A phase I study of the vascular endothelial growth factor inhibitor Vatalanib in combination with Pemetrexed disodium in patients with advanced solid tumors

Invest New Drugs. 2019 Aug;37(4):658-665. doi: 10.1007/s10637-018-0690-x. Epub 2018 Oct 31.


Introduction Vatalanib is an oral receptor tyrosine kinase inhibitor that blocks all known VEGF, PDGF, and c-Kit receptors. This phase I study evaluated the safety, tolerability, and biologic activity of the combination of vatalanib with pemetrexed disodium in patients with advanced solid tumors. Methods Patients were administered escalating twice daily doses of vatalanib in combination with pemetrexed disodium in 21-day cycles. A dose expansion cohort was enrolled to further define the maximum tolerated dose (MTD) and further evaluate efficacy. Results A total of 29 patients were enrolled in the study (dose escalation, 9; dose expansion, 20). Dose-limiting toxicities included grade 4 thrombocytopenia (6.9%) and febrile neutropenia, anorexia, constipation, and dehydration. Other common adverse events were fatigue (75%), nausea (66%), vomiting (48%), oral mucositis (31%) and diarrhea (28%). The majority of these toxicities were Grade 1-2. The MTD was reached at vatalanib 250 mg twice daily continuously combined with pemetrexed disodium 500 mg/m2 day 1. Overall, 2 patients (6.9%) had partial responses, 8 (27.6%) had stable disease for at least 4 cycles, 5 had progressive disease (17.2%) and 5 went off study before disease assessment. Conclusion The combination of vatalanib with pemetrexed disodium was feasible, but not well tolerated. The modest efficacy results are consistent with other results obtained from combinations of chemotherapy and a large number of VEGF tyrosine kinase inhibitors. This combination should not be developed further unless predictive biomarkers can be identified.

Keywords: Pemetrexed; Phase I; Solid tumors; VEGF inhibitor; Vatalanib.

Publication types

  • Clinical Trial, Phase I
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage*
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Female
  • Humans
  • Male
  • Maximum Tolerated Dose
  • Middle Aged
  • Neoplasms / drug therapy*
  • Pemetrexed / administration & dosage*
  • Pemetrexed / adverse effects
  • Phthalazines / administration & dosage*
  • Phthalazines / adverse effects
  • Protein Kinase Inhibitors / administration & dosage*
  • Protein Kinase Inhibitors / adverse effects
  • Pyridines / administration & dosage*
  • Pyridines / adverse effects
  • Random Allocation
  • Treatment Outcome
  • Vascular Endothelial Growth Factor A / antagonists & inhibitors*


  • Antineoplastic Agents
  • Phthalazines
  • Protein Kinase Inhibitors
  • Pyridines
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • Pemetrexed
  • vatalanib