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

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