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

Study Overview
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Brief Summary
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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).

Official Title
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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

Conditions
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Metastatic Colorectal Cancer

Intervention / Treatment
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* Drug: Sevacizumab
* Drug: Irinotecan
* Drug: 5-FU
* Drug: Leucovorin


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 74 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sevacizumab+FOLFIRI<br>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<br>* escalating doses of Sevacizumab : 3mg/kg，4mg/kg，5mg/kg<br>Drug: Irinotecan<br>* Irinotecan: IV solution, IV over 90 minutes, 180 mg/m², Every 14 days, Until disease progression/toxicity<br>Drug: 5-FU<br>* 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<br>Drug: Leucovorin<br>* Leucovorin: IV solution, IV over 2 hours, 400 mg/m², Every 14 days, Until disease progression/toxicity<br>|

What is the study measuring?
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Primary Outcome Measures

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

Secondary Outcome Measures

| Outcome Measure | Measure Description | 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 |