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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 has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT00950300
First Posted: July 31, 2009
Last Update Posted: November 1, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Information provided by (Responsible Party):
Hoffmann-La Roche
  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: None (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
Actual Study Start Date: October 16, 2009
Study Completion Date: January 24, 2017
Primary Completion Date: July 12, 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

Information from the National Library of Medicine

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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
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00950300


  Show 106 Study Locations
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 ( EudraCT Number )
First Submitted: July 30, 2009
First Posted: July 31, 2009
Results First Submitted: November 4, 2016
Results First Posted: January 23, 2017
Last Update Posted: November 1, 2017
Last Verified: October 2017

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