A phase 2, randomized trial evaluating the combination of dalantercept plus axitinib in patients with advanced clear cell renal cell carcinoma

Cancer. 2019 Jul 15;125(14):2400-2408. doi: 10.1002/cncr.32061. Epub 2019 Apr 5.

Abstract

Background: In a prior open-label study, the combination of dalantercept, a novel antiangiogenic targeting activin receptor-like kinase 1 (ALK1), plus axitinib was deemed safe and tolerable with a promising efficacy signal in patients with advanced renal cell carcinoma (RCC).

Methods: In the current phase 2, randomized, double-blind, placebo-controlled study, patients with clear cell RCC previously treated with 1 prior angiogenesis inhibitor were randomized 1:1 to receive axitinib plus dalantercept versus axitinib plus placebo. Randomization was stratified by the type of prior therapy. The primary endpoint was progression-free survival (PFS). Secondary endpoints were PFS in patients with ≥2 prior lines of anticancer therapy, overall survival, and the objective response rate.

Results: Between June 10, 2014, and February 23, 2017, a total of 124 patients were randomly assigned to receive axitinib plus dalantercept (59 patients) or placebo (65 patients). The median PFS was not found to be significantly different between the treatment groups (median, 6.8 months vs 5.6 months; hazard ratio, 1.11 [95% CI, 0.71-1.73; P = .670]). Neither group reached the median overall survival (hazard ratio, 1.39 [95% CI, 0.70-2.77; P = .349]). The objective response rate was 19.0% (11 of 58 patients; 95% CI, 9.9%-31.4%) in the dalantercept plus axitinib group and 24.6% (15 of 61 patients; 95% CI, 14.5%-37.3%) in the placebo plus axitinib group. At least 1 treatment-emergent adverse event of ≥grade 3 was observed in 59% of patients (34 of 58 patients) in the dalantercept group and 64% of patients (39 of 61 patients) in the placebo group. One treatment-related death occurred in the placebo plus axitinib group.

Conclusions: Although well tolerated, the addition of dalantercept to axitinib did not appear to improve treatment-related outcomes in previously treated patients with advanced RCC.

Trial registration: ClinicalTrials.gov NCT01727336.

Keywords: angiogenesis; antiangiogenic agents; chemotherapy; drug therapy; randomized controlled trial; renal cell carcinoma.

Publication types

  • Clinical Trial, Phase II
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activin Receptors, Type II / administration & dosage
  • Activin Receptors, Type II / adverse effects
  • Activin Receptors, Type II / metabolism
  • Activin Receptors, Type II / therapeutic use*
  • Adult
  • Aged
  • Aged, 80 and over
  • Angiogenesis Inhibitors / administration & dosage
  • Angiogenesis Inhibitors / adverse effects
  • Angiogenesis Inhibitors / therapeutic use*
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Axitinib / administration & dosage
  • Axitinib / adverse effects
  • Axitinib / therapeutic use*
  • Carcinoma, Renal Cell / drug therapy*
  • Carcinoma, Renal Cell / mortality
  • Diarrhea / etiology
  • Double-Blind Method
  • Fatigue / etiology
  • Female
  • Humans
  • Hypertension / etiology
  • Immunoglobulin Fc Fragments / administration & dosage
  • Immunoglobulin Fc Fragments / adverse effects
  • Immunoglobulin Fc Fragments / metabolism
  • Immunoglobulin Fc Fragments / therapeutic use*
  • Kidney Neoplasms / drug therapy*
  • Kidney Neoplasms / mortality
  • Male
  • Middle Aged
  • Progression-Free Survival
  • Recombinant Fusion Proteins / administration & dosage
  • Recombinant Fusion Proteins / adverse effects
  • Recombinant Fusion Proteins / metabolism
  • Recombinant Fusion Proteins / therapeutic use*

Substances

  • Angiogenesis Inhibitors
  • Immunoglobulin Fc Fragments
  • Recombinant Fusion Proteins
  • Axitinib
  • ACVRL1 protein, human
  • ALK1-Fc fusion protein, human
  • Activin Receptors, Type II

Associated data

  • ClinicalTrials.gov/NCT01727336