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A Study to Compare Subcutaneous (SC) Versus Intravenous (IV) Administration of Herceptin (Trastuzumab) in Women With Human Epidermal Growth Factor Receptor (HER) 2-Positive Early Breast Cancer

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche
ClinicalTrials.gov Identifier:
NCT00950300
First received: July 30, 2009
Last updated: November 22, 2016
Last verified: November 2016
  Purpose
In this open-label multicenter trial, participants with operable or locally advanced breast cancer will be randomized to pre-operative treatment with 8 cycles of chemotherapy (4 cycles of docetaxel followed by 4 cycles of 5-fluorouracil, epirubicin, and cyclophosphamide) concurrent with either SC Herceptin or IV Herceptin. After surgery, participants will receive a further 10 cycles of SC or IV Herceptin as per randomization to complete 1 year of treatment. All cycles will be 21 days in length. After the end of study treatment, participants will be followed for safety and efficacy for up to 5 years or until disease recurrence, whichever is earlier.

Condition Intervention Phase
Breast Cancer
Drug: 5-Fluorouracil
Drug: Cyclophosphamide
Drug: Docetaxel
Drug: Epirubicin
Drug: Herceptin IV [trastuzumab]
Drug: Herceptin SC [trastuzumab]
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase III, Randomized Open-Label Study to Compare the Pharmacokinetics, Efficacy, and Safety of Subcutaneous (SC) Trastuzumab With Intravenous (IV) Trastuzumab Administered in Women With HER2-Positive Early Breast Cancer (EBC)

Resource links provided by NLM:


Further study details as provided by Hoffmann-La Roche:

Primary Outcome Measures:
  • Observed Serum Trough Concentration (Ctrough) of Trastuzumab Prior to Surgery [ Time Frame: Pre-dose (0 hours) on Day 1 of Cycle 8 (cycle length of 21 days) ]
    Pre-dose samples were obtained prior to surgery (Cycle 8). The observed Ctrough was recorded, averaged among all participants, and expressed in micrograms per milliliter (μg/mL).

  • Percentage of Participants With Pathological Complete Response (pCR) [ Time Frame: After surgery following eight cycles of Herceptin + chemotherapy (approximately 6 months from Baseline) ]
    Participants were evaluated following eight cycles of treatment and after surgery to assess for pCR, defined as absence of neoplastic invasive cells in the breast according to pathologist examination. The percentage of participants with pCR was reported, and the 95% CI for one-sample binomial was constructed using the Pearson-Clopper method.


Secondary Outcome Measures:
  • Observed Ctrough of Trastuzumab After Surgery [ Time Frame: Pre-dose (0 hours) on Day 1 of Cycle 13 (cycle length of 21 days) ]
    Pre-dose samples were obtained after surgery (Cycle 13). The observed Ctrough was recorded, averaged among all participants, and expressed in μg/mL.

  • Predicted Ctrough of Trastuzumab Prior to Surgery [ Time Frame: Pre-dose (0 hours) on Day 1 of Cycle 8 (cycle length of 21 days) ]
    Predicted Ctrough at pre-dose prior to surgery (Cycle 8) was determined on the basis of a population PK model from Study BP22023 (NCT00800436). The mean predicted Ctrough was expressed in μg/mL.

  • Predicted Ctrough of Trastuzumab After Surgery [ Time Frame: Pre-dose (0 hours) on Day 1 of Cycle 13 (cycle length of 21 days) ]
    Predicted Ctrough at pre-dose after surgery (Cycle 13) was determined on the basis of a population PK model from Study BP22023 (NCT00800436). The mean predicted Ctrough was expressed in μg/mL.

  • Number of Participants With Ctrough of Trastuzumab >20 μg/mL Prior to Surgery [ Time Frame: Pre-dose (0 hours) on Day 1 of Cycle 8 (cycle length of 21 days) ]
    Pre-dose samples were obtained prior to surgery (Cycle 8). The number of participants who had an observed Ctrough >20 μg/mL was reported.

  • Number of Participants With Ctrough of Trastuzumab >20 μg/mL After Surgery [ Time Frame: Pre-dose (0 hours) on Day 1 of Cycle 13 (cycle length of 21 days) ]
    Pre-dose samples were obtained after surgery (Cycle 13). The number of participants who had an observed Ctrough >20 μg/mL was reported.

  • Maximum Serum Concentration (Cmax) of Trastuzumab Prior to Surgery [ Time Frame: Pre-dose (0 hours) and at end of 30-minute infusion (Herceptin IV only) on Day 1 of Cycle 7; on Days 2, 4, 8, 15 of Cycle 7; pre-dose (0 hours) on Day 1 of Cycle 8 (cycle length of 21 days) ]
    PK samples were obtained prior to surgery (Cycle 7). The Cmax during Cycle 7 was recorded, averaged among all participants, and expressed in μg/mL.

  • Time of Maximum Serum Concentration (Tmax) of Trastuzumab Prior to Surgery [ Time Frame: Pre-dose (0 hours) and at end of 30-minute infusion (Herceptin IV only) on Day 1 of Cycle 7; on Days 2, 4, 8, 15 of Cycle 7; pre-dose (0 hours) on Day 1 of Cycle 8 (cycle length of 21 days) ]
    PK samples were obtained prior to surgery (Cycle 7). The Tmax during Cycle 7 was recorded, averaged among all participants, and expressed in days.

  • Area Under the Concentration-Time Curve From 0 to 21 Days (AUC21d) of Trastuzumab Prior to Surgery [ Time Frame: Pre-dose (0 hours) and at end of 30-minute infusion (Herceptin IV only) on Day 1 of Cycle 7; on Days 2, 4, 8, 15 of Cycle 7; pre-dose (0 hours) on Day 1 of Cycle 8 (cycle length of 21 days) ]
    PK samples were obtained prior to surgery (Cycle 7). Values were extrapolated beyond Day 15 to produce the area over the full 21-day cycle. The AUC21d value at Cycle 7 was calculated from trastuzumab concentration-time profiles using standard non-compartmental PK methods, averaged among all participants, and expressed in days multiplied by micrograms per milliliters (d*μg/mL).

  • Cmax of Trastuzumab After Surgery [ Time Frame: Pre-dose (0 hours) and at end of 30-minute infusion (Herceptin IV only) on Day 1 of Cycle 12; on Days 2, 4, 8, 15 of Cycle 12; pre-dose (0 hours) on Day 1 of Cycle 13 (cycle length of 21 days) ]
    PK samples were obtained after surgery (Cycle 12). The Cmax during Cycle 12 was recorded, averaged among all participants, and expressed in μg/mL.

  • Tmax of Trastuzumab After Surgery [ Time Frame: Pre-dose (0 hours) and at end of 30-minute infusion (Herceptin IV only) on Day 1 of Cycle 12; on Days 2, 4, 8, 15 of Cycle 12; pre-dose (0 hours) on Day 1 of Cycle 13 (cycle length of 21 days) ]
    PK samples were obtained after surgery (Cycle 12). The Tmax during Cycle 12 was recorded, averaged among all participants, and expressed in days.

  • AUC21d of Trastuzumab After Surgery [ Time Frame: Pre-dose (0 hours) and at end of 30-minute infusion (Herceptin IV only) on Day 1 of Cycle 12; on Days 2, 4, 8, 15 of Cycle 12; pre-dose (0 hours) on Day 1 of Cycle 13 (cycle length of 21 days) ]
    PK samples were obtained after surgery (Cycle 12). Values were extrapolated beyond Day 15 to produce the area over the full 21-day cycle. The AUC21d value at Cycle 12 was calculated from trastuzumab concentration-time profiles using standard non-compartmental PK methods, averaged among all participants, and expressed in d*μg/mL.

  • Percentage of Participants With Total Pathological Complete Response (tpCR) [ Time Frame: After surgery following eight cycles of Herceptin + chemotherapy (approximately 6 months from Baseline) ]
    Participants were evaluated following eight cycles of treatment and after surgery to assess for tpCR, defined as absence of neoplastic invasive cells in the breast and axillary lymph nodes according to pathologist examination. The percentage of participants with tpCR was reported, and the 95% CI for one-sample binomial was constructed using the Pearson-Clopper method.

  • Percentage of Participants With Complete Response (CR) or Partial Response (PR) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.0, Among Those With Measurable Disease at Baseline [ Time Frame: Tumor assessments at Baseline; on Day 1 of Cycles 3, 5, 7 (cycle length of 21 days); and at time of surgery following eight cycles of Herceptin + chemotherapy (approximately 6 months overall) ]
    Tumor response was assessed using RECIST version 1.0. CR was defined as disappearance of all target lesions and short-axis reduction of any pathological lymph nodes to less than (<) 10 millimeters (mm) with no prior assessment of progressive disease (PD). PR was defined as greater than or equal to (≥) 30% decrease from Baseline in sum diameter of target lesions with no prior assessment of PD. The percentage of participants with overall response of CR or PR at the end of neoadjuvant treatment was reported, and the 95% CI for one-sample binomial was constructed using the Pearson-Clopper method.

  • Time to Response According to RECIST Version 1.0, Among Those With Measurable Disease at Baseline [ Time Frame: Tumor assessments at Baseline; on Day 1 Cycles 3, 5, 7 (cycle length of 21 days); and at time of surgery following eight cycles of chemotherapy (approximately 6 months overall) ]
    Tumor response was assessed using RECIST version 1.0. CR was defined as disappearance of all target lesions and short-axis reduction of any pathological lymph nodes to <10 mm with no prior assessment of PD. PR was defined as ≥30% decrease from Baseline in sum diameter of target lesions with no prior assessment of PD. Time to response was defined as the time from first dose of study medication to the first assessment of CR or PR, which was the date the response was first documented by objective evidence, among participants with an overall response of CR or PR.

  • Percentage of Participants Who Experienced a Protocol-Defined Event as of Clinical Cutoff in January 2014 [ Time Frame: Screening; Day 1 of Cycle 18 (cycle length of 21 days); and Months 6, 12, 24, 36, 48 from last dose of Cycle 18; then every 6 months until withdrawal for any reason (approximately 4 years as of January 2014 data cutoff) ]
    Protocol-defined events included local, regional, or distant recurrence, contralateral breast cancer, or death from any cause. After the last dose of treatment, imaging was performed at specified visits and participants were followed for survival status. The percentage of participants who experienced a protocol-defined event at any time during the study was reported.

  • Event-Free Survival (EFS) as of Clinical Cutoff in January 2014 [ Time Frame: Screening; Day 1 of Cycle 18 (cycle length of 21 days); and Months 6, 12, 24, 36, 48 from last dose of Cycle 18; then every 6 months until withdrawal for any reason (approximately 4 years as of January 2014 data cutoff) ]
    Protocol-defined events included local, regional, or distant recurrence, contralateral breast cancer, or death from any cause. After the last dose of treatment, imaging was performed at specified visits and participants were followed for survival status. EFS was estimated by Kaplan-Meier analysis and defined as the time from randomization to the first protocol-defined event. For participants without an event at the time of analysis, EFS was censored and the date of censoring was the date of last tumor assessment or last recorded visit for the participant.

  • Percentage of Participants Who Died as of Clinical Cutoff in January 2014 [ Time Frame: Continuously during treatment (up to 12 months); at Months 1, 3, 6 from last dose of Cycle 18 (cycle length of 21 days); then every 6 months until withdrawal for any reason (approximately 4 years as of January 2014 data cutoff) ]
    The percentage of participants who died at any time during the study was reported.

  • Overall Survival (OS) as of Clinical Cutoff in January 2014 [ Time Frame: Continuously during treatment (up to 12 months); at Months 1, 3, 6 from last dose of Cycle 18 (cycle length of 21 days); then every 6 months until withdrawal for any reason (approximately 4 years as of January 2014 data cutoff) ]
    OS was estimated by Kaplan-Meier analysis and defined as the time from randomization to death from any cause. Participants who were alive at the time of analysis were censored at the day of last study drug administration, last recorded visit, or last survival follow-up information.

  • Percentage of Participants With Anti-Drug Antibodies (ADAs) Against Trastuzumab [ Time Frame: Baseline; pre-dose (0 hours) on Day 1 of Cycles 2, 5, 13, 18 (cycle length of 21 days); and Months 3, 6, 12, 18, 24, 30, 36, 42, 48 from last dose of Cycle 18 ]
    Participants provided samples for evaluation of anti-trastuzumab antibodies. The cumulative percentage of participants with ADAs against trastuzumab at any time during or after treatment was reported.

  • Percentage of Participants With ADAs Against Recombinant Human Hyaluronidase (rHuPH20) [ Time Frame: Baseline; pre-dose (0 hours) on Day 1 of Cycles 2, 5, 13, 18 (cycle length of 21 days); and Months 3, 6, 12, 18, 24, 30, 36, 42, 48 from last dose of Cycle 18 ]
    Participants in the Herceptin SC arm provided samples for evaluation of anti-rHuPH20 antibodies. The cumulative percentage of participants with ADAs against rHuPH20 (an excipient unique to the SC formulation) at any time during or after treatment was reported.


Enrollment: 596
Study Start Date: October 2009
Estimated Study Completion Date: January 2017
Primary Completion Date: July 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Herceptin IV + Chemotherapy
Participants will receive Herceptin via IV infusion for 8 cycles prior to surgery and an additional 10 cycles after surgery. Docetaxel will be co-administered during Cycles 1 to 4; chemotherapy during Cycles 5 to 8 will include 5-fluorouracil, cyclophosphamide, and epirubicin. Herceptin IV will be given on Day 1 of each 21-day cycle, as 8 milligrams per kilogram (mg/kg) for a loading dose during Cycle 1 and as 6 mg/kg during subsequent cycles.
Drug: 5-Fluorouracil
Participants will receive 5-fluorouracil, 500 milligrams per meter-squared (mg/m^2) via IV bolus or infusion, on Day 1 of every 21-day cycle during Cycles 5 to 8.
Drug: Cyclophosphamide
Participants will receive cyclophosphamide, 500 mg/m^2 via IV bolus, on Day 1 of every 21-day cycle during Cycles 5 to 8.
Drug: Docetaxel
Participants will receive docetaxel, 75 mg/m^2 via IV infusion on Day 1 of every 21-day cycle during Cycles 1 to 4.
Drug: Epirubicin
Participants will receive epirubicin, 75 mg/m^2 via IV bolus or infusion, on Day 1 of every 21-day cycle during Cycles 5 to 8.
Drug: Herceptin IV [trastuzumab]
Herceptin will be administered as 8 mg/kg (loading dose during Cycle 1) and 6 mg/kg (subsequent cycles) via IV infusion on Day 1 of each 21-day cycle for a total of 18 cycles.
Experimental: Herceptin SC + Chemotherapy
Participants will receive Herceptin via SC injection for 8 cycles prior to surgery and an additional 10 cycles after surgery. Docetaxel will be co-administered during Cycles 1 to 4; chemotherapy during Cycles 5 to 8 will include 5-fluorouracil, cyclophosphamide, and epirubicin. Herceptin SC will be given on Day 1 of each 21-day cycle, as a 600-milligram (mg) fixed dose.
Drug: 5-Fluorouracil
Participants will receive 5-fluorouracil, 500 milligrams per meter-squared (mg/m^2) via IV bolus or infusion, on Day 1 of every 21-day cycle during Cycles 5 to 8.
Drug: Cyclophosphamide
Participants will receive cyclophosphamide, 500 mg/m^2 via IV bolus, on Day 1 of every 21-day cycle during Cycles 5 to 8.
Drug: Docetaxel
Participants will receive docetaxel, 75 mg/m^2 via IV infusion on Day 1 of every 21-day cycle during Cycles 1 to 4.
Drug: Epirubicin
Participants will receive epirubicin, 75 mg/m^2 via IV bolus or infusion, on Day 1 of every 21-day cycle during Cycles 5 to 8.
Drug: Herceptin SC [trastuzumab]
Herceptin will be administered as fixed dose 600 mg SC on Day 1 of each 21-day cycle for a total of 18 cycles.

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Adult women greater than or equal to (≥) 18 years of age
  • Non-metastatic primary invasive adenocarcinoma of the breast clinical stage I to IIIC, including inflammatory and multicentric/multifocal breast cancer, with tumor size ≥1 centimeter (cm) by ultrasound or ≥2 cm by palpation, centrally confirmed HER2-positive (immunohistochemical score [IHC] 3+ or in situ hybridization [ISH]-positive)
  • At least 1 measurable lesion in breast or lymph nodes (≥1 cm by ultrasound or ≥2 cm by palpation), except for inflammatory carcinoma (T4d)
  • Baseline left ventricular ejection fraction (LVEF) ≥55%
  • Eastern Cooperative Oncology Group (ECOG) status of 0 or 1
  • Adequate organ function at Baseline

Exclusion Criteria:

  • History of any prior (ipsilateral and/or contralateral) invasive breast carcinoma
  • Past or current history of malignant neoplasms, except for curatively treated basal and squamous cell carcinoma of the skin and in situ carcinoma of the cervix
  • Metastatic disease
  • Any prior therapy with anthracyclines
  • Prior anti-HER2 therapy or biologic or immunotherapy
  • Serious cardiac illness
  • Pregnant or lactating women
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00950300

  Hide Study Locations
Locations
Argentina
Tucuman, Argentina, T4000IAK
Tucuman, Argentina, T400IAK
Brazil
Salvador, BA, Brazil, 41253-190
Curitiba, PR, Brazil, 80060-900
Natal, RN, Brazil, 59040150
Itajai, SC, Brazil, 88301-220
Jau, SP, Brazil, 17210-080
Sao Paulo, SP, Brazil, 01246-000
Sao Paulo, SP, Brazil, 01317-000
Sorocaba, SP, Brazil, 18030-245
Canada, Quebec
Montreal, Quebec, Canada, H1T 2M4
Canada
Quebec, Canada, G1S 4L8
Colombia
Bogota, Colombia, 000472
Bogota, Colombia
Pereira, Colombia, 600004
Czech Republic
Olomouc, Czech Republic, 775 20
Pardubice, Czech Republic, 532 03
Praha, Czech Republic, 140 59
Praha, Czech Republic, 180 81
Estonia
Tallin, Estonia, 13419
Tartu, Estonia, 50406
France
Besancon, France, 25030
Grenoble, France, 38000
La Tronche, France, 38700
Le Mans, France, 72015
Paris, France, 75475
Reims, France, 51056
St Cloud, France, 92210
Germany
Berlin, Germany, 10117
Berlin, Germany, 10719
Bonn, Germany, 53113
Dortmund, Germany, 44137
Hannover, Germany, 30177
Leipzig, Germany, 04277
Lemgo, Germany, 32657
Offenbach, Germany, 63069
Rodewisch, Germany, 08228
Tübingen, Germany, 72076
Guatemala
Guatemala, Guatemala, 01010
Hong Kong
Hong Kong, Hong Kong, 852
Hungary
Budapest, Hungary, 1083
Gyor, Hungary, 9023
Szeged, Hungary, 6720
Israel
Jerusalem, Israel, 91120-01
Petach Tikva, Israel, 49100
Italy
Napoli, Campania, Italy, 80131
Cremona, Lombardia, Italy, 26100
Pavia, Lombardia, Italy, 27100
Korea, Republic of
Incheon, Korea, Republic of, 405-760
Seoul, Korea, Republic of, 135-710
Seoul, Korea, Republic of, 136-705
Seoul, Korea, Republic of, 138-736
Mexico
Obregon, Mexico, 85000
Toluca, Mexico, 50180
Panama
Panama, Panama, 0834-02723
Peru
Arequipa, Peru, 04001
Lima, Peru, 11
Lima, Peru, 41
Piura, Peru, 20011
San Isidro, Peru, Lima 27
Poland
Elblag, Poland, 82-300
Lublin, Poland, 20-090
Olsztyn, Poland, 10-513
Warszawa, Poland, 02-781
Russian Federation
Ivanovo, Russian Federation, 153040
Moscow, Russian Federation, 115478
Moscow, Russian Federation, 143423
Pyatigorsk, Russian Federation, 357502
Ryazan, Russian Federation, 390011
Saint-Petersburg, Russian Federation, 197758
Samara, Russian Federation, 443031
Saratov, Russian Federation, 410053
St Petersburg, Russian Federation, 197022
Stavropol, Russian Federation, 355045
Tula, Russian Federation, 300053
Vladimir, Russian Federation, 600009
Slovakia
Kosice, Slovakia, 04001
Poprad, Slovakia, 05801
South Africa
Bloemfontein, South Africa, 9301
Cape Town, South Africa, 7506
Johannesburg, South Africa, 2193
Pretoria, South Africa, 0081
Rondebosch, South Africa, 7700
Sandton, South Africa, 2196
Spain
Santiago de Compostela, La Coruña, Spain, 15706
Reus, Tarragona, Spain, 43204
Madrid, Spain, 28007
Valencia, Spain, 46010
Zaragoza, Spain, 50009
Sweden
Lund, Sweden, 22185
Uppsala, Sweden, 75185
Taiwan
Changhua, Taiwan, 500
Taipei, Taiwan, 00112
Taipei, Taiwan, 112
Taoyuan, Taiwan, 333
Thailand
Bangkok, Thailand, 10330
Bangkok, Thailand, 10400
Bangkok, Thailand, 10700
Songkhla, Thailand, 90110
Turkey
Antalya, Turkey, 07070
Istanbul, Turkey, 34390
Izmir, Turkey, 35340
Sıhhiye, ANKARA, Turkey, 06100
Sponsors and Collaborators
Hoffmann-La Roche
Investigators
Study Director: Clinical Trials Hoffmann-La Roche
  More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT00950300     History of Changes
Other Study ID Numbers: BO22227  2008-007326-19 
Study First Received: July 30, 2009
Results First Received: November 4, 2016
Last Updated: November 22, 2016

Additional relevant MeSH terms:
Trastuzumab
Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Cyclophosphamide
Fluorouracil
Docetaxel
Epirubicin
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Antimetabolites
Antimetabolites, Antineoplastic
Antibiotics, Antineoplastic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors

ClinicalTrials.gov processed this record on February 20, 2017