Phase I/Randomized Phase II Study of Second Line Therapy With Irinotecan + Cetuximab +/- RAD001 for Colorectal Cancer

Study Overview
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Brief Summary
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The addition of RAD001, an mTOR inhibitor, to irinotecan and anti-EGFR antibody cetuximab may increase efficacy for patients with metastatic colorectal cancer who progressed on prior chemotherapy. This approach is biologically directed to overall target the cancer cell at multiple levels, and potentially preventing chemotherapy and EGFR-therapy resistance.

Detailed Description
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OUTLINE: This is a multi-center study. PHASE I: UGT1A1 *28 7/7 genotype IS NOT present Cetuximab 250 mg/m2 IV days 1, 8, and 15 Irinotecan 125 mg/m2 IV days 1 and 8 RAD001 PO QD (dose determined at the time of registration; subjects will remain at this dose level until treatment discontinuation) PHASE II: Randomization based on UGT1A1 *28 7/7 Genotype or Prior Irinotecan Exposure ARM A: Cetuximab 250 mg/m2 IV days 1, 8, and 15 Irinotecan 125 mg/m2 IV days 1 and 8 AT TIME OF PROGRESSIVE DISEASE, ARM A TREATMENT WILL CROSSOVER: Cetuximab 250 mg/m2 IV days 1, 8, and 15 Irinotecan 125 mg/m2 IV days 1 and 8 RAD001 PO QD (maximum tolerated dose) ARM B: Cetuximab 250 mg/m2 IV days 1, 8, and 15 Irinotecan 125 mg/m2 IV days 1 and 8 RAD001 PO QD (maximum tolerated dose) AT TIME OF PROGRESSIVE DISEASE, ARM B TREATMENT WILL BE DISCONTINUED ECOG performance status 0-2 Life Expectancy: Not specified Hematopoietic: Absolute neutrophil count (ANC) ≥ 1,500 mm3 Platelets ≥ 100,000 mm3 Hemoglobin (Hgb) ≥ 9 g/dL White blood cell count (WBC) ≥ 2,000 mm3 INR < 1.5 x upper limit of normal (ULN) if not on anticoagulation (if on anticoagulation must have an in-range INR (usually between 2 and 3) on a stable dose of warfarin) PTT < 1.5 x ULN Hepatic: Bilirubin ≤ 1.5 x ULN Aspartate aminotransferase (AST, SGOT) ≤ 2.5 x ULN Alanine aminotransferase (ALT, SGPT) ≤ 2.5 x ULN Albumin ≥ 3.0 g/dL Renal: Calculated creatinine clearance of ≥ 60 cc/min using the Cockcroft-Gault formula Cardiovascular: No uncontrolled cardiac arrhythmia requiring medication, transient ischemic attack (TIA), or cerebrovascular accident (CVA) within 6 months prior to being registered for protocol therapy No uncontrolled congestive heart failure, myocardial infarction, or unstable angina within 6 months prior to being registered for protocol therapy Pulmonary: No severely impaired lung function as demonstrated by pulse O2 saturation ≤ 90% at rest on room air, or pulmonary function test FEV1 ≤ 2L No history of prior chronic lung infection such as tuberculosis, atypical tuberculosis, or histoplasmosis as evidenced by a chest CT or x-ray within 21 days prior to being registered for protocol therapy

Official Title
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Phase I / Randomized Phase II Study of Second Line Therapy With Irinotecan and Cetuximab With or Without RAD001, an Oral mTOR Inhibitor for Patients With Metastatic Colorectal Cancer: Hoosier Oncology Group GI05-102

Conditions
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Colorectal Cancer

Intervention / Treatment
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* Drug: Irinotecan
* Biological: Cetuximab
* Biological: RAD001


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histological or cytological proof of colon or rectal adenocarcinoma Measurable site of disease according to RECIST that has not been previously irradiated Must have metastatic colorectal cancer which progressed after first line chemotherapy +/- bevacizumab Blood sample collected within 21 days prior to being registered for protocol therapy for UTG1A1 genotype analysis. (Patients with the UGT1A1 *28 7/7 genotype (homozygosity for the TA7 allele) will be excluded from the Phase I stage of the study. During the Phase II stage of the study, subjects will be allowed to participate but must begin treatment at dose level -1 of irinotecan.) A history of other malignancies (non-colorectal) is allowed, provided it has been curatively treated and demonstrates no evidence for recurrence of that cancer Prior radiation therapy allowed to < 25% of the bone marrow Age ≥ 18 years at the time of consent Written informed consent and HIPAA authorization for release of personal health information Females of childbearing potential and males must be willing to use an effective method of contraception Females of childbearing potential must have a negative pregnancy test within 7 days of being registered for protocol therapy Exclusion Criteria: No more than one prior chemotherapy regimen for metastatic colorectal cancer, at least 28 days prior to being registered for protocol therapy No prior treatment with cetuximab No prior treatment with an mTOR inhibitor No known hypersensitivity to cetuximab, RAD001 (everolimus), other rapamycins (sirolimus, temsirolimus) or to its excipients No treatment with any investigational agent within 28 days prior to being registered for protocol therapy No symptomatic brain metastasis No uncontrolled diabetes as defined by a fasting serum glucose >1.5 x ULN No chronic treatment with systemic steroids or another immuno-suppressive agent No serious non-healing wound, ulcer, bone fracture, major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to being registered for protocol therapy No liver disease such as cirrhosis, chronic active hepatitis or chronic persistent hepatitis No active bleeding or a pathological condition that is associated with a high risk of bleeding No uncontrolled systemic disease including active infections or uncontrolled hypertension No known history of HIV seropositivity No impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of RAD001 (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection) No nonmalignant medical illnesses that are uncontrolled or whose control may be jeopardized by the treatment with protocol therapy No planned immunization with attenuated live viruses during the study period Females must not be breastfeeding

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 |
| --- | --- |
| Active Comparator: Arm A: Irinotecan + Cetuximab +/- RAD001<br> | Drug: Irinotecan<br>* Irinotecan 125 mg/m2 IV days 1 and 8<br>Biological: Cetuximab<br>* Cetuximab 250mg/m2 IV days 1, 8 and 15<br>Biological: RAD001<br>* Patients on Arm A will crossover and receive RAD001 at disease progression<br>|
| Active Comparator: Arm B: Ironotecan + Cetuximab<br> | Drug: Irinotecan<br>* Irinotecan 125 mg/m2 IV days 1 and 8<br>Biological: Cetuximab<br>* Cetuximab 250mg/m2 IV days 1, 8 and 15<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine the MTD of RAD001 in combination with irinotecan and cetuximab as second line therapy in patients with metastatic colorectal cancer |  | Phase I | 
| To evaluate the objective response (CR or PR) rates of patients treated with irinotecan and cetuximab with or without RAD001 in patients with metastatic colorectal cancer |  | Phase II | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate the pharmacokinetic (PK) profile for RAD001 after one cycle of therapy, on cycle 2 day 1 |  | Phase I | 
| To evaluate the time to progression, duration of objective response (CR or PR) and overall survival of patients treated with irinotecan and cetuximab with or without RAD001 |  | Phase II |