Ph I SU011248 + Irinotecan in Treatment of Pts w MG

Study Overview
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Brief Summary
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Primary Objectives To determine maxi tolerated dose & dose limiting toxicity of SU011248 + Irinotecan in recurrent MG pts not on EIAEDs To characterize safety & tolerability of SU011248 + Irinotecan among pts w recurrent MG Secondary Objectives To evaluate pharmacokinetic profile of SU011248 & Irinotecan when co-administered in pts w MG To evaluate anti-tumor activity of SU011248 + Irinotecan

Detailed Description
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Primary interest for combining SU011248 w irinotecan in malignant glioma pts derives from dramatic anti-tumor activity recently demonstrated among RMG pts treated w humanized anti-VEGF monoclonal antibody, bevacizumab, when combined w irinotecan. 63 percent radiographic response rate was observed following treatment w regimen every other wk, & median progression-free survival was 23wks. Similar enhancement of chemo activity by VEGF-directed therapy w bev has been previously demonstrated for colorectal & lung cancer pts. SU011248 is being evaluated in current regimen because it may exert more potent anti-angiogenic effect than bev among MG pts due to its ability to inhibit PDGFR-mediated pericyte stabilization in tumor neovasculature. Current proposed ph I study is designed to determine MTD & DLT of SU011248 when combo w irinotecan for pts w RMG. Both SU01148 & irinotecan are known to be metabolized by CYP3A4 cytochrome system. Current study will limit enrollment to pts who are not on CYP3A4-enzyme inducing anti-epileptic drugs.

Official Title
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A Phase I Study of SU011248 Plus Irinotecan in the Treatment of Patients With Malignant Glioma

Conditions
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Glioblastoma

Intervention / Treatment
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* Drug: SU011248 & Irinotecan


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pts confirmed GBM, GS, AA, AO & AOA w recurrent disease following standard therapy consisting of at least external beam XRT & temo chemo Pts not had tumor biopsy <1 week/surgical resection <2 weeks prior to starting study drug Pts should be on non-increasing dose of steroids >7 days prior to obtaining baseline Gd-MRI of brain Age >18yrs KPS >70 ANC >1.5 x 10 9/L Hgb >9 g/dL Platelets >100 x 10 9/L AST/SGOT & ALT/SGPT <2.5 x ULN Serum bilirubin <1.5 x ULN Serum CA <12 mg/dL Serum creatinine <1.5 x ULN/measured 24-hr CrCl>50mL/min/1.73m^2 Pt has ability to understand & provide signed informed consent that fulfills IRB guidelines Exclusion Criteria: Prior gr3/>toxicity/failure to CPT-11 therapy Prior Sunitinib malate therapy Concurrent administration of EIAEDs Major surgery <2 weeks of enrollment History of impaired cardiac function Other clinically significant cardiac diseases Uncontrolled diabetes Active/uncontrolled infection requiring intravenous antibiotics Impairment of GI function/GI disease that may significantly alter absorption of Sunitinib malate Sutent Acute/chronic liver/renal disease Cerebrovascular accident/transient ischemic attack <6mths of study enrollment Pulmonary embolism <6mths of study enrollment Pre-existing thyroid abnormality w thyroid function that can not be maintained in normal range w medication Pts taking warfarin sodium Pts have received chemo ≤4wks to starting study drug unless they have fully recovered from all anticipated side effects of such therapy Pts have received immunotherapy ≤2wks to starting study drug/have not recovered from side effects of such therapy Pts have received investigational drugs ≤2wks to starting study drug unless they have fully recovered from all anticipated side effects of such therapy Pts have received XRT ≤4wks to starting study drug unless they have fully recovered from all anticipated side effects of such therapy Pts have undergone major non-CNS surgery ≤2wks to starting study drug/pts who have not recovered from side effects of such therapy Cardiac pacemaker Ferromagnetic metal implants other than those approved as safe for use in MR scanners Claustrophobia Obesity Female pts who are pregnant/breast feeding/adults of reproductive potential not employing effective method of birth control Known diagnosis of HIV History of another primary malignancy that is currently clinically significant/currently requiring active intervention Pts unwilling to/unable to comply w protocol Existing intra-tumoral hemorrhage Concurrent participation in another clinical trial except for supportive care/non-treatment trials Other severe acute/chronic medical/psychiatric condition/lab abnormality that may increase risk associated w study participation/study drug administration/ may interfere w interpretation of study results, & in judgment of investigator would make subject inappropriate for entry into this study

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: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: SU011248 & Irinotecan|Sutent given in daily oral manner for 1st 4 wks of each 6wk cycle. You will not take any Sutent during last 14 days of each 6 wk cycle. CPT-11 will be given intravenously over 1 & 1/2 hrs on 1st day of each cycle & then again on days 14 & 28. Sutent is approved for adult subjects w some forms of kidney cancer. It is considered investigational for brain tumors. Dosing will begin on day 1 of cycle 1 & continue daily for 4 wks by mouth. Irinotecan is approved for adult subjects with some forms of colorectal cancer. It is also considered investigational for brain tumors. Irinotecan dose will depend on your height & weight. Irinotecan will be given intravenously over 90 min on days 1, 14 & 28 of 6wk cycle. You will be seen in clinic approximately every 42 days for 1st 3 cycles of study drug, & then every other cycle thereafter. Your brain MRI examination will be done within 1 wk prior to completion of cycles 1-3, & then within 1 week prior to completion of every other cycle.|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine MTD & DLT of SU011248 + Irinotecan in pts w RMG not on EIAEDs |  | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Demographic & baseline characteristics |  | 6 months | 
| Efficacy observations & measurements |  | 6 months | 
| Safety observations & measurements |  | 6 months | 
| PK measurements |  | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Glioblastoma, CPT 11, Sutent, Sunitinib, Sunitinib malate, Malignant Glioma, GBM, Irinotecan, Camptosar, Anaplastic astrocytoma, Anaplastic oligodendroglioma, Anaplastic oligoastrocytoma, SU011248, Brain tumor, Recurrent malignant glioma