A Study of Herceptin (Trastuzumab) in Combination Chemotherapy in Patients With Metastatic or Locally Advanced Breast Cancer

Study Overview
=================
Brief Summary
-----------------
This study will define an optimal chemotherapy dose regimen of Myocet in combination with paclitaxel and intravenous Herceptin and will evaluate the efficacy and safety of this dose regimen in patients with metastatic or locally advanced breast cancer and HER2 overexpression. The anticipated time on study treatment is 3-12 months.

Official Title
-----------------
'A Study of the Effect of First Line Treatment With Paclitaxel and Myocet in Combination With Herceptin on Overall Tumor Response in Patients With Metastatic or Locally Advanced Breast Cancer and HER2 Overexpression.'

Conditions
-----------------
Breast Cancer

Intervention / Treatment
-----------------
* Drug: trastuzumab
* Drug: paclitaxel
* Drug: Myocet


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: women 18-70 years of age; metastatic or locally advanced breast cancer; HER2 overexpression; >= 1 measurable lesion. Exclusion Criteria: prior treatment for advanced breast cancer; prior treatment with Herceptin; bone or central nervous system metastasis as the only site of disease; history of another malignancy (except basal cell skin cancer and cancer in situ of the uterine cervix, and contralateral breast cancer) within 5 years of study.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Trastuzumab, Myocet, Paclitaxel; Phase I<br>Participants received an initial loading dose of trastuzumab 4 milligrams per kilogram (mg/kg), intravenously (IV), over 1.5 hours during Week 1, followed by 2 mg/kg, IV, over 30 minutes once per week from Week 2 to Week 52 or until disease progression. Participants also received myocet, 40 mg/ square meter (m^2), IV, every 3 weeks, from Week 1; if no dose limiting toxicity (DLT) was observed in greater than or equal to (≥) two-thirds (2/3) of cohort for 2 treatment cycles, the dose was increased to 50 mg/m^2, IV, and continued for 6 cycles. Participants also received paclitaxel 60 mg/ m^2, IV, once per week, from Week 19; if no DLT was observed in ≥ 2/3 of cohort for 2 treatment cycles, the dose was increased to 70 mg/m^2, IV, and subsequently 80 mg/m^2, IV, and continued until disease progression. | Drug: trastuzumab<br>* Initial loading does of 4 mg/kg IV, followed by 2 mg/kg IV weekly, until disease progression<br>* Other names: Herceptin;Drug: paclitaxel<br>* 60 mg/m^2 IV weekly; dose increased to 70 mg/m^2, and subsequently 80 mg/m^2, after 2 treatment cycles with no evidence of DLT until disease progression<br>Drug: Myocet<br>* 40 mg/m^2 IV weekly; dose increased to 50 mg/m^2 IV after 2 treatment cycles with no evidence of DLT for 6 cycles<br>|
| Experimental: Trastuzumab, Myocet, Paclitaxel; Phase II<br>Participants received an initial loading dose of trastuzumab 4 mg/kg, IV, over 1.5 hours during Week 1, followed by 2 mg/kg, IV, over 30 minutes once per week from Week 2 to Week 52 or until disease progression. Participants also received myocet, 50 mg/m^2, IV, every 3 weeks, from Week 1 for 6 cycles. Participants also received paclitaxel 80 mg/m^2, IV, once per week, from Week 19 until disease progression. | Drug: trastuzumab<br>* Initial loading does of 4 mg/kg IV, followed by 2 mg/kg IV weekly, until disease progression<br>* Other names: Herceptin;Drug: paclitaxel<br>* 60 mg/m^2 IV weekly; dose increased to 70 mg/m^2, and subsequently 80 mg/m^2, after 2 treatment cycles with no evidence of DLT until disease progression<br>Drug: Myocet<br>* 40 mg/m^2 IV weekly; dose increased to 50 mg/m^2 IV after 2 treatment cycles with no evidence of DLT for 6 cycles<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving Complete Response (CR) or Partial Response (PR) According to World Health Organization (WHO) Handbook for Reporting Results of Cancer Treatment | For measurable disease, CR was defined as the disappearance of all clinically detectable disease determined by 2 observations not less than 4 weeks apart; and PR was defined as a 50 percent (%) decrease in the sum of the products of the 2 greatest diameters of all measurable lesions by 2 observations not less than 4 weeks apart, and no appearance of new lesions or progression of any lesion. For immeasurable disease, CR was defined as the complete disappearance of all known disease for at least 4 weeks; and PR was defined as an estimated decrease in tumor size of 50% or more for at least 4 weeks. | Baseline (BL), Weeks 7, 13, 19, every 8 weeks thereafter until end of study (for up to 3 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Disease Progression - Percentage of Participants With an Event | Disease progression was defined as the time from the start of treatment to the date of the first recorded incident of disease progression, or the date of death due any cause. For measurable disease, disease progression was defined as a ≥25% increase in the sum of the products of diameters of 1 or more measurable lesions with a minimal area of greater than (>)2 square centimeters (cm^2), or the appearance of new lesions; and for malignant lesions with a minimal area of 2 cm^2, an increase of ≥1 cm^2. For immeasurable disease, disease progression was defined as the appearance of any new lesion not previously identified or an estimated increase of ≥50% in existent lesions. | BL, Weeks 7, 13, 19, every 8 weeks thereafter until end of study (for up to 3 years) | 
| Time to Disease Progression | The median time, in months, from the start of treatment to disease progression event. | BL, Weeks 7, 13, 19, every 8 weeks thereafter until end of study (for up to 3 years) | 
| Time to Treatment Response - Percentage of Participants With an Event | Treatment response was defined as the time from the start of treatment to the date of recorded CR or PR of measurable disease. | BL, Weeks 7, 13, 19, every 8 weeks thereafter until end of study (for up to 3 years) | 
| Time to Treatment Response | The median time, in months, from the start of treatment to treatment response event. | BL, Weeks 7, 13, 19, every 8 weeks thereafter until end of study (for up to 3 years) | 
| Duration of Response - Percentage of Participants With an Event | Duration of response was defined as the time from date CR was first recorded to the date progressive disease (PD) was first noted. For measurable disease, PD was defined as a ≥25% increase in the sum of the products of diameters of 1 or more measurable lesions with a minimal area of >2 cm^2, or the appearance of new lesions; and for malignant lesions with a minimal area of 2 cm^2, an increase of ≥1 cm^2. For immeasurable disease, PD was defined as the appearance of any new lesion not previously identified or an estimated increase of ≥50% in existent lesions. | BL, Weeks 7, 13, 19, every 8 weeks thereafter until end of study (for up to 3 years) | 
| Duration of Response | The median time, in months, from enrollment to duration of response event to Week 52. | BL, Weeks 7, 13, 19, every 8 weeks thereafter until end of study (for up to 3 years) | 
| Time to Therapy Failure - Percentage of Participants With an Event | Therapy failure was defined as the date of the start of therapy to the date of withdrawal due to adverse events, progressive disease/insufficient therapeutic response, death, failure to return, or refusal of treatment/lack of cooperation/withdrawal of consent. Participants were censored at the last dose of treatment if no event was recorded. | BL, Weeks 7, 13, 19, every 8 weeks thereafter until end of study (for up to 3 years) | 
| Time to Therapy Failure | The median time, in months, from treatment start to therapy failure event. Participants were censored at the last date of treatment if no event was recorded. | BL, Weeks 7, 13, 19, every 8 weeks thereafter until end of study (for up to 3 years) | 
| Overall Survival (OS) - Percentage of Participants With an Event | OS was defined as the time from the date of the start of treatment to the date of death or the last date the participant was known to be alive. | BL, Weeks 7, 13, 19, every 8 weeks thereafter until end of study (for up to 3 years) | 
| Overall Survival | The time, in months, from the start of treatment to OS event. The mean survival time and it's standard error were underestimated because the largest observation was censored and the estimation was restricted to the largest event time. | BL, Weeks 7, 13, 19, every 8 weeks thereafter until end of study (for up to 3 years) |