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 and Cetuximab With or Without RAD001, an Oral mTOR Inhibitor for Patients With Metastatic Colorectal Cancer: Hoosier Oncology Group GI05-102

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.

Study Overview

• Status: Completed
• Conditions: Colorectal Cancer
• Intervention / Treatment: Drug: Irinotecan; Biological: Cetuximab; Biological: RAD001

Detailed 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

• Study Type: Interventional
• Enrollment (Actual): 41
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University Feinberg School of Medicine
    • Galesburg, Illinois, United States, 61401
      • Medical & Surgical Specialists, LLC
  • Indiana
    • Bloomington, Indiana, United States, 47403
      • Cancer Care Center of Southern Indiana
    • Evansville, Indiana, United States, 47714
      • Oncology Hematology Associates of SW Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University Simon Cancer Center
    • Indianapolis, Indiana, United States, 46202
      • IN Onc/Hem Associates
    • Indianapolis, Indiana, United States, 46206
      • St. Vincent Hospital & Health Centers
    • Indianapolis, Indiana, United States, 46256
      • Community Regional Cancer Center
    • Lafayette, Indiana, United States, 47905
      • Horizon Oncology Center
    • Lafayette, Indiana, United States, 47904
      • Arnett Cancer Care
    • Munster, Indiana, United States, 46321
      • Monroe Medical Associates
    • New Albany, Indiana, United States, 47150
      • Center for Cancer Care, Inc., P.C.
    • South Bend, Indiana, United States, 46601
      • Northern Indiana Cancer Research Consortium
  • Missouri
    • St. Louis, Missouri, United States, 63110
      • Siteman Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Arm A: Irinotecan + Cetuximab +/- RAD001	Drug: Irinotecan; Irinotecan 125 mg/m2 IV days 1 and 8; Biological: Cetuximab; Cetuximab 250mg/m2 IV days 1, 8 and 15; Biological: RAD001; Patients on Arm A will crossover and receive RAD001 at disease progression
Active Comparator: Arm B: Ironotecan + Cetuximab	Drug: Irinotecan; Irinotecan 125 mg/m2 IV days 1 and 8; Biological: Cetuximab; Cetuximab 250mg/m2 IV days 1, 8 and 15

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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	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

Collaborators and Investigators

• Sponsor: Hoosier Cancer Research Network
• Collaborators: Pfizer; Novartis Pharmaceuticals
• Investigators: Study Chair: Gabriela Chiorean, M.D., Hoosier Oncology Group, Inc.

Publications and helpful links

General Publications

• Chiorean EG, Picus J, Breen T, Ansari RH, Harb WA, Burns M, Spittler AJ, Loehrer PJ. Phase I/II study of everolimus (E) with irinotecan (Iri) and cetuximab (C) in 2nd line metastatic colorectal cancer (mCRC): Hoosier Cancer Research Network GI05-102. J Clin Oncol 33:5s, 2015 (suppl; abstr 3618)

Helpful Links

• Hoosier Cancer Research Network Homepage

Study record dates

Study Major Dates

• Study Start: August 1, 2007
• Primary Completion (Actual): May 1, 2011
• Study Completion (Actual): February 1, 2015

Study Registration Dates

• First Submitted: August 28, 2007
• First Submitted That Met QC Criteria: August 28, 2007
• First Posted (Estimate): August 30, 2007

Study Record Updates

• Last Update Posted (Estimate): May 15, 2015
• Last Update Submitted That Met QC Criteria: May 14, 2015
• Last Verified: May 1, 2015

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Topoisomerase Inhibitors; Antineoplastic Agents, Immunological; Topoisomerase I Inhibitors; Irinotecan; Everolimus; Cetuximab
• Other Study ID Numbers: GI05-102