A Phase Ib Study of Humanized Anti-VEGF Monoclonal Antibody (Sevacizumab) Injection Plus FOLFIRI in Chinese Patients With Metastatic Colorectal Cancer

A Phase Ib, Dose Escalation Study to Assess the Safety, Tolerability, and Pharmacokinetics of Humanized Anti-VEGF Monoclonal Antibody(Sevacizumab) Injection Plus FOLFIRI in Chinese Patients With Metastatic Colorectal Cancer

This is an open-label, multicenter, dose-escalation study designed to assess the safety, tolerability, and pharmacokinetics of Humanized Anti-VEGF Monoclonal Antibody (Sevacizumab) Injection in combination with FOLFIRI in patients with previously treated metastatic colorectal cancer. This study includes two stages. Stage 1 is the dose-escalation stage. Once the maximum tolerated dose (MTD) of Sevacizumab has been established, additional patients will be enrolled in the cohort-expansion stage (Stage 2).

Study Overview

• Status: Unknown
• Conditions: Metastatic Colorectal Cancer
• Intervention / Treatment: Drug: Sevacizumab; Drug: Irinotecan; Drug: 5-FU; Drug: Leucovorin

• Study Type: Interventional
• Enrollment (Anticipated): 36
• Phase: Phase 1

Contacts and Locations

Study Locations

• China
  • Jilin
    • Changchun, Jilin, China, 130021
      • Recruiting
      • The First Bethune Hospital of Jilin University
      • Contact: Yanhua Ding
  • Shanghai
    • Shanghai, Shanghai, China, 200032
      • Recruiting
      • Fudan University Shanghai Cancer Center
  • Zhejiang
    • Hangzhou, Zhejiang, China, 310003
      • Recruiting
      • The First Hospital of Zhejiang Province
      • Contact: Nong Xu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 74 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Histological/cytological confirmed unresectable metastatic colorectal cancer patients who have failed first-line oxaliplatin-based chemotherapy
• At least one measurable lesion (according to RECIST 1.1 )
• At least 4 weeks from the last chemotherapy. If patients received anti-tumor biological products, at least four t1/2 of washout period is needed
• Toxicity from previous treatment has to restore to ≤ grade 1 (NCI CTC4.0)
• ECOG performance status 0-1
• Life expectancy ≥ 3 months
• Adequate hematologic function: ANC ≥ 1.5 × 10^9 /L, HB ≥ 90 g /L (blood transfusion allowed), PLT ≥ 100 ×10^9 /L; Adequate hepatic function: ALT ≤ 2.5 × ULN, AST ≤ 2.5 × ULN, TBIL ≤ 1.5 × ULN (patients with liver metastases ALT ≤ 5 × ULN, AST ≤ 5 × ULN); Adequate renal function: creatinine ≤ 1 × ULN; Coagulation function: INR ≤ 1.5 × ULN, APTT ≤ 1.5 × ULN
• Patients of childbearing potential (male and female) must agree to use reliable methods of contraception until at least 12 weeks after the last dose
• Patients signed written inform consent
• Willingness and capability to communicate with investigators and to comply with protocol requirements

Exclusion Criteria:

• HCV, TP or HIV antibody positive
• Previously received anti-VEGF protein drugs, such as Bevacizumab,Sevacizumab
• Previously treated with irinotecan
• History of dihydropyrimidine dehydrogenase deficiency
• Patients with alcohol or drug dependence
• Participation in other clinical trials within 4 weeks before enrollment
• Active or chronic hepatitis B infection with HBV DNA > 1.0 * 10^3 IU/mL
• Serious infection requiring intravenous antibiotic therapy
• Symptomatic brain metastases
• Patients with proteinuria at screening (urine protein ≥ 1+)
• History of abdominal fistula, gastrointestinal perforation, abdominal abscess within 6 months prior to enrollment
• History of intestinal obstruction, inflammatory bowel disease, or other intestinal diseases with chronic diarrhea as the major symptom
• Serious non-healing wounds, ulcers or fractures
• Major surgery (excluding biopsy) or significant trauma within 4 weeks prior to enrollment
• Active bleeding within 3 months prior to enrollment
• Bleeding diathesis or coagulation disorder
• History of arterial or venous thrombosis
• History of myocardial infarction or stroke within 6 months prior to enrollment
• Unstable angina, congestive heart failure, New York Heart Association (NYHA) class II heart failure, uncontrollable arrhythmia, uncontrolled hypertension
• Expected to receive surgery during the study or within 1 month after the last dose
• The investigators consider the patients are not suitable for this trial
• Pregnant and lactating women
• Known allergies to any excipient in the study drug
• Patients can not complete this study for any other reason

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Sevacizumab+FOLFIRI; Two weeks as one cycle. Cycle 1: FOLFIRI on day1-2, Sevacizumab on day3; Cycle 2 and after: Sevacizumab on day 1, and then FOLFIRI on day1-2

Drug: Sevacizumab; escalating doses of Sevacizumab : 3mg/kg，4mg/kg，5mg/kg; Drug: Irinotecan; Irinotecan: IV solution, IV over 90 minutes, 180 mg/m², Every 14 days, Until disease progression/toxicity; Drug: 5-FU; 5-FU: IV solution, IV bolus over 2-4 minutes, 400 mg/m²; IV infusion over 46 hours, 2400 mg/m²; Every 14 days, Until disease progression/toxicity; Drug: Leucovorin; Leucovorin: IV solution, IV over 2 hours, 400 mg/m², Every 14 days, Until disease progression/toxicity

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Maximum Tolerated Dose (MTD)	up to 56 days

Secondary Outcome Measures

Outcome Measure	Time Frame
Adverse Events (NCI-CTC 4.0)	28 days after the last dose
Plasma pharmacokinetics (PK) parameters for Sevacizumab	Cycle 1(Day3, Day4, Day7, Day10, Day13); Cycle 2-4(Day1);Cycle 4(Day1, Day2, Day5, Day8 ,Day11)
Plasma pharmacokinetics (PK) parameters (Cmax, Tmax, AUC, T1/2) for Irinotecan and its major metabolite SN-38	Day1, Day2, Day3, Day15, Day16, Day17
Plasma pharmacokinetics (PK) parameters for 5-FU	Day1, Day3, Day15, Day17
Potential biomarkers, including VEGF and ADA	VEGF:Cycle 1(Day3, Day4, Day7, Day10, Day13); Cycle 2-4(Day1);Cycle 4(Day1, Day2, Day5, Day8, Day11); ADA : within 15 minutes before each Sevacizumab administration
Objective Response Rate (ORR)	up to 3 years from date of registration
Disease Control Rate (DCR)	up to 3 years from date of registration
Progression Free Survival (PFS)	up to 3 years from date of registration
Overall Survival (OS)	up to 3 years from date of registration

Collaborators and Investigators

• Sponsor: Jiangsu Simcere Pharmaceutical Co., Ltd.
• Investigators: Principal Investigator: Jin Li, MD, Fudan University

Study record dates

Study Major Dates

• Study Start: August 1, 2015
• Primary Completion (Anticipated): December 1, 2016

Study Registration Dates

• First Submitted: May 19, 2015
• First Submitted That Met QC Criteria: May 20, 2015
• First Posted (Estimate): May 25, 2015

Study Record Updates

• Last Update Posted (Estimate): April 20, 2016
• Last Update Submitted That Met QC Criteria: April 19, 2016
• Last Verified: April 1, 2016

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; Protective Agents; Topoisomerase Inhibitors; Micronutrients; Vitamins; Topoisomerase I Inhibitors; Antidotes; Vitamin B Complex; Leucovorin; Irinotecan
• Other Study ID Numbers: SIM129-mCRC-01