel or paclitaxel in the
aforementioned patient population.

Main Objective: •Progression Free Survival (PFS): to compare the efficacy of he combination of T-DM1 plus pertuzumab and/or T-DM1 plus pertuzumab-placebo versus trastuzumab plus
docetaxel/paclitaxel in patients with HER2 positive progressive or recurrent locally advanced breast cancer or previously untreated metastatic breast cancer patients, based on tumor assessments reviewed by an independent review facility (IRF).
• To compare the safety of the combination of T-DM1 plus pertuzumab and T-DM1 plus pertuzumab-placebo versus trastuzumab plus docetaxel or paclitaxel in the
aforementioned patient population.

Secondary ID(s)

BO22589/TDM4788g

2009-017905-13-AT