A Study of Herceptin (Trastuzumab) in Combination With 2nd-Line Chemotherapy in Patients With HER2 Positive Metastatic Breast Cancer.

Study Overview
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Brief Summary
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This 2 arm study will compare the efficacy and safety of continuation or discontinuation of Herceptin treatment in combination with 2nd line chemotherapy, in patients with HER2 positive metastatic breast cancer whose condition has progressed on 1st line chemotherapy plus Herceptin. Patients will be randomized either to continue or discontinue Herceptin treatment (6mg/kg iv infusion every 3 weeks) while receiving second-line chemotherapy of the investigator's choice. The anticipated time on study treatment is until disease progression, and the target sample size is 100-500 individuals.

Official Title
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A Multicenter Phase II Trial of Trastuzumab (Herceptin) Continuation in Combination With 2nd-line Chemotherapies After Progression on a 1st-line Chemotherapy Combined With Trastuzumab in Patients With HER2 Positive Metastatic Breast Cancer (Treatment Beyond Progression, TBP)

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Second line chemotherapy
* Drug: trastuzumab [Herceptin]


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: female patients, >= 18 years of age; metastatic breast cancer; HER2 overexpression (IHC 3+ and/or FISH positive); disease progression during or after previous 1st line chemotherapy + Herceptin; scheduled to receive 2nd line chemotherapy. Exclusion Criteria: concurrent immunotherapy or hormonal therapy; anthracyclines as part of previous 1st line chemotherapy or planned 2nd line chemotherapy; cardiac toxicity during previous 1st line chemotherapy + Herceptin; history of other malignancy within last 5 years.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Trastuzumab + 2nd Line Chemotherapy<br> | Drug: Second line chemotherapy<br>* As prescribed<br>Drug: trastuzumab [Herceptin]<br>* 6mg/kg iv every 3 weeks<br>|
| Active Comparator: Only Chemotherapy<br> | Drug: Second line chemotherapy<br>* As prescribed<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Time to Disease Progression | Time to disease progression (TTP) in days was defined as the time from enrollment to objective disease progression (all categories other than objective disease progression was set to be censored including death before progression). Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a nontarget lesion, or the appearance of new lesions. Tumor assessments were performed using computer tomography or magnetic resonance imaging. TTP as assessed by investigator, along with a recalculation done by computer algorithm is presented below. Median time was not assessed for 'Only Chemotherapy' group as randomization of participants was not feasible considering Trastuzumab widespread use in routine clinical practice. | Up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate | Objective response rate (ORR) is defined as the percentage of participants with tumor shrinkage of a predefined amount. It is a combination of complete response (CR) and partial response (PR) and was assessed according to the RECIST criteria 1.0. Complete response refers to the disappearance of all target lesions and all non-target non-measurable lesions. Partial Response refers to an at least 30 percent decrease in the sum of longest diameter of target lesions, taking as reference the baseline sum longest diameter. Objective response rate was not assessed for 'Only Chemotherapy' group as randomization of participants was not feasible considering Trastuzumab widespread use in routine clinical practice. | Up to 5 years | 
| Clinical Benefit Rate | Clinical benefit rate (CBR) was defined as the percentage of participants taking a benefit from the treatments. CBR includes 1) Complete response (CR): disappearance of all target lesions and all non-target non-measurable lesions 2) Partial response (PR) : >=30% decrease in the sum of the longest diameter of target lesions and 3) Stable disease (SD): non-PR and non-progressive disease. It was evaluated using Response Evaluation Criteria in Solid Tumors (RECIST 1.0) and assessed by CT or MRI by the investigator. CBR was also assessed by computer. Clinical benefit rate was not assessed for 'Only Chemotherapy' group as randomization of participants was not feasible considering Trastuzumab widespread use in routine clinical practice. | Up to 5 years | 
| Median Time to Treatment Failure | Time to treatment failure is defined as a composite endpoint measuring time (number of days) from enrollment to discontinuation of treatment or change in treatment for any reason, including disease progression, treatment toxicity and death. Median time to treatment failure was not assessed for 'Only Chemotherapy' group as randomization of participants was not feasible considering Trastuzumab widespread use in routine clinical practice. | Up to 5 years | 
| Overall Survival | Overall Survival is defined as the time (number of days) between enrollment and the date of death due to any cause. Overall survival was not assessed for 'Only Chemotherapy' group as randomization of participants was not feasible considering Trastuzumab widespread use in routine clinical practice. | Up to 5 years | 
| Number of Participants With Any Adverse Events and Serious Adverse Events | An adverse event (AE) is any untoward medical occurrence in a participant who is administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. A serious adverse event (SAE) is any untoward medical occurrence that at any dose results in death, are life threatening, requires hospitalization or prolongation of hospitalization or results in disability/incapacity, and congenital anomaly/birth defect. | Up to 5 years | 
| Biochemistry Safety Laboratory Parameters: Mean Serum Glutamic Oxaloacetic Transaminase, Serum Glutamic-pyruvic Transaminase and Alkali Phosphatase Levels | Participants in the study were evaluated for the serum glutamic oxaloacetic transaminase (SGOT), serum glutamic-pyruvic transaminase (SGPT) and alkali phosphatase (ALP) at Visit 1 and final study assessments (Up to 5 years). Serum glutamic oxaloacetic transaminase, Serum glutamic-pyruvic transaminase and Alkali Phosphatase levels were not assessed for 'Only Chemotherapy' group as randomization of participants was not feasible considering Trastuzumab widespread use in routine clinical practice. | Visit 1 [Screening Period (6 weeks prior to enrollment)] and Final study Assessments (Up to 5 years) | 
| Biochemistry Safety Laboratory Parameters: Mean Total Bilirubin and Serum Creatinine Levels | Participants in the study were evaluated for the total bilirubin and serum creatinine. Total Bilirubin and serum creatinine levels were not assessed for 'Only Chemotherapy' group as randomization of participants was not feasible considering Trastuzumab widespread use in routine clinical practice. | Visit 1 [Screening Period (6 weeks prior to enrollment)] and Final study Assessments (Up to 5 years) | 
| Biochemistry Safety Laboratory Parameters: Mean Albumin Levels | Participants in the study were evaluated for the albumin at Visit 1 and Final study assessments. Albumin levels were not assessed for 'Only Chemotherapy' group as randomization of participants was not feasible considering Trastuzumab widespread use in routine clinical practice. | Visit 1 [Screening Period (6 weeks prior to enrollment)] and Final study assessments (Up to 5 years) | 
| Biochemistry Safety Laboratory Parameters: Mean Urea, Sodium and Potassium Levels | Participants in the study were evaluated for the biochemical safety laboratory parameters urea, sodium and potassium. Urea, sodium and potassium levels were not assessed for 'Only Chemotherapy' group as randomization of participants was not feasible considering Trastuzumab widespread use in routine clinical practice. | Visit 1 [Screening Period (6 weeks prior to enrollment)] and Final study assessments (Up to 5 years) | 
| Hematology Safety Laboratory Parameters: Mean Hemoglobin Levels | Participants in the study were evaluated for the Hemoglobin up to 5 years. Hemoglobin levels were not assessed for 'Only Chemotherapy' group as randomization of participants was not feasible considering Trastuzumab widespread use in routine clinical practice. | Visit 1 [Screening Period (6 weeks prior to enrollment)] and final study assessments (Up to 5 years) | 
| Hematology Safety Laboratory Parameters: Mean Total Leukocytes Counts | Participants in the study were evaluated for the total leukocytes up to 5 years. Total leukocytes counts were not assessed for 'Only Chemotherapy' group as randomization of participants was not feasible considering Trastuzumab widespread use in routine clinical practice. | Visit 1 [Screening Period (6 weeks prior to enrollment)] and final study assessments (Up to 5 years) | 
| Hematology Safety Laboratory Parameters: Percent of Differential for Neutrophils, Basophils, Eosinophils, Lymphocytes and Monocytes Counts | Participants in the study were evaluated for the Neutrophils, Basophils, Eosinophils, Lymphocytes and Monocytes at Visit 1 and final study assessments. Neutrophils, Basophils, Eosinophils, Lymphocytes and Monocytes counts were not assessed for 'Only Chemotherapy' group as randomization of participants was not feasible considering Trastuzumab widespread use in routine clinical practice. | Visit 1 [Screening Period (6 weeks prior to enrollment)] and final study assessments (Up to 5 years) | 
| Hematology Safety Laboratory Parameter: Mean Platelets Counts | Participants in the study were evaluated for the platelets at Visit 1 and final study assessments. Platelet counts were not assessed for 'Only Chemotherapy' group as randomization of participants was not feasible considering Trastuzumab widespread use in routine clinical practice. | Visit 1 [Screening Period (6 weeks prior to enrollment)] and final study assessments (Up to 5 years) | 
| Mean Left Ventricular Ejection Fraction | Left ventricular ejection fraction (LVEF) is a measure of the percent of blood ejected from the ventricle in one heartbeat. It is a measure of cardiac function and was assessed by echocardiogram or multigated angiogram at Visit 0 [Screening period (6 weeks prior to enrollment)] and final study assessments (Up to 5 years). | Visit 0 [Screening period (6 weeks prior to enrollment)] and final study assessments (Up to 5 years). |