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

Hoosier Cancer Research Network

Status and phase

Completed

Phase 2

Phase 1

Conditions

Colorectal Cancer

Treatments

Biological: RAD001

Biological: Cetuximab

Drug: Irinotecan

Study type

Interventional

Funder types

Other

Industry

Identifiers

NCT00522665

GI05-102

Details and patient eligibility

About

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.

Full description

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

Enrollment

41 patients

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

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