Anlotinib Plus Toripalimab and Nab-paclitaxel in Patients With Locally Advanced or Metastatic Pancreatic Cancer: an Open-label, Non-randomized, Phase Ⅱ Study

Anlotinib Hydrochloride Capsules (12 mg orally, once daily before breakfast; CTTQ, Lianyungang, Jiangsu, China), Toripalimab (240 mg intravenously, once every 3 weeks; Shanghai Junshi Biosciences Co., Ltd., Shanghai, China) and Nab-paclitaxel (125 mg/m2 intravenously, twice every 3 weeks; CSPC, Shijiazhuang, Hebei, China) are to be administered as a second-line therapy at most 6 cycles. Patients assessing as CR/PR/SD continue to receive a maintenance treatment including anlotinib and toripalimab until disease progression, intolerable toxicity, patient request for discontinuation for up to two years.

Observations and assessments will be conducted before treatment, on day 7, 21 of cycle 1, on day 21 of cycle 2, every 2 cycles (42 days) during following cycles and after treatment. Follow-up for survival status and subsequent antineoplastic therapy data collecting will be performed by telephone interview or face-to-face every 6 weeks after treatment until disease progression, death or end of the study (whichever occurs first).

Using 2.9 months served as a control, the expected median PFS of patients treated with anlotinib plus toripalimab and nab-paclitaxel in this study is prespecified as 4.5 months. Significance level α=0.05 (two-tailed) and test power (1-β)=0.80 are used for sample size calculation by PASS (Power Analysis and Sample Size) software. Taking a 20% drop-out rate into consideration, the sample size is approximately 53 patients. An interim analysis will be performed using a Lan-DeMets Pocock type boundary to assess the futility and efficacy when approximately half of the predetermined sample size is allocated. If the interim analysis results indicate that the study is of futility and the benefit/risk ratio is significantly worse, the trial will be terminated by the investigators. Otherwise, the trial will continue until the full sample size of 53 has been accumulated.

Efficacy is to be analyzed in the full analysis set (FAS), the response evaluable set (RES) and per-protocol set (PPS). Safety is to be analyzed in safety set (SS) including all assigned patients who receive at least one dose of study combined therapy and have safety records of medication. Statistical descriptions of subject distribution, demographic data and baseline characteristics will be performed. For study endpoints, the Kaplan-Meier method is to be applied for the PFS and OS curve with estimation for median PFS, median OS and 95% CI. ORR= (CR+PR) / sample size×100%; DCR= (CR+PR+SD) / sample size×100%. The 95% CI of the ORR and DCR are to be calculated by exact binomial method based on the F distribution. ECOG PS scores and QoL scores will be described at each visit time. For safety analysis, only treatment emergent adverse event (TEAE) will be included and analyzed in this experiment, which is defined as AEs that are post-dose or heavier than the baseline. Medical Dictionary for Regulatory Activities (MedDRA), system organ class (SOC), preferred terms (PT) and NCI CTCAE 5.0 will be used to standardize and classify all adverse events and summarize the incidence of AEs and association with treatments. Vital signs, ECG, and laboratory evaluation results will be compared and analyzed before and after treatment.