British journal of cancer, 2018-11, Vol.119 (10), p.1208-1214
2018
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- Autor(en) / Beteiligte
- Titel
- Galunisertib plus gemcitabine vs. gemcitabine for first-line treatment of patients with unresectable pancreatic cancer
- Ist Teil von
- British journal of cancer, 2018-11, Vol.119 (10), p.1208-1214
- Ort / Verlag
- England: Nature Publishing Group
- Erscheinungsjahr
- 2018
- Quelle
- Free E-Journal (出版社公開部分のみ）
- Beschreibungen/Notizen
- Galunisertib is the first-in-class, first-in-human, oral small-molecule type I transforming growth factor-beta receptor (ALK5) serine/threonine kinase inhibitor to enter clinical development. The effect of galunisertib vs. placebo in patients with unresectable pancreatic cancer was determined. This was a two-part, multinational study: phase 1b was a non-randomised, open-label, multicentre, and dose-escalation study; phase 2 was a randomised, placebo- and Bayesian-augmented controlled, double-blind study in patients with locally advanced or metastatic pancreatic adenocarcinoma considered candidates for first-line chemotherapy with gemcitabine. Patients were randomised 2:1 to galunisertib-gemcitabine (N = 104) or placebo-gemcitabine (N = 52). Gemcitabine dose was 1000 mg/m QW. Primary endpoints for phases 1b and 2, respectively, were phase 2 dose and overall survival. Secondary objectives included tolerability and biomarkers. Dose-escalation suggested a 300-mg/day dose. Primary objective was met: median survival times were 8.9 and 7.1 months for galunisertib and placebo, respectively (hazard ratio [HR] = 0.79 [95% credible interval: 0.59-1.09] and posterior probability HR < 1 = 0.93). Lower baseline biomarkers macrophage inflammatory protein-1-alpha and interferon-gamma-induced protein 10 were associated with galunisertib benefit. Galunisertib-gemcitabine combination improved overall survival vs. gemcitabine in patients with unresectable pancreatic cancer, with minimal added toxicity. Future exploration of galunisertib in pancreatic cancer is ongoing in combination with durvalumab.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0007-0920eISSN: 1532-1827DOI: 10.1038/s41416-018-0246-zTitel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6251034
- Format
- –
- Schlagworte
- Adenocarcinoma, Adult, Aged, Antineoplastic Combined Chemotherapy Protocols - administration & dosage, Antineoplastic Combined Chemotherapy Protocols - adverse effects, Antineoplastic Combined Chemotherapy Protocols - pharmacokinetics, Antineoplastic Combined Chemotherapy Protocols - therapeutic use, Bayesian analysis, Biomarkers, Biomarkers, Tumor - metabolism, Chemotherapy, Clinical trials, Conditional probability, Deoxycytidine - administration & dosage, Deoxycytidine - adverse effects, Deoxycytidine - analogs & derivatives, Deoxycytidine - pharmacokinetics, Deoxycytidine - therapeutic use, Dose-Response Relationship, Drug, Enzyme inhibitors, Female, Gemcitabine, Humans, Inflammation, Interferon, Macrophage inflammatory protein, Macrophage inflammatory protein 1, Male, Metastases, Middle Aged, Monoclonal antibodies, Pancreatic cancer, Pancreatic Neoplasms - drug therapy, Pancreatic Neoplasms - metabolism, Patients, Placebos, Protein-serine/threonine kinase, Pyrazoles - administration & dosage, Pyrazoles - adverse effects, Pyrazoles - pharmacokinetics, Pyrazoles - therapeutic use, Quinolines - administration & dosage, Quinolines - adverse effects, Quinolines - pharmacokinetics, Quinolines - therapeutic use, Randomization, Signal Transduction, Targeted cancer therapy, Toxicity, Transforming Growth Factor beta - metabolism, Transforming growth factor-b, α-Interferon, γ-Interferon