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
- Conditions
- Breast Cancer
- Interventions
- Registration Number
- NCT00950300
- Lead Sponsor
- Hoffmann-La Roche
- 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 available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- Female
- Target Recruitment
- 596
- 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
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Herceptin SC + Chemotherapy Herceptin SC [trastuzumab] 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. Herceptin IV + Chemotherapy Herceptin IV [trastuzumab] 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. Herceptin IV + Chemotherapy 5-Fluorouracil 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. Herceptin IV + Chemotherapy Cyclophosphamide 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. Herceptin IV + Chemotherapy Docetaxel 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. Herceptin IV + Chemotherapy Epirubicin 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. Herceptin SC + Chemotherapy 5-Fluorouracil 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. Herceptin SC + Chemotherapy Cyclophosphamide 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. Herceptin SC + Chemotherapy Docetaxel 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. Herceptin SC + Chemotherapy Epirubicin 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.
- Primary Outcome Measures
Name Time Method Observed Serum Trough Concentration (Ctrough) of Trastuzumab Prior to Surgery 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) 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
Name Time Method Number of Participants With Ctrough of Trastuzumab >20 μg/mL After Surgery 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 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 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.
Observed Ctrough of Trastuzumab After Surgery 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 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 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 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.
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 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.
Area Under the Concentration-Time Curve From 0 to 21 Days (AUC21d) of Trastuzumab Prior to Surgery 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 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 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 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) 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.
Time to Response According to RECIST Version 1.0, Among Those With Measurable Disease at Baseline 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 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) 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 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) 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 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) 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).
Trial Locations
- Locations (106)
Centro Medico San Roque; Oncology Dept
🇦🇷Tucuman, Argentina
Caipo; Oncology
🇦🇷Tucuman, Argentina
Hospital Sao Rafael - HSR
🇧🇷Salvador, BA, Brazil
Hospital das Clinicas - UFPR; Quimioterapia
🇧🇷Curitiba, PR, Brazil
Liga Norte Riograndense Contra O Câncer
🇧🇷Natal, RN, Brazil
Clinica de Neoplasias Litoral
🇧🇷Itajai, SC, Brazil
Hospital Amaral Carvalho
🇧🇷Jau, SP, Brazil
Instituto do Cancer do Estado de Sao Paulo - ICESP
🇧🇷Sao Paulo, SP, Brazil
Hospital Perola Byington
🇧🇷Sao Paulo, SP, Brazil
Instituto de Oncologia de Sorocaba - CEPOS
🇧🇷Sorocaba, SP, Brazil
Scroll for more (96 remaining)Centro Medico San Roque; Oncology Dept🇦🇷Tucuman, Argentina