Phase 1 and Biomarker Study of the Wnt Pathway Modulator DKN-01 in Combination with Gemcitabine/Cisplatin in Advanced Biliary Tract Cancer
Mené sur 51 patients atteints d'un cancer des voies biliaires de stade avancé, cet essai de phase I évalue la dose maximale tolérée de DKN-01, un anticorps monoclonal ciblant DKK1, en combinaison avec la gemcitabine et le cisplatine, et analyse les caractéristiques pharmacocinétiques de cette combinaison en traitement de première ligne
Purpose: Dickkopf1 (DKK1) modulates Wnt signaling, promoting tumor growth, metastasis, and immunosuppression. High DKK1 expression has been detected in various tumor types-including biliary tract cancer (BTC)-and is associated with poor prognosis. DKN-01-a humanized monoclonal antibody targeting DKK1-was evaluated in a phase I multicenter study in combination with gemcitabine and cisplatin in patients with unresectable or metastatic BTC with no prior systemic therapy for advanced disease. Methods: This study included a dose-escalation phase assessing DKN-01 at two dose levels (150mg and 300mg) combined with gemcitabine (1,000mg/m2) and cisplatin (25mg/m2) followed by dose-expansion. Primary endpoints evaluated safety and tolerability; secondary endpoints evaluated efficacy, pharmacokinetics, and circulating biomarkers. Results: Fifty-one patients with intrahepatic cholangiocarcinoma (63%), extrahepatic cholangiocarcinoma (8%), and gallbladder cancer (29%) were enrolled. No dose-limiting toxicities were seen, and the expansion phase proceeded with DKN-01 300mg (N=47). The most frequent grade 3/4 treatment-emergent adverse events included neutropenia (60%), thrombocytopenia (34%), and anemia (23%). The objective response rate was 21.3% and median progression-free survival was 8.7months (95%CI: 5.4, 10.3months). Better outcomes were associated with biomarkers of angiogenesis inhibition (increased sVEGFR1 and lower VEGF-C) and reduced inflammation (lower IL-6 and decreased TNF-α). Conclusions: DKN-01 300mg was well tolerated in this combination but did not appear to have additional activity beyond historically reported efficacy with gemcitabine/cisplatin alone. Exploratory pharmacokinetic and biomarker data indicate potential antiangiogenic and immunomodulatory activity of DKN-01/chemotherapy and the need for increased dose/intensity. A study with DKN-01 600mg in combination with a PD-1 inhibitor in BTC is ongoing.