Patient eligibility
Patients aged 18–70 years with pathologically confirmed CRC who had prior treatment failure with fluorouracil/oxaliplatin/irinotecan, wild-type KRAS/NRAS/BRAF, measurable/nonmeasurable tumor lesions, an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0–1 and life expectancy over 3 months, with adequate organ functions and no history of other malignancies were enrolled. The main exclusion criteria were: prior treatment with EGFR inhibitors, anticancer therapy or surgery within 4 weeks, Grade ≥ 2 toxicity due to prior anticancer therapy, and any other condition deemed inappropriate by the investigator. The mutation status (exons 2, 3 and 4 for both KRAS and NRAS, and BRAF V600E) of all patients were examined in the screening period, and patients with RAS (KRAS/NRAS 2, 3 and 4 exons) and BRAF V600E mutation were excluded from the study. The detailed study protocol Synopsis was presented in Supplementary file 1.
This study was approved by the Ethics Committee of the National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College (approval number: 14–057/ 847), and was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. All patients provided written informed consent.
Study design
The study was composed of the dose-escalation phase and dose-expansion phase. SCT200 was administrated intravenously to groups of three to six patients. The starting dose and the maximum dose of SCT200 was set as 0.5 mg/kg and 15.0 mg/kg, respectively based on the results of preclinical studies. Patients in the six low-dose escalation groups (0.5 mg/kg, 1.0 mg/kg, 2.0 mg/kg, 4.0 mg/kg, 6.0 mg/kg, and 8.0 mg/kg) first received a single ascending dose (SAD), were monitored for 3 weeks, and then entered the multiple ascending dose (MAD) stage. In the MAD stage, patients in 0.5 mg/kg, 1.0 mg/kg, 2.0 mg/kg, and 4.0 mg/kg groups were administered SCT200 once per week for 4 weeks. In the 6.0 mg/kg group, three patients were administered one dose of SCT200 per week for 6 weeks and another three patients received one dose of SCT200 in 2 week intervals for 6 weeks. The 8.0 mg/kg group was administered with SCT200 once in 2 weeks for 6 weeks. Patients in three high-dose MAD groups (9.0 mg/kg, 12.0 mg/kg, and 15.0 mg/kg) were administered one dose of SCT200 per week for 6 weeks. SAD/MAD of the next dose group were started on the premise that the dose level of SCT200 on the previous dose group was safely tolerated in a 3-week observation period. In addition, a dose-expansion phase for evaluating a target dose of SCT200 was initiated when the dose escalation phase was completed. The target dose was determined based on the PK analysis of the dose escalation phase, and a total of 25 patients were administered one dose of SCT200 at the target level per week for 6 weeks. After the completion of the pre-specified multiple dosing cycles, if the tumor was in remission or stable, patients were allowed to continue the treatment of SCT200 at the respective dose levels until disease progression or intolerable toxicity occurred (Fig. 1). The dose-limiting toxicity (DLT) was defined as (1) Grade 3/4 adverse events (AEs) (other than Grade 3 rash) that were related to SCT200, based on the judgment of the investigator; (2) any serious/life-threatening AEs that were not listed in the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0, which was deemed by the investigator to be related to SCT200; (3) Grade 3 rash, if the following serious dermotoxicities were present: desquamation, extensive urticaria, symptomatic dermotoxicity requiring pharmacologic intervention (analgesics/corticosteroids), and dermotoxicity that was intolerable to the patient; and (4) any interruption of two scheduled infusions owing to Grade 3 dermotoxicity.
Assessments
Safety and efficacy evaluations were performed on all patients who received ≥ one dose of SCT200 treatment. Safety assessments were performed at baseline, during the 21-day single-dose period, before and once a month after entering the multiple-dose period. CTCAE version 4.0 was used to determine the severity of AEs. Tumor response was assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 at baseline, the end of the multiple-dose treatment cycle, and every 8 weeks after entering the multiple-dose expansion period until disease progression (PD) or intolerable toxicity occurred. Objective response rate (ORR) was defined as the percentage of complete response (CR) or partial response (PR). The disease control rate (DCR) was defined as the proportion of patients with CR or PR or stable disease (SD). Progression-free survival (PFS) was defined as the time from the first dose of SCT200 to the date of PD or death of any reason. OS was defined as the time from the first dose of SCT200 to the date of death due to any reason or last follow-up.
Single-dose PK blood samples were collected within 60 min before dosing and at 0.5, 2, 6, 24, 48, 96, 168, 264, 336, 408, and 504 h after dosing. For multiple dosing, PK blood samples were collected within 60 min before each dose and 30 min after dosing. Intensive blood collection was also performed for the first and last doses.
Statistical analyses
All statistical analyses were performed using SAS (version 9.4; SAS Institute, Cary, NC, USA). Safety and efficacy evaluations were performed on all patients who received ≥ one dose of SCT200 treatment, and all AEs were recorded according to MedDRA (version 22.1). Survival was estimated using the Kaplan–Meier method, and the time to the onset of AEs of dermotoxicity and hypomagnesemia was analyzed. 95% confidence intervals (CIs) were calculated using the Clopper–Pearson method. Blood concentrations of SCT200 were measured at various time points using an enzyme-linked immunosorbent assay, and key PK parameters were calculated using a non-compartmental model (WinNonlin pharmacokinetic analysis software).