Anlotinib, Toripalimab and Nab-paclitaxel in Locally Advanced/Metastatic Pancreatic Cancer

This is an open-label, non-randomized, single-arm phase Ⅱ study aiming to evaluate the efficacy and safety profile of above-mentioned combination strategy in first-line therapy-failed advanced pancreatic cancer. Totally 53 patients with locally advanced or metastatic pancreatic cancer are to be enrolled and receive anlotinib plus toripalimab and nab-paclitaxel.

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.

Eligibility Criteria:
Inclusion Criteria:

1. Males or females aged 18-75.
2. Locally advanced / metastatic pancreatic cancer confirmed by histopathology.
3. Life expectancy ≥ 3 months.
4. Treatment failure after first-line monotherapy or combination chemotherapy (at least one cycle) or after adjuvant / neoadjuvant therapy.
5. At least one measurable tumor lesions without local treatment such as radiotherapy according to the Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1); or tumor lesions in target area of previous radiotherapy confirmed progress.
6. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-1.
7. Adequate organ and bone marrow function.
8. Female of childbearing age must have a negative pregnancy test (serum or urine) within 7 days prior to enrolment. Males and females voluntarily use appropriate methods of contraception during study.
9. Voluntary provision of informed consents.

Exclusion Criteria:

1. Previous treatment with anlotinib, toripalimab or nab-paclitaxel.
2. Coexistence with intestinal perforation, massive intestinal gas, acute intestinal obstruction, severe infection and so on.
3. Multiple factors affecting oral medication such as inability to swallow, chronic diarrhea and intestinal obstruction.
4. Active bleeding of primary lesions within 2 months.
5. History of congenital/acquired immunodeficiency or organ transplantation.
6. Symptomatic brain metastases or meningeal metastases.
7. Existence with anyone of the following conditions: severe cardiovascular diseases, liver diseases, psychiatric disorders, poorly-controlled diabetes (fasting blood glucose\>10mmol/L) or hypertension (systolic blood pressure≥150 mmHg and/ or diastolic blood pressure≥100 mmHg), active or uncontrolled severe infections, significant bleeding tendencies or under thrombolytic or anticoagulant treatment; occurrence of arterial and venous thrombotic events or clinically significant cardiovascular events within 6 months before enrollment；routine urinalysis showing urine protein ≥ ++ and confirmed 24-hour urine protein quantification \> 1.0 g.
8. Known to be allergic to the test drug.
9. Pregnant or breastfeeding female patients
10. Other serious hazards to the safety of patients or complications that affect the study according to the judgment of the researchers.