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Phase I and Biomarker Study of the Wnt Pathway Modulator DKN-01 in Combination with Gemcitabine/Cisplatin in Advanced Biliary Tract Cancer.
Goyal, Lipika; Sirard, Cynthia; Schrag, Michael; Kagey, Michael H; Eads, Jennifer R; Stein, Stacey; El-Khoueiry, Anthony B; Manji, Gulam A; Abrams, Thomas A; Khorana, Alok A; Miksad, Rebecca; Mahalingam, Devalingam; Zhu, Andrew X; Duda, Dan G.
Afiliación
  • Goyal L; Hematology/Oncology, Massachusetts General Hospital Cancer Center, Boston, Massachusetts. lgoyal@partners.org.
  • Sirard C; Leap Therapeutics, Cambridge, Massachusetts.
  • Schrag M; ProPharma Services LLC, Superior, Louisville, Colorado.
  • Kagey MH; Leap Therapeutics, Cambridge, Massachusetts.
  • Eads JR; Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania.
  • Stein S; Yale School of Medicine, New Haven, Connecticut.
  • El-Khoueiry AB; Keck School of Medicine of USC, Los Angeles, California.
  • Manji GA; Columbia University Irving Medical Center, New York, New York.
  • Abrams TA; Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Khorana AA; Cleveland Clinic, Cleveland, Ohio.
  • Miksad R; Boston Medical Center, Boston, Massachusetts, and Flatiron Health, New York, New York.
  • Mahalingam D; Northwestern Medical Group, Robert H Lurie Cancer Center, Chicago, Illinois.
  • Zhu AX; Hematology/Oncology, Massachusetts General Hospital Cancer Center, Boston, Massachusetts.
  • Duda DG; Jiahui International Cancer Center, Shanghai, China.
Clin Cancer Res ; 26(23): 6158-6167, 2020 12 01.
Article en En | MEDLINE | ID: mdl-32878766
PURPOSE: Dickkopf-1 (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 mAb 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. PATIENTS AND METHODS: This study included a dose-escalation phase assessing DKN-01 at two dose levels (150 mg and 300 mg) combined with gemcitabine (1,000 mg/m2) and cisplatin (25 mg/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-01 300 mg (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 8.7 months (95% confidence interval, 5.4-10.3 months). Better outcomes were associated with biomarkers of angiogenesis inhibition (increased sVEGFR1 and lower VEGF-C) and reduced inflammation (lower IL6 and decreased TNFα). CONCLUSIONS: DKN-01 300 mg 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-01 600 mg in combination with a PD-1 inhibitor in BTC is ongoing.
Asunto(s)

Texto completo: 1 Base de datos: MEDLINE Asunto principal: Neoplasias del Sistema Biliar / Protocolos de Quimioterapia Combinada Antineoplásica / Péptidos y Proteínas de Señalización Intercelular / Vía de Señalización Wnt / Anticuerpos Monoclonales Tipo de estudio: Clinical_trials / Observational_studies / Prognostic_studies / Risk_factors_studies Idioma: En Revista: Clin Cancer Res Asunto de la revista: NEOPLASIAS Año: 2020 Tipo del documento: Article

Texto completo: 1 Base de datos: MEDLINE Asunto principal: Neoplasias del Sistema Biliar / Protocolos de Quimioterapia Combinada Antineoplásica / Péptidos y Proteínas de Señalización Intercelular / Vía de Señalización Wnt / Anticuerpos Monoclonales Tipo de estudio: Clinical_trials / Observational_studies / Prognostic_studies / Risk_factors_studies Idioma: En Revista: Clin Cancer Res Asunto de la revista: NEOPLASIAS Año: 2020 Tipo del documento: Article