A RANDOMIZED, PHASE 2 STUDY OF FOLFOX OR FOLFIRI WITH AG-013736 OR BEVACIZUMAB IN PATIENTS WITH METASTATIC COLORECTAL CANCER AFTER FAILURE OF AN IRINOTECAN OR OXALIPLATINCONTAINING FIRST-LINE REGIMEN - ND

• Register: EUCTR
• Last refreshed on: 24 April 2012
• Main ID: EUCTR2007-006283-30-IT
• Date of registration: 30/06/2008
• Prospective Registration: No
• Primary sponsor: PFIZER
• Public title: A RANDOMIZED, PHASE 2 STUDY OF FOLFOX OR FOLFIRI WITH AG-013736 OR BEVACIZUMAB IN PATIENTS WITH METASTATIC COLORECTAL CANCER AFTER FAILURE OF AN IRINOTECAN OR OXALIPLATINCONTAINING FIRST-LINE REGIMEN - ND
• Scientific title: A RANDOMIZED, PHASE 2 STUDY OF FOLFOX OR FOLFIRI WITH AG-013736 OR BEVACIZUMAB IN PATIENTS WITH METASTATIC COLORECTAL CANCER AFTER FAILURE OF AN IRINOTECAN OR OXALIPLATINCONTAINING FIRST-LINE REGIMEN - ND
• Date of first enrolment: 08/05/2008
• Target sample size: 176
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2007-006283-30
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: yes Single blind: no Double blind: no Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: yes Placebo: no Other: no

Countries of recruitment

Belgium, Czech Republic, France, Italy, Spain

Key inclusion & exclusion criteria

Inclusion criteria:
1. Histologically-documented metastatic CRC plus any one of the following:
Failure of one prior irinotecan- or oxaliplatin-containing regimen documented with radiographic evidence of disease progression as defined by RECIST criteria and
documented with 2 sets of CT/MRI scans during irinotecan or oxaliplatin therapy or within 6 months after the last dose of the irinotecan- or oxaliplatin-containing
regimen (patients with prior adjuvant chemotherapy or radiation therapy are eligible);
or
Intolerance to prior oxaliplatin therapy, defined as occurrence of Grade 3 or 4 neurotoxicity that is persistent between cycles.
2. Adequate organ function, as defined by the following criteria:
Absolute neutrophil count (ANC) >/= 1500 cells/mm3
Platelets >/=100,000 cells/mm3
Hemoglobin >/=9.0 g/dL
Total serum bilirubin AST and ALT abnormalities are due to underlying malignancy
Serum creatinine Urinary protein <1+ by urine dipstick. If dipstick is >/=1+ then a 24-hour urine collection should be done and the patient may enter only if urinary protein is
<2 grams per 24 hours
3. Measurable disease by RECIST. Measurable diseases that have been previously radiated
will not be considered target lesions unless an increase in size has been observed following completion of radiation therapy.
4. Male or female, >/=18 years of age
5. Life expectancy >/=12 weeks
6. ECOG performance status 0 or 1
7. Resolution of all acute toxic effects of prior radiotherapy (except for alopecia), or
surgical procedures to NCI CTCAE Grade elective surgery, study treatment should not be administered until surgical incision is
fully healed
8. No evidence of preexisting uncontrolled hypertension as documented by 2 baseline blood
pressure readings taken at least 1 hour apart. The baseline systolic blood pressure
readings must be be are eligible.
9. Women of childbearing potential must have a negative serum or urine pregnancy test
within 3 days prior to treatment.
10. Signed and dated informed consent document indicating that the patient (or legally
acceptable representative) has been informed of all pertinent aspects of the trial before
enrollment.
11. Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests,
and other study procedures, including completion of PRO measures.
12. Eligible to receive FOLFIRI or FOLFOX in combination with bevacizumab
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range

Exclusion criteria:
1. Prior treatment of metastatic CRC with more than 1 systemic chemotherapy regimen for
metastatic disease. Patients who participated in study A4061020 are not eligible to
participate in this study.
2. Prior irradiation to >/=25% of the bone marrow (whole pelvis =25%; a patient with prior
whole pelvis irradiation is ineligible).
3. Pleural effusion or ascites that causes >/= Grade 2 dyspnea.
4. Current use or anticipated need for food or drugs that are known cytochrome P450 (CYP)
3A4 inhibitors (i.e., grapefruit juice, verapamil, ketoconazole, itraconazole,
erythromycin, clarithromycin, indinavir, saquinavir, ritonavir, nelfinavir, lopinavir, and
delavirdine) during the course of the study
5. Current use or anticipated need for drugs that are known CYP3A4 or CYP1A2 inducers
(i.e., carbamazepine, dexamethasone, felbamate, omeprazole, phenobarbital, phenytoin,
primidone, rifabutin, rifampin, and St John's wort) during the course of study (Note: the
short-term use of dexamethasone as a premedication for chemotherapy is not an
exclusion criterion)
6. History of hemoptysis > œ tsp of bright red blood in one day within past 1 week.
7. Patients with active seizure disorder or brain metastases
8. Gastrointestinal abnormalities including:
inability to take oral medication
requirement for intravenous alimentation
prior surgical procedures affecting absorption including total gastric resection
treatment for active peptic ulcer disease in the past 6 months
active gastrointestinal bleeding, unrelated to cancer, as evidenced by hematemesis,
hematochezia or melena in the past 3 months without evidence of resolution
documented by endoscopy or colonoscopy
malabsorption syndromes
9. History of any second malignancy except those patients treated with curative intent for
skin cancer (other than melanoma) or in situ breast or cervical cancer, or those treated
with curative intent for any other cancer with no evidence of disease for 5 years.
10. Major surgical procedure, open biopsy, or significant traumatic injury within 4 weeks of
treatment. (Also excluded are patient with fine needle aspirations within 7 days of
treatment) Note: Insertion of a vascular access device is not considered major or minor
surgery.
11. Dementia or significantly altered mental status that would prohibit the understanding or
rendering of informed consent and compliance with the requirements of this protocol.
12. Any of the following within the 12 months prior to study drug administration: myocardial
infarction, severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic
congestive heart failure, cerebrovascular accident or transient ischemic attack, deep vein
thrombosis or pulmonary embolism.
13. Known dihydropyridine dehydrogenase deficiency.
14. History of hypersensitivity to 5-FU or LV.
15. Known human immunodeficiency virus (HIV) seropositivity or acquired
immunodeficiency syndrome (AIDS)-related illness.
16. Serious active infection (viral, fungal, bacterial). Infection requiring parenteral
antibiotics at time of enrollment will disqualify the patient.


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Axitinib (AG-013736) in combination with intravenous 5-fluorouracil-based chemotherapy is indicated for the second-line treatment of patients with metastatic carcinoma of colon and rectum.
MedDRA version: 9.1 Level: LLT Classification code 10052358 Term: Colorectal cancer metastatic

Intervention(s)

Product Name: AG-013736
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Axitinib
CAS Number: 319460-85-0
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 1-

Product Name: AG-013736
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Axitinib
CAS Number: 319460-85-0
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 5-

Trade Name: AVASTIN*INFUS 1FL 100MG 4ML
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: Bevacizumab
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 25-

Trade Name: ELOXATIN*IV 1FL POLV 50MG
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: Oxaliplatin
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 5-

Trade Name: ELOXATIN*IV 1FL POLV 100MG
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: Oxaliplatin
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 5-

Trade Name: CAMPTO*1FL 40MG 2ML
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: Irinotecan
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 20-

Trade Name: CAMPTO*1FL 100MG/5ML
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: Irinotecan
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 20-

Trade Name: CALCIO LEVOF.TEVA*EV FL 100MG
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: Calcium levofolinate
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 50-

Trade Name: FLUOROURACILE TEVA
Pharmaceutical Form: Solution for injection
INN or Proposed INN: Fluorouracil
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Con

Primary Outcome(s)

Main Objective: To demonstrate that the combination of AG-013736 with either FOLFIRI or
FOLFOX is superior to FOLFIRI or FOLFOX in combination with bevacizumab in
prolonging the PFS in the second-line treatment of patients with metastatic CRC after failure of an irinotecan or oxaliplatin-containing first-line regimen.

Secondary Objective: To compare the OS in patients randomized to AG-013736 with either FOLFIRI or
FOLFOX versus that in patients randomized to FOLFIRI or FOLFOX in combination
with bevacizumab.
To compare the ORR and duration of response (DR) in patients randomized to AG-
013736 with either FOLFIRI or FOLFOX versus that in patients randomized to
FOLFIRI or FOLFOX in combination with bevacizumab.
To evaluate the safety and tolerability of AG-013736 in combination with either
FOLFIRI or FOLFOX.
To evaluate patient reported symptom severity and interference using the M D
Anderson Symptom Inventory -Diarrhea (MDASI-D).

Primary end point(s): PFS defined as the time from randomization to the date of progression or death due any
cause, whichever occurs first.

Secondary ID(s)

A4061034

2007-006283-30-ES