Clinical Trial Result Information

Title of Study:
A single arm study to assess the efficacy and safety of bevacizumab in combination with irinotecan and infusional 5-fluorouracil/folic acid regimens as first line treatment for patients with metastatic colorectal cancer.

Fast Facts:

Protocol number:	MO18458
Sponsor:	Hoffmann-La Roche Ltd
Company division:	Pharmaceutical
Product name:	Avastin
Generic name:	bevacizumab
Phase of development:	IV
Therapeutic area, approved indication:	Colorectal Cancer
Date of report:	5/1/2007

Clinical study summary:
This was a multicenter, open-label, single arm study designed to assess the efficacy and safety of Avastin (bevacizumab) in combination with irinotecan and infusional 5-fluorouracil plus folinic acid based regimens (FOLFIRI) in patients with metastatic colorectal cancer who have had no prior chemotherapy.

Study center(s) :
31 centers in Australia, Canada, China, Italy and Spain.

Objectives:
Primary: To determine the efficacy of Avastin in combination with irinotecan and infusional 5-fluorouracil plus folinic acid based regimens as compared with historical controls, based on progression-free survival.
Secondary: To evaluate the safety profile of Avastin in combination with irinotecan and infusional 5-fluorouracil plus folinic acid based regimens; to determine the overall response rate, time to response, duration of response, and overall survival of Avastin in combination with irinotecan and infusional 5-fluorouracil plus folinic acid based regimens as compared with historical controls.

Methodology:
After initial screening assessments, patients were enrolled on to the study to receive Avastin 5mg/kg plus FOLFIRI (irinotecan, folinic acid and 5-fluorouracil) every 2 weeks for a minimum of 6 weeks or until clear evidence of disease progression or unmanageable toxicity. Tumor measurements/assessments were made based on RECIST criteria using CT scan, MRI scan, X-ray, bone scan, ultrasound for soft tissue lesions and clinical examination until evidence of disease progression. Post screening assessments were performed every 12 weeks for the first year and every 16 weeks thereafter until disease progression.
Adverse events were recorded on an ongoing basis. Hematology and blood chemistry were performed before each chemotherapy treatment and thereafter at 4-weekly intervals.
Survival follow-up for all patients (upon disease progression) continued until study closure, with visits scheduled every 6 months.

Number of patients (planned/analyzed):
209 enrolled

Diagnosis and main criteria for inclusion:
Metastatic colorectal cancer, with no prior chemotherapy.

Test product, dose and mode of administration or test procedure:
Avastin (bevacizumab) (5mg/kg iv infusion every 2 weeks) plus FOLFIRI regimen (irinotecan 180mg/m², folinic acid 200mg/m², 5-fluorouracil [5-FU] 400mg/m² as intravenous bolus then 5-FU 2400mg/m² as continuous infusion) until disease progression.

Duration of treatment:
Until disease progression or unmanageable toxicity.

Reference therapy, dose and mode of administration or reference procedure:
N/A

Criteria for evaluation (efficacy, safety):
Efficacy: Primary: Progression-free survival (PFS).
Secondary: Best overall response rate; duration of response; time to response; overall survival; disease control rate.
Safety: Adverse events, laboratory tests, vital signs, ECOG performance status, ECG.

Statistical methods:
All statistical analyses were of a descriptive, exploratory nature; point estimates and confidence intervals but no p-values are presented.

Summary (efficacy, safety, other results):
Efficacy: The primary endpoint was PFS, defined as the time from the start of study medication to disease progression or death from any cause, based on investigator assessment. The ITT population was the primary population for the efficacy analyses; similar outcomes were obtained from the PP population. The median duration of PFS was 337 days (11.1 months). Overall survival was not mature at the time of clinical cut-off for the analysis; approximately 60% of all patients were alive at 18 months.

Parameter (Median value)	Overall population Avastin 5mg/kg q2wk+FOLFIRI n = 209 (Median value)	Subgroup Avastin5+FOLFIRI (FOLFIRI regimen as defined in protocol) n = 156 (Median value)	Subgroup Avastin5+FOLFIRI modified (FOLFIRI regimen modified according to local practice) n = 53 (Median value)
Progression-free survival	11.1 months	11.3 months	10.0 months
Overall response rate Complete response Partial response Stable disease Progressive disease Missing	111 (53.1%) 7 (3.3%) 104 (49.8%) 68 (32.5%) 15 (7.2%) 15 (7.2%)	83 (53.2%) 5 (3.2%) 78 (50.0%) 49 (31.4%) 11 (7.1%) 13 (8.3%)	28 (52.8%) 2 (3.8%) 26 (49.1%) 19 (35.8%) 4 (7.5%) 2 (3.8%)
Duration of response	8.5 months	9.0 months	8.3 months
Time to response	4.5 months	-	-
Disease control rate	180 (86.1%)	-	-

Safety: The safety profile obtained was generally in line with observations in previous studies of Avastin in cancer patients. Overall, gastrointestinal disorders of all grades were the most frequently reported events, particularly diarrhea and nausea, which occurred in over 78% and 77% of patients, respectively. Gastrointestinal events which occurred in over 20% of the patients were constipation (49%), abdominal pain (36%), stomatis (32%) and dyspepsia (22%).
Adverse events other than gastrointestinal disorders, observed at an incidence of more than 20%, were fatigue (57%), alopecia (46%), neutropenia (42%), anorexia (40%), epistaxis (38%), mucosal inflammation (37%), headache and hypertension (each 26%), insomnia (22%) and dyspnea (21%).
For adverse events of NCI-CTC grade 3-5, gastrointestinal disorders (35%) and blood and lymphatic disorders (34%) were the most frequently reported events. Neutropenia, an event commonly associated with irinotecan administration, was recorded in 29% of patients; febrile neutropenia was observed in 6% of patients. Other events of grade 3 or above that were recorded in over 5% of patients included diarrhea (12%), fatigue (9%), vomiting (7%), pulmonary embolism (7%) and nausea (6%).
A total of 78% of patients experienced adverse events of special interest to Avastin. Of these, the most frequently reported were (grade 3-5): bleeding (3.4%), hypertension (3.8%), arterial thromboembolic events (4.8%) and venus thromboembolic events (19.6%). The incidence of grade 3-5 gastrointestinal perforation and proteinuria was 2% in each case.
Six patients died due to an adverse event. No particular pattern was seen in the types of events that resulted in death.
Laboratory tests did not show new clinically relevant safety signals. The most common hematological grade 3-4 abnormalities were low neutrophil counts observed in 44% of patients. The most common clinical chemistry grade 3-4 abnormalities were high uric acid (24%) and high gamma-GT (18%).
No notable changes in vital signs, ECG or ECOG performance status were observed during the study.

Conclusions:
This study demonstrated that the addition of Avastin to irinotecan with infusional 5-FU/folinic acid (FOLFIRI) resulted in a progression-free survival time of 11.1 months, with a response duration of 8.5 months and a disease control rate of 86.1%, thus providing clinically meaningful benefit to patients with previously untreated metastatic colorectal cancer.
The overall safety profile was favourable, consistent with previous observations in metastatic colorectal cancer patients receiving Avastin and no new safety signals were observed. The pattern and incidence of common adverse events included both the established side effects of FOLFIRI (neutropenia, diarrhea) as well as Avastin-associated toxicities, such as bleeding, hypertension, proteinuria and thromboembolic events.

Click here for the protocol registry listing of this trial.