Durvalumab + Tremelimumab ± Paclitaxel in Advanced BTC After Platinum Chemotherapy.

IMMUNO-BIL is a non-comparative randomized 1:1 phase II study. This study will assess the efficacy and safety of the combination of durvalumab plus tremelimumab with or without weekly paclitaxel in patients with advanced BTC after failure of platinum-based chemotherapy. On the 25th June 2019, the maximum DLT event number was reached (6/10) in the durvalumab plus tremelimumab combination with paclitaxel Arm (Arm B). According to the Pocock boundary described in the protocol, GERCOR has updated the study to discontinue enrollment in Arm B (durvalumab plus tremelimumab with paclitaxel) . No safety concerns were raised by the IDMC in Arm A. Consequently, the study will resume with Arm A (durvalumab plus tremelimumab) only, without randomization. Discontinuation of ARM B(June 2019): Durvalumab plus tremelimumab plus paclitaxel One cycle equals 4 weeks (D1=D28); Durvalumab: 1,500 mg by IV infusion on D1, until progression or unacceptable toxicity or withdrawal of consent. Tremelimumab: 75 mg by IV infusion on D1 for the first 4 cycles. Paclitaxel: 80 mg/m2, every week for 3 weeks (D1-D8-D15), by IV infusion, until progression or unacceptable toxicity or withdrawal of consent (at least 6 cycles, at the discretion of the investigator). December 2020: Tremelimumab dosage modification based on the results of the Study 22 study (Kelley RK, et al. ASCO20 Virtual Scientific Program 2020) showing increased efficacy (response rate and progression-free survival) without safety concerns with one dose of tremelimumab 300 mg (cycle 1) instead of four doses of 75 mg (cycle 1 to cycle 4) in combination with durvalumab 1,500 mg Q4W in hepatocellular carcinoma. Following these results, we have changed the tremelimumab 75 mg x 4 schedule for the 300 mg x 1 schedule. The inclusion of 106 additional patients will be required to adequately evaluate the efficacy of this administration schedule. ARM A : Durvalumab plus tremelimumab ( patients included before 31/12/2020) One cycle equals 4 weeks (D1=D28); Durvalumab: 1,500 mg by IV infusion on D1, until progression or unacceptable toxicity or withdrawal of consent. Tremelimumab: 75 mg by IV infusion on D1 for the first 4 cycles.

Biliary tract carcinoma (BTC, adenocarcinoma in more than 90% of cases) is the second primary liver tumor in incidence after hepatocellular carcinoma (2,000 new cases/year in France). The prognosis of biliary malignancies is poor, with a 5-year overall survival rate (OS) of about 10-15%, most often due to late diagnosis, at an advanced stage. In advanced BTC, the gemcitabine plus platinum (cisplatin \[GEMCIS\] or oxaliplatin \[GEMOX\]) doublet of chemotherapy is the standard first-line treatment and no targeted therapy has been validated in this indication to date. There is no second-line therapeutic standard; chemotherapy (mainly, 5-FU-based combination) yields limited median progression-free survival (PFS) and OS of abouty 2-3 months and 6-7 months respectively, justifying the exploration of new therapeutic options. Immune therapies (mainly, immune checkpoint inhibitors \[ICI\]) have opened new opportunities in cancer therapy. Hence, anti-CTLA-4 and anti-PD-1/PD-L1 monoclonal antibodies (mAb) have demonstrated robust clinical activity and obtained FDA approval in several cancers. Recent data showed encouraging results with anti-PD-1 mAb as a monotherapy in PD-L1-positive pre-treated advanced BTC. The effects of ICI in combination with second-line chemotherapy in patients with advanced BTC have not been explored to date. Platinum salts can induce "immunogenic cell death". Therefore, previous treatment with platinum may increase tumor immunogenicity and sensitivity to immune therapy, particularly, ICI. The second-line setting after failure of platinum-based chemotherapy may then be an optimal biological context for testing immune therapy in advanced BTC. Durvalumab is a human immunoglobulin (Ig) G1 kappa (IgG1κ) anti-PD-L1 mAb. Tremelimumab is a human IgG2 anti-CTLA-4 mAb. Paclitaxel is a chemotherapy belonging to the taxane family. Taxanes may enhance the effect of immunotherapy by increasing the sensitivity of the tumor and activating the immune system. Taxanes are used in some patients with advanced biliary cancer. These data suggest that BTC may be a good candidate for immune therapy. The combination of anti-CTL4 and anti-PD1/PD-L1 mAb is expected to be active in both immune-inflamed and non-inflamed BTC, and in PD-L1 high and low tumors.