Overview of clinical trial The therapeutic dose in mice was 1x108 PFU, and the maximum starting dose in humans was 2.67x10\^9 PFU according to the "Guidelines for the estimation of the maximum recommended starting dose of drugs in the First clinical trial of Healthy Adult Volunteers".
Phase 1: Dose escalation phase:
We plan to enroll 10 to 19 patients in China with histologically or cytologically confirmed advanced solid tumors who have failed to respond to standard treatment or have no standard treatment options for IDOV-SAFETM intravenous administration. Patients with MSS colorectal cancer were included in this stage.
This phase included four dose groups of 1x10\^9 PFU, 3x10\^9 PFU, 1x10\^10 PFU and 3x10\^10 PFU. One subject was enrolled in the first dose group, and the other dose groups were increased by a "3+3" method, with 3-6 subjects in each group. All participants in each dose arm could not be escalated to the next dose arm until they had completed the 21-day safety assessment.
Dose escalation or Settings may be adjusted at the discretion of the Safety Committee (SMC).
Phase 2: Security Extension Phase:
One or two dose levels determined by MTD or SMC were selected for expansion. This phase was divided into four cohorts,:
Cohort IIA: Patients with MSS colorectal cancer who progressed after IDOV-SAFETM monotherapy were treated with IDOV-SAFETM+ toripalimab-furoquininib combination therapy
IIA1: Approximately 6\~12 subjects were enrolled in the first dose group. IIA2: About 6\~12 subjects were enrolled in the second dose group;
Cohort IIB: Patients with cholangiocarcinoma, gastric cancer, esophageal squamous cell carcinoma, liver cancer and other digestive system tumors were enrolled.
Enroll 6-12 subjects in the second dose group;
Cohort IIC: patients with MSS colorectal cancer were enrolled. After 2 cycles of IDOV-SAFETM treatment, the subjects were treated with IDOV-SAFETM, toripalimab and fuquinitinib combination therapy.
IIC1: Approximately 6\~12 subjects were enrolled in the first dose group. IIC2: About 6\~12 subjects were enrolled in the second dose group;
ⅡD：Patients with MSS-type colorectal cancer were included. After one cycle of IDOV-SAFETM treatment, combined therapy with IDOV-SAFETM and fruquintinib was initiated starting from the second cycle.
About 6\~12 subjects were enrolled in the second dose group;
Phase III: Dose expansion phase:
According to the safety, PK and clinical data of the four cohorts in the second phase, one or two cohorts were selected by SMC for dose expansion, and the sample size of each cohort was expanded to 20 cases.
After completing the first cycle of dosing, all subjects received subsequent cycles of dosing after 21 days of safety assessment. The course of treatment, related examinations and tumor efficacy evaluation were consistent between the monotherapy phase and the combination phase. The patients were treated with intravenous injection on D1, 3 and 5 of each course of treatment according to every 3 weeks (21 days) as a course of treatment. Safety checks were performed for each cycle. Tumor efficacy was evaluated every 2 cycles (every 6 weeks) according to RECIST1.1 and iRECIST standards. Pharmacodynamic tests (including tumor markers, T cell subsets, cytokines, viral load in tumor tissue, etc.), viral distribution detection, and TCR-Seq detection were performed regularly.
When the subject met the 9.1 criteria for the end of treatment for the subject, the treatment period ended and the subject entered the long-term safety and survival follow-up period.
Long-term SAFETY AND SURVIVAL FOLLOW-UP:
Adverse events that occurred in each subject from the first dose of the study were collected throughout the course of the study, and long-term safety and survival follow-up was to continue for 2 years after the last dose (visits were performed every 8 weeks until death or loss to follow-up or the end of survival follow-up). Before the subjects started a new antineoplastic therapy, they were examined accordingly according to the "6.9 Clinical Trial Schedule". Survival was confirmed by telephone visits after the initiation of a new antineoplastic therapy.
Other medications:
If, according to the investigator's judgment during the trial, the patient is considered to be safe but not effective at the current dose, the subject needs to withdraw from the trial, and the trial SMC meeting has decided and the next (higher) dose group has been initiated. At the discretion of the investigator, the higher dose of the trial drug could be administered to the subject who was withdrawing from the trial.
In order to ensure the interests of the subjects to the greatest extent, after the end of the treatment, if the subjects are evaluated by the investigators and the subjects agree, this clinical trial can provide "compensatory medication", and provide IDOV-SAFETM to the subjects for free. At the same time, the patients need to sign the informed consent for the use of "compensatory medication".
