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