Official Title: “Phase I/II Study of Gamma Interferon (IFN-γ) Added to Bolus + Infusional 5-Fluorouracil (5-FU) and Leucovorin (LV) +/- Bevacizumab (BV) in Metastatic Colorectal Carcinoma”

The first phase of the trial is designed to find a safe biologically active dose (SBD) of the GFL combination. The second phase is to evaluate the toxicities associated with adding IFN-y to 5 FU/LV.

Study Type: Interventional

Study Design: Treatment, Non-Randomized, Open Label, Dose Comparison, Crossover Assignment, Safety/Efficacy Study

Study Primary Completion Date: April 2009

Primary Objectives - Phase I

1. To determine a safe biologically active dose (SBD) of IFN-γ added to a bolus + infusional regimen of 5-FU/LV (GFL) for metastatic colorectal cancer

2. To determine a safe biologically active dose of IFN-γ added to a bolus + infusional regimen of 5-FU/LV (GFL) plus bevacizumab (BV) for metastatic colorectal cancer

Secondary Objectives - Phase I

1. To evaluate the toxicities associated with adding IFN-γ to 5-

2. To evaluate the toxicities associated with adding IFN-γ to 5-FU/LV plus BV

3. To evaluate pharmacokinetics of (a) 5-FU and (b) IFN-γ when given in the schedule specified in this protocol

4. To evaluate the level of Fas expression in peripheral blood mononuclear cells (PBMC) at various time points after IFN-γ administration

Primary Objective - Phase II

1. To evaluate the overall response rate of metastatic colorectal cancer to GFL+/-BV at the SBD identified in 1.1

Secondary Objectives - Phase II

1. To evaluate time to progression, the progression-free survival and overall survival for patients treated with GFL (+/- BV)

2. To evaluate the early response rate to GFL at 8 weeks

3. To evaluate the toxicity of GFL (+/- BV)

4. To evaluate pharmacokinetics of (a) 5-FU and (b) IFN-γ

5. To evaluate the level of Fas expression in PBMC after IFN-γ administration

Intervention(s) in this Clinical Trial

• Drug: 5-Fluorouracil
  • 5-FU is commercially available as an antimetabolite that interferes with RNA and DNA synthesis. Fluororacil Injection (Roche Laboratories): 50 mg/ml, 10 ml vials; clear, yellow, aqueous solution; Fluorouracil (Cetus, Lyphomed, Americal): 50 mg/ml; 10 ml, 20 ml, 100 ml ampules; Fluorouracil (Solopak): 50 mg/ml; 10 ml, 50 ml, 100 ml vials; 10 ml ampules; Adrucil (Adria Laboratories): 50 mg/ml; 10 ml ampules.
• Drug: Leucovorin Calcium
  • Leucovorin calcium is commercially available, and is a stable reduced formyl derivative and the active form of folic acid.Leucovorin Calcium (Folinic Acid); Leucovorin Calcium (calcium folinate; citrovorum factor; N 5—formyltetrahydrofolate; 5-formyl- FH4; folinic acid; folinic acid-SF; (6RS)-folinic acid; Wellcovorin).
• Drug: Gamma-Interferon-1b (IFN-γ)
  • ACTIMMUNE® (Gamma-Interferon-1b), a biologic response modifier, is a single-chain polypeptide containing 140 amino acids.
• Drug: Bevacizumab
  • Bevacizumab is a clear to slightly opalescent, sterile liquid ready for parenteral administration. Each 5ml. glass vial (100-mg, 25 mg/mL) contains sodium phosphate, trehalose, polysorbate 20, and Sterile Water for Injection (SWFI), USP

Primary Measures

• To determine a safe biologically active dose of IFN-γ added to a bolus + infusional regimen of (GFL) for metastatic colorectal cancer
  • Time Frame: 14 days
    Safety Issue?: Yes
• To evaluate the overall response rate of metastatic colorectal cancer to GFL+/-BV at the SBD identified in 1.1
  • Time Frame: 56 days
    Safety Issue?: Yes
• To determine a safe biologically active dose of IFN-γ added to a bolus + infusional regimen of 5-FU/LV
  • Time Frame: 14 days
    Safety Issue?: Yes

Secondary Measures

• To evaluate the toxicities associated with adding IFN-γ to 5- FU/LV
  • Time Frame: cycle 1 ,1st week
    Safety Issue?: Yes
• To evaluate the toxicities associated with adding IFN-γ to 5-FU/LV plus BV
  • Time Frame: 48 hours
    Safety Issue?: Yes
• To evaluate pharmacokinetics of (a) 5-FU and (b) IFN-γ when given in the schedule specified in this protocol
  • Time Frame: 1 week
    Safety Issue?: Yes
• To evaluate the level of Fas expression in peripheral blood mononuclear cells (PBMC) at various time points after IFN-γ administration
  • Time Frame: 1 week
    Safety Issue?: Yes
• To evaluate time to progression, the progression-free survival and overall survival for patients treated with GFL (+/- BV)
  • Time Frame: 1 week
    Safety Issue?: Yes
• To evaluate the early response rate to GFL at 8 weeks
  • Time Frame: 8 weeks
    Safety Issue?: Yes
• To evaluate the toxicity of GFL (+/- BV)
  • Time Frame: week 2
    Safety Issue?: Yes
• To evaluate pharmacokinetics of (a) 5-FU and (b) IFN-γ
  • Time Frame: week 2
    Safety Issue?: Yes
• To evaluate the level of Fas expression in PBMC after IFN-γ administration
  • Time Frame: week 2
    Safety Issue?: Yes

Inclusion Criteria:

• Metastatic colorectal cancer, histologically or cytologically confirmed
• Age 18 or greater
• Adequate hematologic function (ANC > 1500, hemoglobin > 10 g/dl, platelet count >
• 100,000)
• Adequate hepatic parameters (bilirubin < 2.0, Alk. Phos < 5 times normal, ALT < 5 times normal)
• Adequate renal function (creatinine < 2.0)
• Performance status ECOG 0-2
• 0-2 prior lines of chemotherapy for metastatic colorectal cancer are allowed. Prior 5-FU/LV or capecitabine allowed either in the adjuvant setting, or in the metastatic setting or both.
• Absence of other serious concurrent medical illnesses
• Evaluable or measurable disease for phase I; measurable disease only for phase II

Exclusion Criteria:

• Histologies other than adenocarcinoma
• Previous grade 4 toxicity to 5-FU +/- LV or capecitabine
• Uncontrolled brain metastases
• Chronic diarrhea (greater than five bowel movements per day)
• Previous chemotherapy or radiation therapy less than 4 weeks prior to study day 1 (less than 6 weeks for chemotherapy with Mitomycin or nitrosoureas)
• Major surgery within 2 weeks before study entry
• Known allergic sensitivity to leucovorin
• Prior exposure to IFN-γ
• Previous hematopoietic growth factor (e.g. epoetin alfa or darbepoietin less than 2 weeks prior to study day 1)
• Pregnancy or breast feeding. Women of child-bearing potential must have a negative pregnancy test before the first dose.
• Other co-existing malignancies or malignancies diagnosed within the last 5 years, with the exception of basal cell carcinoma or cervical cancer in situ
• Inability to provide written and informed consent
• Uncontrolled hypertension
• History of deep venous thrombosis or CVA
• Prior exposure to bevacizumab
• Proteinuria > 500 mg/24 hr

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: Accelerated Community Oncology Research Network

Information obtained from ClinicalTrials.gov on July 02, 2009

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00786643

Study ID Number: WITMMCC0301

ClinicalTrials.gov Identifier: NCT00786643

Health Authority: United States: Food and Drug Administration