A Study of Herceptin (Trastuzumab) in Combination Chemotherapy in Women With Locally Advanced Breast Cancer

A Randomized, Open-label Study of the Effect of Paclitaxel, Doxorubicin, and CMF Neoadjuvant Chemotherapy, With and Without Herceptin, on Tumor Response in Women With HER2-positive Breast Cancer

This study will assess the efficacy and safety of adding Herceptin to a paclitaxel-containing regimen followed by cyclophosphamide/methotrexate/fluorouracil (CMF) chemotherapy in women with locally advanced breast cancer and HER2/c-erbB-2 gene amplification. In a parallel observational study patients with HER2-negative disease will receive the same chemotherapy without Herceptin.

Study Overview

• Status: Completed
• Conditions: Breast Cancer
• Intervention / Treatment: Drug: Trastuzumab; Drug: Doxorubicin; Drug: Paclitaxel; Drug: CMF

• Study Type: Interventional
• Enrollment (Actual): 330
• Phase: Phase 3

Contacts and Locations

Study Locations

• Austria
  • Wien, Austria, 1090
• Germany
  • Muenchen, Germany, 80637
• Italy
  • Emilia-Romagna
    • Bologna, Emilia-Romagna, Italy, 40138
    • Carpi, Emilia-Romagna, Italy, 41012
  • Friuli-Venezia Giulia
    • Udine, Friuli-Venezia Giulia, Italy, 33100
  • Lombardia
    • Milano, Lombardia, Italy, 20133
    • Pavia, Lombardia, Italy, 27100
    • Varese, Lombardia, Italy, 21100
  • Puglia
    • San Giovanni Rotondo, Puglia, Italy, 71013
  • Sardegna
    • Sassari, Sardegna, Italy, 07100
  • Toscana
    • Pisa, Toscana, Italy, 56100
  • Trentino-Alto Adige
    • Trento, Trentino-Alto Adige, Italy, 38100
  • Veneto
    • Bellunoi, Veneto, Italy, 32100
    • Castelfranco Veneto, Veneto, Italy, 31033
    • Mirano, Veneto, Italy, 30035
    • Santorso, Veneto, Italy, 36014
    • Vicenza, Veneto, Italy, 36100
• Portugal
  • Lisboa, Portugal, 1099-023
• Russian Federation
  • Kazan, Russian Federation, 420029
  • Moscow, Russian Federation, 107005
  • Moscow, Russian Federation, 115478
  • Moscow, Russian Federation, 129128
  • Moscow, Russian Federation, 117837
  • Saint-Petersburg, Russian Federation, 197758
  • St Petersburg, Russian Federation, 197022
• Spain
  • Barcelona, Spain, 08035
  • Barcelona, Spain, 08907
  • Barcelona, Spain, 08041
  • Barcelona, Spain, 08022
  • Madrid, Spain, 28041
  • Valencia, Spain, 46010
  • Valencia, Spain, 46009
  • Zaragoza, Spain, 50009
  • Barcelona
    • Terrassa, Barcelona, Spain, 08221
  • Cadiz
    • Jerez de La Frontera, Cadiz, Spain, 11407
  • Guipuzcoa
    • San Sebastian, Guipuzcoa, Spain, 20080

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• female patients, >=18 years of age, with locally advanced breast cancer.

Exclusion Criteria:

• previous therapy for any invasive malignancy.

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

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: HER-2+ Trastuzumab, Doxorubicin/Paclitaxel/CMF; Participants with HER2 proto-oncogene positive breast cancer (HER2+) were treated with trastuzumab 8 milligrams per kilogram (mg/kg), intravenous (IV), on Day 1 of Cycle 1, followed by 6 mg/kg, IV, on Day 1 of Cycle 2 to up a maximum of Cycle 17. Participants also received doxorubicin 60 mg/ square meter (m^2), IV, and paclitaxel 150 mg/m^2, IV, on Day 1 of Cycles 1 through 3. Followed by paclitaxel 175 mg/m^2, IV, alone on Day 1 of Cycles 4 through 7. Participants also received CMF: cyclophosphamide 600 mg/m^2, IV; methotrexate 40 mg/m^2, IV; and 5-fluorouracil 600 mg/m^2, IV, on Day 1 of Cycles 8 through 10.	Drug: Trastuzumab; 8mg/kg IV on Day 1 of Cycle 1, followed by 6 mg/kg on Day 1 of Cycle 2 up a maximum of Cycle 17; Other Names: Herceptin; Drug: Doxorubicin; 60 mg/m2 IV on Day 1 of Cycles 1 through 3; Drug: Paclitaxel; 150 mg/m2 IV on Day 1 of Cycles 1 through 3, followed by 175 mg/m2 IV on Day 1 of Cycles 4 through 7; Drug: CMF; CMF: Cyclophosphamide (600 mg/m2 IV bolus), methotrexate (40 mg/m2 IV bolus), 5-fluorouracil (600 mg/m2 IV bolus) on Day 1 of Cycles 8 through 10
Active Comparator: HER-2+ Doxorubicin/Paclitaxel/CMF; Participants with HER2 proto-oncogene positive breast cancer were treated with doxorubicin 60 mg/m^2, IV, and paclitaxel 150 mg/m^2, IV, on Day 1 of Cycles 1 through 3. Followed by paclitaxel 175 mg/m^2, IV, alone on Day 1 of Cycles 4 through 7. Participants also received CMF on Day 1 of Cycle 8 through 10.	Drug: Doxorubicin; 60 mg/m2 IV on Day 1 of Cycles 1 through 3; Drug: Paclitaxel; 150 mg/m2 IV on Day 1 of Cycles 1 through 3, followed by 175 mg/m2 IV on Day 1 of Cycles 4 through 7; Drug: CMF; CMF: Cyclophosphamide (600 mg/m2 IV bolus), methotrexate (40 mg/m2 IV bolus), 5-fluorouracil (600 mg/m2 IV bolus) on Day 1 of Cycles 8 through 10
Active Comparator: HER-2- Doxorubicin/Paclitaxel/CMF; Participants with HER2 proto-oncogene negative breast cancer were treated with doxorubicin 60 mg/m^2, IV, and paclitaxel 150 mg/m^2, IV, on Day 1 of Cycles 1 through 3. Followed by paclitaxel 175 mg/m^2, IV, alone on Day 1 of Cycles 4 through 7. Participants also received CMF on Day 1 of Cycle 8 through 10.	Drug: Doxorubicin; 60 mg/m2 IV on Day 1 of Cycles 1 through 3; Drug: Paclitaxel; 150 mg/m2 IV on Day 1 of Cycles 1 through 3, followed by 175 mg/m2 IV on Day 1 of Cycles 4 through 7; Drug: CMF; CMF: Cyclophosphamide (600 mg/m2 IV bolus), methotrexate (40 mg/m2 IV bolus), 5-fluorouracil (600 mg/m2 IV bolus) on Day 1 of Cycles 8 through 10

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Event-Free Survival (EFS) - Percentage of Participants With an Event	EFS was defined as the time between randomization and date of documented occurrence of disease recurrence or progression (local, regional, distant or contralateral) or death due to any cause.	Baseline (BL), Presurgery: Day 1 (Cycles 1-7) and Days 1 and 8 (Cycles 8-10); Postsurgery: Day 1 (Cycles 1-17); every 6 months up to 60 months after last dose of study drug; yearly thereafter
Event-Free Survival	The median time, in months, between randomization and date of documented occurrence of an EFS event.	BL, Presurgery: Day 1 (Cycles 1-7) and Days 1 and 8 (Cycles 8-10); Postsurgery: Day 1 (Cycles 1-17); every 6 months up to 60 months after last dose of study drug; yearly thereafter
Percentage of Participants Event Free at 1 Year		BL, Presurgery: Day 1 (Cycles 1-7) and Days 1 and 8 (Cycles 8-10); Postsurgery: Day 1 (Cycles 1-17); every 6 months up to 60 months after last dose of study drug; yearly thereafter
Percentage of Participants Event Free at 2 Years		BL, Presurgery: Day 1 (Cycles 1-7) and Days 1 and 8 (Cycles 8-10); Postsurgery: Day 1 (Cycles 1-17); every 6 months up to 60 months after last dose of study drug; yearly thereafter
Percentage of Participants Event Free at 3 Years		BL, Presurgery: Day 1 (Cycles 1-7) and Days 1 and 8 (Cycles 8-10); Postsurgery: Day 1 (Cycles 1-17); every 6 months up to 60 months after last dose of study drug; yearly thereafter

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Breast Pathological Complete Response (bpCR)	bpCR was defined as an absence of any invasive cancer cell of the primary tumor at the time of major surgery after neoadjuvant chemotherapy with and without trastuzumab.	BL, Day 1 of Cycles 1-10 (pre-surgery)
Percentage of Participants With Total Pathological Complete Response (tpCR)	tpCR was defined as a determination of bpCR and an absence of positive axillary nodes on pathology.	BL, Day 1 of Cycles 1-10 (pre-surgery)
Percentage of Participants Achieving Either Complete Response (CR) or Partial Response (PR) According to Modified Response Evaluation Criteria in Solid Tumors (RECIST) Criteria	Assessments were made based on objective tumor measurements of the lesions as recorded in the case report form. In inflammatory cancer, progressive disease (PD) was defined as progression of any of the 2 signs of breast edema and erythema. In non-inflammatory cancer, PD was concluded if either the investigator judged the participant as having progressed at any time prior to surgery, or there was at least a 20% increase in the sum of target lesions (TLs), any new lesion, or clear progression of any nontarget lesion (NTLs). Clear progression of any NTL was defined as at least a 20% increase in the sum of NTLs compared to BL. PR was defined as at least a 30% decrease from BL in the sum of the longest diameter of TLs. CR was defined as no PD as assessed by the investigator and complete disappearance of all lesions.	BL, Presurgery: Day 1 of Cycles 1-10
Overall Survival (OS) - Percentage of Participants With an Event	OS was defined as the time from the date of randomization to the date of the death due to any cause.	BL, Presurgery: Day 1 (Cycles 1-7) and Days 1 and 8 (Cycles 8-10); Postsurgery: Day 1 (Cycles 1-17); every 6 months up to 60 months after last dose of study drug; yearly thereafter
Overall Survival	OS was defined as the time from the date of randomization to the date of the death due to any cause.	BL, Presurgery: Day 1 (Cycles 1-7) and Days 1 and 8 (Cycles 8-10); Postsurgery: Day 1 (Cycles 1-17); every 6 months up to 60 months after last dose of study drug; yearly thereafter
Percentage of Participants Surviving at 1 Year		BL, Presurgery: Day 1 (Cycles 1-7) and Days 1 and 8 (Cycles 8-10); Postsurgery: Day 1 (Cycles 1-17); every 6 months up to 60 months after last dose of study drug; yearly thereafter
Percentage of Participants Surviving at 2 Years		BL, Presurgery: Day 1 (Cycles 1-7) and Days 1 and 8 (Cycles 8-10); Postsurgery: Day 1 (Cycles 1-17); every 6 months up to 60 months after last dose of study drug; yearly thereafter
Percentage of Participants Surviving at 3 Years		BL, Presurgery: Day 1 (Cycles 1-7) and Days 1 and 8 (Cycles 8-10); Postsurgery: Day 1 (Cycles 1-17); every 6 months up to 60 months after last dose of study drug; yearly thereafter

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche

Study record dates

Study Major Dates

• Study Start: May 1, 2002
• Primary Completion (Actual): July 1, 2012
• Study Completion (Actual): July 1, 2012

Study Registration Dates

• First Submitted: November 25, 2013
• First Submitted That Met QC Criteria: November 25, 2013
• First Posted (Estimate): December 2, 2013

Study Record Updates

• Last Update Posted (Estimate): October 28, 2014
• Last Update Submitted That Met QC Criteria: October 24, 2014
• Last Verified: October 1, 2014

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antineoplastic Agents, Immunological; Antibiotics, Antineoplastic; Paclitaxel; Trastuzumab; Doxorubicin
• Other Study ID Numbers: MO16432