IBI343 Combined With Chemotherapy in Advanced Pancreatic Cancer
This is a Phase Ib/II study to evaluate the safety, tolerability and efficacy of IBI343 in combination with chemotherapy in patients with advanced pancreatic cancer, including a Phase Ib safety introduction and Phase II expansion phase. In phase Ib (safe introduction phase), participants with CLDN18.2-positive advanced pancreatic adenocarcinoma (PAC) who had previously received first-line gemcitabine-based systemic therapy were enrolled to receive IBI343 in combination with chemotherapy.A classic "3+3" dose-escalation design was used to determine the dose of the combination therapy, including the following two cohorts: Cohort A: received IBI343+ capecitabine TBD mg/m2 BID PO×14d Q3W; Cohort B: received IBI343+ capecitabine TBD mg/m2 BID PO×14d Q3W+ oxaliplatin TBD mg/m2 IV Q3W (each subject received up to 8 cycles of oxaliplatin). In cohort A, 3 subjects were enrolled in Intravenous (IV) Q3W, and the starting dose of IBI343 was 6 mg/kg.The preset starting dose of capecitabine was 750mg/m2 BID PO, D1-14, Q3W. The observation period of safe introduction of DLT was 21 days (3 weeks) after the first administration, and IBI343 was administered only once during the DLT observation period.If the first 3 subjects did not develop DLT during the DLT observation period, 3-6 subjects were allowed to receive IBI343 6mg/kg combined with capecitabine 1000mg/m2 BID PO, D1-14, Q3W;If DLT occurs in 1 of these 3 subjects, the other 3 subjects will be included in the same dose group.If no DLT occurred in the three additional subjects, 3-6 subjects were allowed to receive IBI343 6mg/kg combined with capecitabine 1000mg/m2BID PO, D1-14, Q3W;If DLT occurred in ≥1 of the 3 subjects included in the supplement, or ≥2 of the 6 subjects in total, or ≥2 of the first 3 subjects, 3 to 6 subjects were allowed to receive IBI343 4.5mg/kg Q3W;If intolerance remains, the mode and dose of administration will be further discussed. If the dose level of 1000mg/m2 in combination with capecitabine is confirmed to be safe, subjects in combination with capecitabine 750mg/m2 are allowed to increase the dose of capecitabine to 1000mg/m2 in subsequent cycles. If IBI343 combined with capecitabine is tolerated according to the above safety introduction rules, the safe introduction of IBI343 in cohort B (IBI343 combined with oxaliplatin and capecitabine) is initiated after the dose of IBI343 combined with capecitabine is determined.The preset starting dose of oxaliplatin in cohort B was 75mg/m2 IV D1 Q3W, and A preset climbing dose level of 100mg/m2 IV D1 Q3W was introduced in the same way as in cohort A.If both dose levels of oxaliplatin are not tolerated, the administration mode and dose will be further discussed, such as downregulating the administration dose of IBI343. The sponsor is allowed to adjust the safe dose of IBI343 based on the results of the preliminary study. To allow sponsors to further explore the dose of combination chemotherapy based on the observed safety during the Phase Ib safety introduction phase. Each cohort will enter the Phase II expansion phase of the cohort after safety introduction, determination of the combination dose and safety of IBI343. Participants enrolled in the expansion phase are consistent with those enrolled in the safety introduction phase, i.e., CLDN18.2-positive advanced PAC subjects who have previously received first-line gemcitabine-based systemic therapy: Phase II Cohort A: Approximately 32 subjects (including Phase Ib Cohort A dosing subjects) were scheduled to receive IBI343+ capecitabine Q3W. Phase II Cohort B: Approximately 24 subjects (including Phase Ib Cohort B dosing subjects) were scheduled to receive IBI343+ capecitabine + oxaliplatin Q3W.Each subject received a maximum of 8 cycles of oxaliplatin therapy. Queue A and queue B are expanded sequentially. Queue A is expanded first. After queue A is expanded, queue B is expanded.The investigator may also terminate the expansion of a cohort based on early efficacy and safety data, in which case only one of the cohorts should be expanded. Sponsors and funders are allowed to adjust the CLDN18.2 expression level requirements of enrolled subjects based on the results of other trials of IBI343. Subjects will continue to receive treatment until disease progression, toxicity intolerance, withdrawal of informed consent, loss of follow-up, death, or any other reason for discontinuation of study therapy (whichever occurs first). After discontinuation of study treatment, participants will be followed up for safety and survival. During the study, participants were evaluated by imaging according to RECIST v1.1. In the oxaliplatin combination cohort, oxaliplatin was used for a maximum of 8 cycles, and subjects in this cohort could continue maintenance therapy with IBI343+ capecitabine after oxaliplatin withdrawal.
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