Combination Therapy With MYOCET® (Doxorubicin HCL Liposome for Injection) in Participants With HER2-Positive Breast Cancer

Prospective, Open-Label, Randomized Study of Combination Therapy of MYOCET® Plus Cyclophosphamide and Trastuzumab Versus Free Doxorubicin Plus Cyclophosphamide Alone, Each Followed by Docetaxel and Trastuzumab, in Neoadjuvant Setting in Treatment-Naive Patients With HER2-Positive Breast Cancer

To evaluate the efficacy and safety of treatment with MYOCET® (doxorubicin hydrochloride) in combination with cyclophosphamide and trastuzumab, 4 cycles, followed by docetaxel plus trastuzumab, 4 cycles, in women with stage II or III breast cancer whose tumour overexpresses the human epidermal growth factor receptor 2 (HER2) gene.

Study Overview

• Status: Completed
• Conditions: Breast Cancer
• Intervention / Treatment: Drug: Liposomal doxorubicin hydrochloride; Drug: Cyclophosphamide; Drug: Trastuzumab; Drug: Docetaxel; Drug: Free doxorubicin hydrochloride

• Study Type: Interventional
• Enrollment (Actual): 126
• Phase: Phase 2

Contacts and Locations

Study Locations

• Austria
  • Kufstein, Austria
    • Teva Investigational Site 16
  • Wien, Austria
    • Teva Investigational Site 15
• Belgium
  • Brussels, Belgium
    • Teva Investigational Site 9
  • Yvoir, Belgium
    • Teva Investigational Site 29
• France
  • Clichy Cedex, France
    • Teva Investigational Site 4
  • Nancy, France
    • Teva Investigational Site 5
  • Reims, France
    • Teva Investigational Site 33
  • Vandoeuvre-Les-Nancy CEDEX, France
    • Teva Investigational Site 8
• Germany
  • Aachen, Germany
    • Teva Investigational Site 30
  • Dusseldorf, Germany
    • Teva Investigational Site 11
  • Dusseldorf, Germany
    • Teva Investigational Site 25
  • Essen, Germany
    • Teva Investigational Site 32
  • Lorrach, Germany
    • Teva Investigational Site 34
  • Munchen, Germany
    • Teva Investigational Site 14
  • München, Germany
    • Teva Investigational Site 27
• Italy
  • Napoli, Italy
    • Teva Investigational Site 20
  • Roma, Italy
    • Teva Investigational Site 23
  • Verona, Italy
    • Teva Investigational Site 21
• Spain
  • Barcelona, Spain
    • Teva Investigational Site 26
  • Barcelona, Spain
    • Teva Investigational Site 3
  • Lleida, Spain
    • Teva Investigational Site 1
  • Zaragoza, Spain
    • Teva Investigational Site 2

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 68 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Main Inclusion Criteria:

• Treatment-naive participants with stage II or III invasive breast cancer (proven histologically/cytologically) and with tests showing an overexpressing of HER2.
• Participants have at least 1 bidimensionally measurable lesion according to the World Health Organization (WHO) criteria.
• The participant has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• The participant has an LVEF of at least 55% as assessed by multigated acquisition (MUGA) scan (preferred) or echocardiography.
• The participant has hematology and serum chemistry laboratory test results within specific protocol-defined ranges.
• Women of childbearing potential must use a medically accepted method of contraception and must agree to continue use of this method for the duration of the treatment period and for 6 months after the last administration of study drug.

Main Exclusion Criteria:

The participant:

• Has received previous cancer therapy for breast cancer.
• Has any history of CHF, angina pectoris, or myocardial infarction.
• Has uncontrolled hypertension.
• Has infection, peptic ulcer, or unstable diabetes mellitus.
• Has been treated with live virus vaccines within 8 weeks before the first administration of study drug.
• Has impaired hepatic or renal function.
• Is a pregnant or lactating woman. (Any women becoming pregnant during the study will be withdrawn from the study.)
• Has used an investigational drug within one month before the screening visit.
• Has a known hypersensitivity to any of the study drugs or to their active ingredients.
• Has an inflammatory breast cancer.
• Has had any other malignancies within five years (except for adequately treated carcinoma in situ of the cervix or basal or squamous cell skin cancer).

Note: Other inclusion and exclusion criteria may apply.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Doxorubicin (MYOCET) + Cyclophosphamide + Trastuzumab (MCH) and Docetaxel + Trastuzumab (TH); Participants will receive MCH (liposomal doxorubicin hydrochloride [60 milligrams {mg}/square meter {m^2}], cyclophosphamide (600 mg/m^2), and trastuzumab (8 or 6 mg/kilogram {kg}), administered as intravenous (IV) infusion on Day 1 of each of 4 consecutive 21-day cycles. For the first cycle, the loading dose of trastuzumab will be 8 mg/kg; 6 mg/kg will be used for the remaining cycles. After 4 cycles of MCH, the treatment will be changed to 4 consecutive 21-day cycles of TH (docetaxel [100 mg/m^2] and trastuzumab [6 mg/kg]).	Drug: Liposomal doxorubicin hydrochloride; Liposomal doxorubicin hydrochloride will be administered per dose and schedule specified in the arm description.; Other Names: Myocet®; Drug: Cyclophosphamide; Cyclophosphamide will be administered per dose and schedule specified in the arm description.; Drug: Trastuzumab; Trastuzumab will be administered per dose and schedule specified in the arm description.; Drug: Docetaxel; Docetaxel will be administered per dose and schedule specified in the arm description.
Active Comparator: Doxorubicin (Anthracycline) + Cyclophosphamide (AC) and Docetaxel + Trastuzumab (TH); Participants will receive AC (free doxorubicin hydrochloride [60 mg/m^2] and cyclophosphamide [600 mg/m^2]), administered as IV infusion on Day 1 of each of 4 consecutive 21-day cycles. After 4 cycles of AC, the treatment will be changed to 4 consecutive 21-day cycles of TH (docetaxel [100 mg/m^2] and trastuzumab [8 or 6 mg/kg]). For the first cycle, the loading dose of trastuzumab will be 8 mg/kg; 6 mg/kg will be used for the remaining cycles.	Drug: Cyclophosphamide; Cyclophosphamide will be administered per dose and schedule specified in the arm description.; Drug: Trastuzumab; Trastuzumab will be administered per dose and schedule specified in the arm description.; Drug: Docetaxel; Docetaxel will be administered per dose and schedule specified in the arm description.; Drug: Free doxorubicin hydrochloride; Free doxorubicin hydrochloride will be administered per dose and schedule specified in the arm description.; Other Names: Anthracycline

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants Exhibiting a Pathological Complete Response (pCR) in Breast	The pCR of breast was based upon histologic examination, as confirmed by a central panel of experts, of resected tissue .	At the end of Cycle 8 (each cycle length = 21 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants Who Achieved an Objective Response (Complete Response [CR] or Partial Response [PR]), as Defined by World Health Organization (WHO) Guidelines	CR: Disappearance of the lesions and no new lesions. In case of bone metastasis a CR is represented by the normalization of radiography or the complete sclerotic healing of lytic area. PR: In the case of bidimensionally measurable lesions/tumors, a decrease by at least 50% of the sum of the products of the largest perpendicular diameters of each individual lesion/tumor. In the case of unidimensionally measurable lesions a decrease by at least 50% in the largest linear tumour measurement. In the case of non-measurable but evaluable lesions an appreciable change of lesions referable to disease improvement. For bone lesions partial decrease in size or recalcification of lytic areas. No lesion should have progressed and no new lesion should appear.	At the end of Cycle 8 (each cycle length = 21 days)
Percentage of Participants With Class III or IV New York Health Association (NYHA) Congestive Heart Failure (CHF)	Occurrence of Class III or IV (NYHA) CHF has been reported. Class III: Participants with cardiac disease resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary activity causes fatigue, palpitation, dyspnea, or anginal pain. Class IV: Participants with cardiac disease resulting in inability to carry on any physical activity without discomfort. Symptoms of heart failure or the anginal syndrome may be present even at rest. If any physical activity is undertaken, discomfort is increased.	Baseline up to the end of Cycle 8 (each cycle length = 21 days)
Change From Baseline in Left Ventricular Ejection Fraction (LVEF)	The LVEF is a fraction of blood (in percent) pumped out of the left ventricle of the heart (the main pumping chamber). LVEF was measured using multigated acquisition (MUGA) or echocardiography.	Baseline, up to 5 years
Number of Participants With Treatment-Emergent Adverse Events (TEAEs)	An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. AEs included both SAEs and non-serious AEs. The TEAE was an AE that began or worsened after treatment with study drug. A summary of other non-serious AEs and all SAEs, regardless of causality is located in the 'Reported AE section'.	Baseline up to the end of Cycle 8 (cycle length = 21 days)
Percentage of Participants With Progression or Death	Progression was defined as a 25% or more increase in the size of the lesion or appearance of new lesion. If the participant did not develop an event (disease progression or death), the participant was censored at the last known tumor assessment date (or last follow-up visit without progression documented).	Up to 5 Years after randomization
Percentage of Participants Achieving a Pathological Complete Response (pCR) in Breast and Node	The pCR of breast and node was based upon histologic examination, as confirmed by a central panel of experts, of breast tissue resected.	At the end of Cycle 8 (each cycle length = 21 days)
Number of Participants Undergoing Breast Conservative Surgery		At the end of Cycle 8 (each cycle length = 21 days)
Severity of Adverse Events as Characterized by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE)	AEs were recorded and graded per the NCI CTCAE scale. The NCI CTCAE is a toxicity scale used to grade the severity of adverse events experienced with cancer treatment. Grade 1= Mild; Grade 2= Moderate; Grade 3= Severe; Grade 4= Life-threatening or disabling; Grade 5= Death related to AE. For summaries for the toxicity grade, participants were counted once at the greatest NCI CTCAE grade.	Up to Week 24

Collaborators and Investigators

• Sponsor: Cephalon, Inc.
• Investigators: Study Director: Teva Medical Expert, Teva Branded Pharmaceutical Products R&D, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): October 13, 2008
• Primary Completion (Actual): September 17, 2015
• Study Completion (Actual): September 17, 2015

Study Registration Dates

• First Submitted: July 8, 2008
• First Submitted That Met QC Criteria: July 9, 2008
• First Posted (Estimated): July 10, 2008

Study Record Updates

• Last Update Posted (Actual): February 23, 2024
• Last Update Submitted That Met QC Criteria: July 17, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antineoplastic Agents, Immunological; Antibiotics, Antineoplastic; Docetaxel; Cyclophosphamide; Trastuzumab; Doxorubicin; Liposomal doxorubicin
• Other Study ID Numbers: C19562/2037; 2008-000709-12 (EudraCT Number)