The IMMUNOBIL PRODIGE 57 phase II trial, designed to assess the efficacy and safety of durvalumab and tremelimumab with or without weekly paclitaxel in patients with advanced biliary tract carcinoma (BTC) after failure of platinum-based chemotherapy, has been modified due to significant safety concerns. The trial's safety run-in revealed an unexpectedly high rate of anaphylactic adverse events in the arm combining durvalumab, tremelimumab, and paclitaxel, leading to the discontinuation of that arm. The study will now proceed solely with the durvalumab and tremelimumab combination arm.
Unexpected Toxicities Lead to Trial Modification
The initial phase of the IMMUNOBIL PRODIGE 57 trial enrolled 20 patients, with 10 receiving durvalumab (1500 mg) and tremelimumab (75 mg) every 28 days (Arm A), and 10 receiving the same immunotherapy regimen in combination with paclitaxel (80 mg/m2 weekly) (Arm B). While Arm A reported no dose-limiting toxicities (DLTs), Arm B experienced six DLTs in five patients (50%), triggering a pre-defined stopping rule. These DLTs included three serious anaphylactic reactions (one with cardiac arrest), two cases of enterocolitis, and one instance of infectious pneumopathy with septic shock. Notably, none of the patients had a history of autoimmune disease.
Concerns Regarding Triplet Combination
The observed toxicities, particularly the anaphylactic reactions, have raised significant concerns regarding the co-administration of paclitaxel with durvalumab and tremelimumab in BTC. Researchers noted that this combination appears more toxic than taxane-based chemotherapy combined with anti-PD-L1 therapy without anti-CTLA4. The decision was made to discontinue the paclitaxel-containing arm to protect patient safety.
Biliary Tract Cancer and the Need for Innovative Treatments
Biliary tract carcinoma is the second most common primary liver tumor, with a majority of patients diagnosed at an advanced stage. Standard first-line treatment involves gemcitabine plus cisplatin chemotherapy. However, after failure of this regimen, second-line options like FOLFOX offer limited overall survival benefits, underscoring the need for innovative therapeutic strategies. Immune checkpoint inhibitors have shown promise in various cancers, including BTC, leading to investigations into their potential in combination with chemotherapy.
Future Directions for IMMUNOBIL PRODIGE 57
The IMMUNOBIL PRODIGE 57 trial will continue to evaluate the efficacy and safety of the durvalumab and tremelimumab combination in patients with advanced BTC who have progressed on platinum-based chemotherapy. The primary endpoint is progression-free survival (PFS) as assessed by iRECIST criteria. Full data on primary and secondary endpoints will be presented in the final analysis. This study highlights the complexities of combining immunotherapy with chemotherapy and the critical importance of vigilant safety monitoring in clinical trials.
