This is a Phase 3, multicenter, randomized and double-blind study assessing the interchangeability between TRS003 and China-approved Bevacizumab® (also called China-approved Avastin) for first-line treatment of patients with metastatic Colorectal Cancer (CRC), approximately 126 patients will be enrolled in this study. Patients who sign the informed consent, meet the eligibility criteria and are confirmed as non-progressors after lead-in treatment period with Bevacizumab® in combination with modified FOLFOX6 chemotherapy for 6 cycles, will be randomized (1:1) to either the non-switching arm and receive Bevacizumab® + modified FOLFOX6 for all subsequent cycles or to the switching arm and receive TRS003 alternating with Bevacizumab® in combination with mFOLFOX6 until disease progression or intolerability.
This is a randomized, double-blind Phase 3 clinical trial evaluating the interchangeability, by a comparison of PK parameters between non-Switching and the Switching arms following the final switch between TRS003 and Bevacizumab® in patients with metastatic adenocarcinoma of the colon or rectum (please note that Bevacizumab® means China-approved Bevacizumab® in this protocol, unless otherwise specified). Approximately 126 patients will be enrolled in this study. Patients who sign the informed consent, meet the eligibility criteria and are confirmed as non-progressors after lead-in treatment period with Bevacizumab® in combination with modified FOLFOX6 chemotherapy for 6 cycles, will be randomized (1:1) to either the non-switching arm and receive Bevacizumab® + modified FOLFOX6 for all subsequent cycles or to the switching arm and receive TRS003 alternating with Bevacizumab® in combination with mFOLFOX6 until disease progression or intolerability. There will be 3 switches as detailed in the Treatment section (below) and the Schema. If oxaliplatin-induced neurotoxicity requires discontinuation of oxaliplatin, treatment will continue using leucovorin (LCV) plus 5-fluorouracil (5-FU) in combination with either Bevacizumab® or TRS003 until progressive disease (PD), intolerability, or other cause for stopping treatment.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
126
* TRS003, 5 mg/kg IV every 14 days with mFOLFOX6 for 1 cycle followed by switch to: * Bevacizumab®, 5 mg/kg IV every 14 days with mFOLFOX6 for 1 cycle followed by switch to: * TRS003, 5 mg/kg IV every 14 days with mFOLFOX6 until end of treatment due to PD, intolerability or other cause for stopping treatment. Intensive PK sampling will be performed after 7 cycles of this TRS003 switch period
• Bevacizumab®, 5 mg/kg IV every 14 days with mFOLFOX6 for 1 cycle
The mFOLFOX6 regimen is: * Oxaliplatin, 85 mg/m2 administered IV over 2 hours * LCV, 400 mg/m2 administered over 2 hours concurrent with oxaliplatin * 5-FU, 400 mg/m2 given as a slow IV push (bolus) over 5 minutes administered immediately after LCV * 5-FU, 2400 mg/m2 administered IV over 46 hours by infusion pump beginning immediately after FU IV bolus.
AUCtau,Area under the curve over the dosing interval
The natural log-transformed AUCtau in Cycle 14 will be analyzed.
Time frame: Cycle 14 (each cycle is 14 days)
C trough, trough concentration
Besides AUCtau, the PK parameters to be estimated will include the trough concentration (Ctrough), the maximum concentration (Cmax), and time to reach Cmax (Tmax).
Time frame: Cycle 14 (each cycle is 14 days)
C max,maximum concentration
Besides AUCtau, the PK parameters to be estimated will include the trough concentration (Ctrough), the maximum concentration (Cmax), and time to reach Cmax (Tmax).
Time frame: Cycle 14 (each cycle is 14 days)
T max,the time to reach Cmax
Besides AUCtau, the PK parameters to be estimated will include the trough concentration (Ctrough), the maximum concentration (Cmax), and time to reach Cmax (Tmax).
Time frame: Cycle 14 (each cycle is 14 days)
ADA,anti-drug antibody
anti-drug antibody (ADA) and neutralizing antibody if ADA is positive
Time frame: at Day 1 of every 2 cycles(each cycle is 14 days)
PFS,Progression-free survival
Progression-free survival (PFS) is defined as the time from randomization to Investigator-determined PD or death due to any cause in the absence of documented PD.
Time frame: Cycle 14 (each cycle is 14 days)
OS,Overall survival
Overall survival (OS) is defined as the time from randomization to death due to any cause.
Time frame: Cycle 14 (each cycle is 14 days)
ORR,objective response rate
ORR in the TRS003 Arm/ORR in the China-approved bevacizumab Arm Confidence interval of ORR in each group will be estimated by the Clopper-Pearson Exact method.
Time frame: Cycle 14 (each cycle is 14 days)
DOR,Duration of response
Duration of response (DOR) is defined as the time from the date of the first documentation of Investigator-determined response in patients with confirmed objective tumor response (CR or PR) to the first documentation of Investigator determined disease progression (PD) or to death due to any cause in the absence of documented PD.
Time frame: Cycle 14 (each cycle is 14 days)
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