Sunitinib Malate and Combination Chemotherapy as Front-Line Therapy in Treating Patients With Metastatic Rectal Cancer That Cannot Be Removed by Surgery

Study Overview
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Brief Summary
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RATIONALE: Sunitinib malate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. Drugs used in chemotherapy, such as irinotecan hydrochloride, leucovorin calcium, and fluorouracil, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) together with sunitinib malate may kill more tumor cells. PURPOSE: This phase II trial is studying how well giving sunitinib malate together with combination chemotherapy works as front-line therapy in treating patients with metastatic rectal cancer that cannot be removed by surgery.

Detailed Description
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OBJECTIVES: Primary Evaluation of the efficacy of front-line treatment with sunitinib malate and FOLFIRI chemotherapy at 3 months in patients with rectal cancer and synchronous metastases deemed unresectable in a multidisciplinary consultation. Secondary Evaluate the rate of resection of secondary metastases and rectal cancer, rate of R0 resection of metastases and rectal cancer, and the rate of complete response after resection. Evaluate the rate of local failure (progression of rectal cancer). Evaluate the rate of local complications. Evaluate disease-free survival. Evaluate progression-free survival, metastatic progression-free survival, and local progression-free survival. Evaluate symptom-free survival. Evaluate overall survival. Evaluate quality of life, specifically fatigue and global health score (EORTC QLQ-C30). Evaluate the tolerance to treatment. Conduct translational research, in particular, pharmacokinetic studies of plasma and rectal tumor biopsies, and histological and molecular studies. OUTLINE: Patients receive simplified FOLFIRI chemotherapy comprising irinotecan hydrochloride IV over 90 minutes, leucovorin calcium IV over 2 hours, and fluorouracil IV over 46 hours on days 1, 15, and 29. Patients also receive oral sunitinib malate once daily on days 1-28. Treatment repeats every 6 weeks in the absence of disease progression or unacceptable toxicity. Patients may undergo surgical resection and/or local radiotherapy if the tumor regresses. After resection or radiotherapy, patients may undergo up to 4 more courses of study treatment. Biopsies of the tumor and healthy mucosa are collected for translational research at baseline. Blood samples are collected for pharmacodynamic and pharmacogenetic studies at baseline and at week 6. Patients also complete a quality-of-life questionnaire (EORTC QLQ-C30) at baseline and periodically thereafter. After completion of study therapy, patients are followed up every 12 weeks.

Official Title
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Front-line Combination Therapy of Sunitinib Malate Plus Chemotherapy With Leucovorin/5-Fluorouracil and Irinotecan (FOLFIRI) for Rectal Cancer Patients With Synchronous Non-Resectable Metastases: A Phase II Non Controlled Study. (SUREMETS)

Conditions
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Colorectal Cancer, Metastatic Cancer

Intervention / Treatment
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* Drug: FOLFIRI regimen
* Drug: fluorouracil
* Drug: irinotecan hydrochloride
* Drug: leucovorin calcium
* Drug: sunitinib malate
* Other: laboratory biomarker analysis
* Other: pharmacogenomic studies
* Other: pharmacological study


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed adenocarcinoma of the rectum Lower pole of the tumor < 12 cm from the anal margin Synchronous metastases of the liver and/or lung Unresectable or resectability uncertain according to the decision of a local multidisciplinary consultation Lesions measurable in 1 dimension by RECIST criteria (metastases and primary rectal cancer) No rectal obstruction requiring surgery or the emergency fitting of a prosthesis No CNS metastases PATIENT CHARACTERISTICS: WHO performance status 0-2 ANC ≥ 1,500/mm^3 Platelet count ≥ 100,000/mm^3 Creatinine clearance ≥ 60 mL/min Hemoglobin ≥ 10 g/dL (transfusions allowed) FEV ≥ 50% QT interval ≤ 450 ms (in men) or ≤ 470 ms (in women) Total bilirubin ≤ 1.5 times upper limit of normal Serum albumin ≥ 25 g/L Not pregnant or nursing Fertile patients must use effective contraception No history of another cancer except for nonmelanoma skin cancer or curatively treated carcinoma in situ of the cervix History of other cancers allowed provided the patient has been disease-free > 3 years None of the following: Congestive heart failure or coronary heart disease Myocardial infarction within the past year Uncontrolled hypertension (systolic BP > 160 mm Hg or diastolic BP > 100 mm Hg) despite optimal medical management No active severe rectal bleeding No liver failure No known Gilbert syndrome No severe uncontrolled infection No chronic diarrhea, malabsorption syndrome, or intestinal obstruction/subocclusion No severe uncontrolled pain (visual analogue scale 5/10) with morphine treatment No other medical, psychological, or social condition that, in the investigator's opinion, could affect the patient's compliance with study treatment No hypersensitivity to any component of study treatment PRIOR CONCURRENT THERAPY: See Patient Characteristics No prior radiotherapy to the pelvis More than 4 weeks since prior experimental therapy More than 7 days since prior CYP3A4 inhibitor before the administration of sunitinib malate More than 12 days since prior CYP3A4 inducer No concurrent participation in another clinical study No other concurrent anticancer therapy

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 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
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: FOLFIRI regimen|nan|
|Drug: fluorouracil|nan|
|Drug: irinotecan hydrochloride|nan|
|Drug: leucovorin calcium|nan|
|Drug: sunitinib malate|nan|
|Other: laboratory biomarker analysis|nan|
|Other: pharmacogenomic studies|nan|
|Other: pharmacological study|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response rate at 3 months as assessed by RECIST criteria |  |  | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of complete response after resection |  |  | 
| Rate of R0 resection of metastases |  |  | 
| Rate of local failure |  |  | 
| Rate of local complications |  |  | 
| Metastatic progression-free survival |  |  | 
| Local progression-free survival |  |  | 
| Disease-free survival |  |  | 
| Symptom-free survival |  |  | 
| Overall survival |  |  | 
| Quality of life, specifically fatigue and global health score (EORTC QLQ-C30) |  |  | 
| Time to deterioration of the final score for overall health and fatigue |  |  | 
| Tolerance and incidence of side effects as assessed by NCI CTCAE v2 |  |  | 
| Translational research including pharmacodynamic studies of plasma and rectal tumor biopsies and histological and molecular studies |  |  | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage IV rectal cancer, adenocarcinoma of the rectum, liver metastases, lung metastases