A Phase III Trial For Patients With Metastatic Breast Cancer

Study Overview
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Brief Summary
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This is a phase III randomized study between the docetaxel/gemcitabine and docetaxel/ capecitabine doublets, with crossover to the alternate agent. The experimental arm will receive gemcitabine 1000 mg/m2 intravenous (IV) over 30 minutes days 1 and 8 and docetaxel 75 mg/m2 IV day 1 over 1 hour repeated every three weeks. The comparator arm will receive docetaxel 75 mgm/m2 IV day 1 over 1 hour and oral capecitabine 1000 mg/m2 twice daily, days 1 through 14 repeated every three weeks. Patients who progress on the experimental arm, will be treated with capecitabine as dosed on the comparator arm. Patients who progress on the comparator arm will be treated with gemcitabine as dosed on the experimental arm.

Official Title
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Randomized Trial of Gemcitabine Plus Docetaxel vs. Docetaxel Plus Capecitabine in Metastatic Breast Cancer in 1st and 2nd

Conditions
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Breast Cancer, Breast Neoplasms, Cancer of the Breast

Intervention / Treatment
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* Drug: gemcitabine
* Drug: docetaxel
* Drug: capecitabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologic or cytologic confirmation of breast cancer with locally advanced and/or metastatic disease Patients may have received prior neo-adjuvant or adjuvant taxane regimen as long as it has been greater than or equal to 6 months since completion of the regimen Patients may have had 0-1, but no more than one prior course of chemotherapy for metastatic disease Patients must have either measurable or non-measurable (evaluable) disease Prior radiation therapy allowed of less than 25% of the bone marrow Exclusion Criteria: Second primary malignancy (except in situ carcinoma of the cervix or adequately treated nonmelanomatous carcinoma of the skin or other malignancy treated at least 5 years previously with no evidence of recurrence) Parenchymal or leptomeningeal brain metastases Peripheral neuropathy greater than or equal to grade 2 Prior treatment with gemcitabine and capecitabine will not be allowed. Prior treatment with a taxane in the metastatic setting will not be allowed. Prior taxane therapy in the neo-adjuvant or adjuvant setting is allowed if completion of therapy greater than or equal to 6 months prior to enrollment. Active cardiac disease not controlled by therapy and/or myocardial infarction within the preceding 6 months. Concomitant Herceptin is not allowed

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

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: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Gemcitabine + Docetaxel<br> | Drug: gemcitabine<br>* 1000 mg/m2, intravenous (IV) day 1 and day 8 every 21 days until disease progression<br>* Other names: Gemzar;Drug: docetaxel<br>* 75 mg/m2, intravenous (IV), every 21 days until disease progression<br>|
| Active Comparator: Capecitabine + Docetaxel<br> | Drug: docetaxel<br>* 75 mg/m2, intravenous (IV), every 21 days until disease progression<br>Drug: capecitabine<br>* 1000 mg/m2, by mouth (PO) twice a day (BID), days 1-14, every 21 days until disease progression<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Disease Progression (Initial Treatment) | Time to disease progression (TTDP) at initial treatment was defined as the number of months between date of randomization and the date of first documented disease progression or the date of death due to disease under study, whichever came first. TTDP censored at earliest of: 1) date of death not due to disease; or 2) date of last contact for participants alive without disease progression; or 3) start date of other anti-tumor therapy; or 4) first dose date of crossover treatment. | Randomization date to the earliest date of first documented disease progression date or the date of death if the participant died due to study disease (up to 82 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Disease Progression (Crossover Treatment) | For crossover treatment, time to disease progression (TTDP) was defined as the number of months between the first dose date of crossover treatment and the date of disease progression or the date of death due to disease under study, whichever came first. TTDP for crossover treatment only applied to those participants who crossed over from initial treatment to crossover treatment. TTDP censored at earliest of: 1)date of death not due to disease; or 2)date of last contact for participants alive without disease progression; or 3)start date of other anti-tumor therapy due to progression. | Date of first dose of crossover treatment to date of first-documented disease progression after receiving first crossover treatment or date of death due to study disease, whichever came first (up to 82 months) | 
| Progression-Free Survival (Initial Treatment) | For initial treatment, progression-free survival (PFS) was defined as the number of months between the date of randomization and the date of first documented disease progression or the date of death due to any cause, whichever came first. Time to PFS was censored at the earliest of: 1) date of last contact for participants alive without disease progression; or 2) start date of other anti-tumor therapy for progression; or 3) first dose date of crossover treatment. | Date of randomization until the date of first documented progression or date of death from any cause, whichever came first (up to 82 months) | 
| Progression-Free Survival (Crossover Treatment) | For crossover treatment, progression-free survival (PFS) was defined as the number of months between first dose date of crossover treatment and date of documented disease progression or date of death due to any cause, whichever came first. PFS for crossover treatment only applied to those participants who crossed over from initial treatment to crossover treatment. PFS was censored at the earliest of: 1) date of last contact for participants alive without disease progression; or 2) start date of other anti-tumor therapy for participants with documented disease progression. | First dose date of crossover treatment to date of first-documented progression after receiving crossover treatment or date of death due to any cause, whichever came first (up to 82 months) | 
| Duration of Response (Initial Treatment) | Among tumor responders, duration of tumor response was measured from the date of response (complete response [CR] or partial response [PR] until the first date of documented progression or death from any cause. Duration of response was censored at the earliest of: 1) date of last contact for participants alive without disease progression (DP); or 2) start date of other anti-tumor therapy for DP; or 3) dose date of crossover treatment. | Date of response (CR or PR) until the first date of documented progression or death from any cause (up to 82 months) | 
| Duration of Response (Crossover Treatment) | At crossover treatment, duration of response was measured from the time criteria were met for complete response (CR) or partial response (PR), until first date that recurrent or progressive disease was objectively documented or date of death due to any cause, whichever came first. This definition only applied to those who crossed over & achieved CR or PR in crossover treatment. Duration of response censored at earliest of: 1) date of last contact for those alive without disease progression; or 2) start date of other anti-tumor therapy for documented disease progression. | Date of CR or PR until first date of recurrent or progressive disease after receiving crossover treatment was objectively documented or date of date due to any cause, whichever came first (up to 82 months) | 
| Overall Survival | Overall survival time was defined as the number of months between the date of randomization and the date of death due to any cause. The overall survival time was censored at the date of last contact for participants who were still alive. | Date of randomization to date of death from any cause (up to 82 months) | 
| Best Overall Response (Initial Treatment) | Best overall response was the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started). Response was assessed using Response Evaluation Criteria In Solid Tumors (RECIST) criteria. Complete Response=disappearance of all target lesions; Partial Response=30% decrease in sum of longest diameter of target lesions; Progressive Disease=20% increase in sum of longest diameter of target lesions; Stable Disease=small changes that did not meet above criteria. | Best response from start of treatment until disease progression/recurrence (up to 82 months) | 
| Best Overall Response (Crossover Treatment) | Best overall response was the best response recorded from the start of treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started). Response assessed using RECIST criteria. Complete Response=disappearance of all target lesions; Partial Response=30% decrease in sum of longest diameter of target lesions; Progressive Disease=20% increase in sum of longest diameter of target lesions; Stable Disease=small changes that did not meet above criteria. | Best response from start of treatment until disease progression/recurrence (up to 82 months) | 
| Summary of Changes in Karnofsky Performance Status (KPS) by Treatment (Initial Treatment) | KPS ranges from 0 to 100, subdivided into three categories: incapacitated (0-40), self-care (50-70), and normal activity (80-100). | Baseline until crossover treatment began (up to 82 months) | 
| Summary of Changes in Karnofsky Performance Status (KPS) by Treatment (Crossover Treatment) | KPS ranges from 0 to 100, subdivided into three categories: incapacitated (0-40), self-care (50-70), and normal activity (80-100). | First day of crossover treatment until end of crossover treatment at trial discontinuation (up to 82 moths) | 
| Summary of Changes in Rotterdam Symptom Checklist (RSCL) by Treatment (Initial Treatment) | RSCL includes 4 scales to assess quality of life (QOL) endpoints: 1) a 23-item physical distress level with scale score ranges from 23 to 92 [low score represents better QOL] 2)a 7-item psychological distress level with scale score ranges from 7 to 28[low score represents better QOL] 3)8-item activity level with scale score ranges from 8 to 32 [high score represents better QOL]; 1-item overall valuation of life with score range from 1 to 7 [low score represents better QOL]. | Baseline until crossover treatment began (up to 82 months) | 
| Summary of Changes in Rotterdam Symptom Checklist by Treatment (Crossover Treatment) | RSCL includes 4 scales to assess quality of life (QOL) endpoints: 1) a 23-item physical distress level with scale score ranges from 23 to 92 [low score represents better QOL] 2)a 7-item psychological distress level with scale score ranges from 7 to 28[low score represents better QOL] 3)8-item activity level with scale score ranges from 8 to 32 [high score represents better QOL]; 1-item overall valuation of life with score range from 1 to 7 [low score represents better QOL]. | First day of crossover treatment until end of crossover treatment at trial discontinuation (up to 82 months) |