Metastatic Colorectal Cancer
Conditions
Brief summary
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).
Interventions
DRUGSevacizumab
escalating doses of Sevacizumab : 3mg/kg，4mg/kg，5mg/kg
DRUGIrinotecan
Irinotecan: IV solution, IV over 90 minutes, 180 mg/m², Every 14 days, Until disease progression/toxicity
DRUG5-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
DRUGLeucovorin
Leucovorin: IV solution, IV over 2 hours, 400 mg/m², Every 14 days, Until disease progression/toxicity
Sponsors
Jiangsu Simcere Pharmaceutical Co., Ltd.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 74 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Maximum Tolerated Dose (MTD) | up to 56 days |
Secondary
| Measure | Time frame |
|---|---|
| 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 |
| Adverse Events (NCI-CTC 4.0) | 28 days after the last dose |
| 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 |
| Objective Response Rate (ORR) | up to 3 years from date of registration |
Countries
China
Contacts
Primary ContactHaijun Li, MS
Outcome results
None listed