A Study of Avastin (Bevacizumab) in Combination With Chemotherapy in Patients With Endocrine Tumors of the Gastrointestinal Tract.

Study Overview
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Brief Summary
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This 2 arm study will assess the efficacy and safety of two systemic treatments including Avastin in patients with previously-untreated progressive locally advanced/metastatic well-differentiated digestive endocrine tumors. Patients with duodeno-pancreatic tumors (arm 1) will be treated with 5FU/streptozotocin iv (5FU 400mg/m2/d D1 to D5;streptozotocin 500mg/m2/d/iv D1 to D5;D1=D42) every 6 weeks, plus Avastin 7.5mg/kg iv every 3 weeks. Patients with gastrointestinal tract tumors (arm 2) will be treated with Xeloda 1000mg/m2 po bid D1 to D14 plus Avastin 7.5mg/kg iv D1=D21 every 3 weeks. The patients will be treated with chemotherapy for a minimum of 6 months, unless there is tumor progression and/or unacceptable toxicity. The anticipated time on study treatment is until disease progression or unacceptable toxicity, and the target sample size is <100 individuals.

Official Title
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An Open Label Study to Evaluate the Effect of Avastin in Association With Chemotherapy on Progression-free Survival in Patients With Progressive Advanced/Metastatic Well-differentiated Digestive Endocrine Tumors of the Gastrointestinal Tract

Conditions
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Neoplasms

Intervention / Treatment
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* Drug: bevacizumab [Avastin]
* Drug: 5 FU
* Drug: Streptozotocin
* Drug: Xeloda


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: adult patients, >=18 years of age; well-differentiated gastrointestinal tract endocrine tumors, or duodeno-pancreatic endocrine tumors; no previous anti-cancer therapy, other than surgery; progressive metastatic disease; >=1 measurable lesion. Exclusion Criteria: abnormal cardiac function, with history of ischemic heart disease in past 6 months and/or abnormal 12 lead ECG; patients with known bleeding disorders; unstable systemic disease; chronic daily treatment with high-dose aspirin, NSAIDs or corticosteroids; previous history of malignancy (other than successfully treated basal and squamous cell cancer of the skin, and/or in situ cancer of the cervix).

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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br> | Drug: bevacizumab [Avastin]<br>* 7.5mg/kg iv on day 1 every 3 weeks<br>Drug: 5 FU<br>* 400mg/m2/day iv on days 1-5 every 6 weeks<br>Drug: Streptozotocin<br>* 500mg/m2/day iv on days 1-5 every 6 weeks<br>|
| Experimental: 2<br> | Drug: bevacizumab [Avastin]<br>* 7.5mg/kg iv on day 1 every 3 weeks<br>Drug: Xeloda<br>* 1000mg/m2 po bid on days 1-14 every 3 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) - Percentage of Participants With an Event | PFS is defined as the interval between the date of start of treatment and the date of evaluation by the investigator of progressive disease or death from any cause. The progression was assessed according to Response Evaluation Criteria In Solid Tumors (RECIST) using medical imaging during the treatment period and by the investigators (confirmed by medical imaging) during the follow-up period. Data for participants who were lost to follow-up were censored at the date of last evaluation without progression. Data for participants who completed the study without an event of disease progression or death were censored at the date of the last visit or follow-up without progression. | Screening, every 3 months during treatment, every 6 months during follow-up to 2 years | 
| PFS - Time to Event | PFS is defined as the interval between the date of start of treatment and the date of evaluation by the investigator of progressive disease or death from any cause. The progression was assessed according to RECIST using medical imaging during the treatment period and by the investigators (confirmed by medical imaging) during the follow-up period. Data for participants who were lost to follow-up were censored at the date of last evaluation without progression. Data for participants who completed the study without an event of disease progression or death were censored at the date of the last visit or follow-up without progression. Median PFS was estimated using the Kaplan-Meier method. | Screening, every 3 months during treatment, every 6 months during follow-up to 2 years | 
| PFS - Percentage of Participants Estimated to be Progression Free at 12 and 24 Months | PFS is defined as the interval between the date of start of treatment and the date of evaluation by the investigator of progressive disease or death from any cause. The progression was assessed according to RECIST using medical imaging during the treatment period and by the investigators (confirmed by medical imaging) during the follow-up period. Data for participants who were lost to follow-up were censored at the date of last evaluation without progression. Data for participants who completed the study without an event of disease progression or death were censored at the date of the last visit or follow-up without progression. | Screening, every 3 months during treatment, every 6 months during follow-up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With a Response by Best Overall Response | Best overall response defined as best response recorded during the study as defined according to RECIST; performed by the investigator and by centralized review. Complete response (CR): complete disappearance of all target lesions and non-target disease. All lesions, both target and non-target, must have decreased to normal (short axis, less than [<]10 millimeters [mm]). No new lesions. Partial response (PR): greater than or equal to (≥)30 percent (%) decrease under baseline of the sum of diameters of all target lesions. The short axis was used in the sum for target nodes, while the longest diameter (LD) was used in the sum for all other target lesions. No unequivocal progression of non-target disease. No new lesions. Stable disease (SD): not qualifying for CR, PR, or Progressive Disease (PD). PD: at least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of 1 or more new lesions. | Screening, every 3 months during treatment, every 6 months during follow-up to 2 years | 
| Duration of Overall Response (OR) - Percentage of Participants With an Event | Determined only for those participants with an overall response (CR or PR) and was defined as the time interval between the response (CR or PR) and the date of progression or death from any cause. Data for participants who were lost to follow-up were censored at the date of last evaluation without progression. Data for participants who completed the study without an event of progression or death were censored at the data of last visit or follow-up without progression. | Screening, every 3 months during treatment, every 6 months during follow-up to 2 years | 
| Duration of OR - Time to Event | Determined only for those participants with an overall response (CR or PR) and was defined as the time interval between the response (CR or PR) and the date of progression or death from any cause. Data for participants who were lost to follow-up were censored at the date of last evaluation without progression. Data for participants who completed the study without an event of progression or death were censored at the data of last visit or follow-up without progression. Median duration of OR was estimated using the Kaplan-Meier method. | Screening, every 3 months during treatment, every 6 months during follow-up to 2 years | 
| Duration of OR - Percentage of Participants With Sustained Response at 12 and 24 Months | Duration of OR was determined only for those participants with an overall response of CR or PR and was defined as the time interval between the response (CR or PR) and the date of progression or death from any cause. Data for participants who were lost to follow-up were censored at the date of last evaluation without progression. Data for participants who completed the study without an event of progression or death were censored at the data of last visit or follow-up without progression. | Screening, every 3 months during treatment, every 6 months during follow-up to 2 years | 
| Duration of Overall Disease Control (ODC) - Percentage of Participants With an Event | Determined only for those participants with overall disease control (CR, PR or SD per RECIST) and was defined as the time interval between the first occurrence of disease control (CR, PR or SD) and the date of progression or death from any cause. Data for participants who were lost to follow-up were censored at the date of last evaluation without progression. Data for participants who completed the study without an event of progression or death were censored at the data of last visit or follow-up without progression. | Screening, every 3 months during treatment, every 6 months during follow-up to 2 years | 
| Duration of ODC - Time to Event | Determined only for those participants with overall control disease (CR, PR, or SD per RECIST) and was defined as the time interval between the first occurrence of disease control (CR, PR or SD) and the date of progression or death from any cause. Data for participants who were lost to follow-up were censored at the date of last evaluation without progression. Data for participants who completed the study without an event of progression or death were censored at the data of last visit or follow-up without progression. Median time to event was estimated using the Kaplan-Meier method. | Screening, every 3 months during treatment, every 6 months during follow-up to 2 years | 
| Duration of ODC - Percentage of Participants Maintaining Disease Control at 12 and 24 Months | Duration of ODC was determined only for those participants with overall control disease (CR, PR, or SD per RECIST) and was defined as the time interval between the first occurrence of disease control (CR, PR, or SD) and the date of progression or death from any cause. Data for participants who were lost to follow-up were censored at the date of last evaluation without progression. Data for participants who completed the study without an event of progression or death were censored at the data of last visit or follow-up without progression. | Screening, every 3 months during treatment, every 6 months during follow-up to 2 years | 
| Overall Survival (OS) - Percentage of Participants With an Event | OS was defined as the time from the first treatment administration to death from any cause. Data for participants who were lost to follow-up were censored at the date of last evaluation. Data for participants who were alive at the end of the study were censored at the date of last visit. | Screening, Day 1 of every cycle during treatment, every 6 months during follow-up to 2 years | 
| OS - Time to Event | OS was defined as the time from the first treatment administration to death from any cause. Data for participants who were lost to follow-up were censored at the date of last evaluation. Data for participants who were alive at the end of the study were censored at the date of last visit. Median OS was estimated using the Kaplan-Meier method. | Screening, Day 1 of every cycle during treatment, every 6 months during follow-up to 2 years | 
| OS - Percentage of Participants Surviving at 12 and 24 Months | OS was defined as the time from the first treatment administration to death from any cause. Data for participants who were lost to follow-up were censored at the date of last evaluation. Data for participants who were alive at the end of the study were censored at the date of last visit. | Screening, Day 1 of every cycle during treatment, every 6 months during follow-up to 2 years | 
| Global Health Status as Assessed by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - C30 (EORTC QLQ-C30) | EORTC QLQ-C30: included functional scales (physical, role, cognitive, emotional, and social), global health status, symptom scales (fatigue, pain, nausea/vomiting) and single items (dyspnoea, appetite loss, insomnia, constipation/diarrhea and financial difficulties). Most questions used 4-point scale (1 'Not at all' to 4 'Very much'; 2 questions used 7-point scale [1 'very poor' to 7 'Excellent']). Scores were averaged and transformed to 0-100 scale; higher score=better level of functioning or greater degree of symptoms. | Screening, every 3 months during treatment | 
| Percentage of Participants With Change From Baseline in Global Health Status by EORTC QLQ-C30 Improvement Category | EORTC QLQ-C30: included functional scales (physical, role, cognitive, emotional, and social), global health status, symptom scales (fatigue, pain, nausea/vomiting) and single items (dyspnoea, appetite loss, insomnia, constipation/diarrhea and financial difficulties). Most questions used 4-point scale (1 'Not at all' to 4 'Very much'; 2 questions used 7-point scale [1 'very poor' to 7 'Excellent']). Scores averaged, transformed to 0-100 scale; higher score=better level of functioning or greater degree of symptoms. Changes from baseline were categorized as follows: Very much worsening (less than [<]-20); Moderate worsening (greater than or equal to [≥]-20 to <-10); Little worsening (≥-10 to <-5); No change (≥-5 to less than or equal to [≤]5); Little improvement (>5 to ≤10); Moderate improvement (>10 to ≤20); and Very much improved (>20). | Screening, every 3 months during treatment | 
| EORTC QLQ-C30 Functional and Symptom Scale Scores | EORTC QLQ-C30: included functional scales (physical, role, cognitive, emotional, and social), global health status, symptom scales (fatigue, pain, nausea/vomiting) and single items (dyspnoea, appetite loss, insomnia, constipation/diarrhea and financial difficulties). Most questions used 4-point scale (1 'Not at all' to 4 'Very much'; 2 questions used 7-point scale [1 'very poor' to 7 'Excellent']). Scores averaged, transformed to 0-100 scale; for functional scores, a higher score represents a better level of functioning. For symptom scale scores a higher level represents a more severe level of symptoms. | Screening, every 3 months during treatment |