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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

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ClinicalTrials.gov Identifier: NCT00950300
Recruitment Status : Completed
First Posted : July 31, 2009
Results First Posted : January 23, 2017
Last Update Posted : January 23, 2018
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche

Tracking Information
First Submitted Date  ICMJE July 30, 2009
First Posted Date  ICMJE July 31, 2009
Results First Submitted Date  ICMJE November 4, 2016
Results First Posted Date  ICMJE January 23, 2017
Last Update Posted Date January 23, 2018
Actual Study Start Date  ICMJE October 16, 2009
Actual Primary Completion Date July 12, 2011   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 22, 2016)
  • 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.
Original Primary Outcome Measures  ICMJE
 (submitted: July 30, 2009)
  • trastuzumab serum concentrations, comparing sc versus iv administration [ Time Frame: throughout cycles 1 to 8 ]
  • pathologic complete response [ Time Frame: after surgery between cycles 8 and 9 ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: December 21, 2017)
  • 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 (SD) of target lesions with no prior assessment of PD. PD was defined as ≥20% relative increase and ≥5 mm of absolute increase in the SD of target lesions, taking as reference the smallest SD recorded since treatment started; or appearance of 1 or more new lesions. 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 SD of target lesions with no prior assessment of PD. PD was defined as ≥20% relative increase and ≥5 mm of absolute increase in the SD of target lesions, taking as reference the smallest SD recorded since treatment started; or appearance of 1 or more new lesions. 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 [ Time Frame: Screening; Day 1 of Cycle 18 (cycle length of 21 days); and Months 6, 12, 24, 36, 48, 60 from last dose of Cycle 18; then every 6 months until withdrawal for any reason (up to approximately 87 months overall) ]
    Protocol-defined events included disease recurrence/progression (local, regional, distant, contralateral) or death from any cause. Imaging was performed at specified visits for up to 5 years after last dose. Thereafter, participants were followed for survival only. The percentage of participants who experienced a protocol-defined event at any time during the study was reported.
  • Event-Free Survival (EFS) [ Time Frame: Screening; Day 1 of Cycle 18 (cycle length of 21 days); and Months 6, 12, 24, 36, 48, 60 from last dose of Cycle 18; then every 6 months until withdrawal for any reason (up to approximately 87 months overall) ]
    Protocol-defined events included disease recurrence or progression (local, regional, distant, contralateral) or death from any cause. Imaging was performed at specified visits for up to 5 years after last dose. Thereafter, participants were followed for survival only. EFS was estimated by Kaplan-Meier analysis and defined as the time from randomization to the first protocol-defined event.
  • Percentage of Participants Who Died [ 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 (up to approximately 87 months overall) ]
    The percentage of participants who died at any time during the study was reported.
  • Overall Survival (OS) [ 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 (up to approximately 87 months overall) ]
    OS was estimated by Kaplan-Meier analysis and defined as the time from randomization to death from any cause.
  • Number 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, 54, 60 from last dose of Cycle 18 ]
    Participants provided PK samples for evaluation of anti-trastuzumab antibodies. The number of participants with "Treatment-induced ADAs" and "Treatment-enhanced ADA" against trastuzumab at any time during or after treatment was reported. Treatment-induced ADA = a participant with negative or missing Baseline ADA result(s) and at least one positive post-Baseline ADA result. Treatment-enhanced ADA = a participant with positive ADA result at Baseline who has one or more post Baseline titer results that are at least 0.60 titer unit greater than the Baseline titer result (four-fold increase of titer).
  • Number 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, 54, 60 from last dose of Cycle 18 ]
    Participants in the Herceptin SC arm provided PK samples for evaluation of anti-rHuPH20 antibodies. The number of participants with "Treatment-induced ADAs" and "Treatment-enhanced ADA" against rHuPH20 (an excipient unique to the SC formulation) at any time during or after treatment was reported. Treatment-induced ADA = a participant with negative or missing Baseline ADA result(s) and at least one positive post-Baseline ADA result. Treatment-enhanced ADA = a participant with positive ADA result at Baseline who has one or more post Baseline titer results that are at least 0.60 titer unit greater than the Baseline titer result (four-fold increase of titer).
Original Secondary Outcome Measures  ICMJE
 (submitted: July 30, 2009)
  • trastuzumab serum concentrations, comparing sc versus iv administration after surgery [ Time Frame: throughout cycles 9 to 13 ]
  • total pathologic complete response [ Time Frame: after surgery between cycles 8 and 9 ]
  • overall response rate [ Time Frame: after 2, 4, 6 and 8 cycles of treatment ]
  • progression and recurrence free survival [ Time Frame: after 2,4,6,8 and 18 cycles of treatment and after 6, 12 and 24 months of follow-up ]
  • overall survival [ Time Frame: event-driven ]
  • safety and tolerability [ Time Frame: throughout the study ]
  • immunogenicity (formation of anti-trastuzumab antibodies) [ Time Frame: sampling at follow-up visits 3, 6, 12, 18 and 24 months after last dose of study drug ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE 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
Official Title  ICMJE 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)
Brief Summary 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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Breast Cancer
Intervention  ICMJE
  • 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.
  • 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.
Study Arms  ICMJE
  • 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.
    Interventions:
    • Drug: 5-Fluorouracil
    • Drug: Cyclophosphamide
    • Drug: Docetaxel
    • Drug: Epirubicin
    • Drug: Herceptin IV [trastuzumab]
  • 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.
    Interventions:
    • Drug: 5-Fluorouracil
    • Drug: Cyclophosphamide
    • Drug: Docetaxel
    • Drug: Epirubicin
    • Drug: Herceptin SC [trastuzumab]
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: November 15, 2011)		 596
Original Estimated Enrollment  ICMJE
 (submitted: July 30, 2009)		 552
Actual Study Completion Date  ICMJE January 24, 2017
Actual Primary Completion Date July 12, 2011   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Argentina,   Brazil,   Canada,   Colombia,   Czechia,   Estonia,   France,   Germany,   Guatemala,   Hong Kong,   Hungary,   Israel,   Italy,   Korea, Republic of,   Mexico,   Panama,   Peru,   Poland,   Russian Federation,   Slovakia,   South Africa,   Spain,   Sweden,   Taiwan,   Thailand,   Turkey
Removed Location Countries Costa Rica,   Czech Republic,   Ecuador
 
Administrative Information
NCT Number  ICMJE NCT00950300
Other Study ID Numbers  ICMJE BO22227
2008-007326-19 ( EudraCT Number )
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Current Responsible Party Hoffmann-La Roche
Original Responsible Party Clinical Trials, Study Director, Hoffmann-La Roche
Current Study Sponsor  ICMJE Hoffmann-La Roche
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Clinical Trials Hoffmann-La Roche
PRS Account Hoffmann-La Roche
Verification Date December 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP