Galunisertib plus gemcitabine vs. gemcitabine for first-line treatment of patients with unresectable pancreatic cancer

Br J Cancer. 2018 Nov;119(10):1208-1214. doi: 10.1038/s41416-018-0246-z. Epub 2018 Oct 15.

Abstract

Background: 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.

Methods: 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/m2 QW. Primary endpoints for phases 1b and 2, respectively, were phase 2 dose and overall survival. Secondary objectives included tolerability and biomarkers.

Results: 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.

Conclusions: 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.

Publication types

  • Clinical Trial, Phase I
  • Clinical Trial, Phase II
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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*
  • Biomarkers, Tumor / metabolism
  • Deoxycytidine / administration & dosage
  • Deoxycytidine / adverse effects
  • Deoxycytidine / analogs & derivatives*
  • Deoxycytidine / pharmacokinetics
  • Deoxycytidine / therapeutic use
  • Dose-Response Relationship, Drug
  • Female
  • Humans
  • Male
  • Middle Aged
  • Pancreatic Neoplasms / drug therapy*
  • Pancreatic Neoplasms / metabolism
  • Placebos
  • Pyrazoles / administration & dosage
  • Pyrazoles / adverse effects
  • Pyrazoles / pharmacokinetics
  • Pyrazoles / therapeutic use*
  • Quinolines / administration & dosage
  • Quinolines / adverse effects
  • Quinolines / pharmacokinetics
  • Quinolines / therapeutic use*
  • Signal Transduction
  • Transforming Growth Factor beta / metabolism

Substances

  • Biomarkers, Tumor
  • Placebos
  • Pyrazoles
  • Quinolines
  • Transforming Growth Factor beta
  • Deoxycytidine
  • LY-2157299
  • gemcitabine