Phase I Study of IGF-Methotrexate Conjugate in the Treatment of Advanced Tumors Expressing IGF-1R

Am J Clin Oncol. 2019 Nov;42(11):862-869. doi: 10.1097/COC.0000000000000611.


Objectives: Insulin-like growth factor-methotrexate (IGF-MTX) is a conjugate of methotrexate and 765IGF, a variant of IGF-1 with high affinity for insulin-like growth factor type 1 receptor. The study aim was to determine the maximum tolerated dose of IGF-MTX in refractory solid organ and hematologic malignancies expressing insulin-like growth factor type 1 receptor.

Materials and methods: This phase I trial used a modified toxicity probability interval design with 5 cohort dose levels, and expansion cohort at maximum tolerated dose. IGF-MTX was given intravenously over 90 minutes on days 1, 8, and 15 of a 28-day cycle.

Results: A total of 17 patients were enrolled. The highest tolerated dose tested was 0.80 µEq/kg with dose-limiting toxicity of grade 3 hypoglycemia. Drug-related grade 3 and 4 toxicities included abdominal pain (26%), hypoglycemia (10%), and hypotension (10%). Of the 15 evaluable for response, 3 patients (20%) had stable disease, including the patient with Hodgkin lymphoma with stable disease for 12 cycles of therapy. IGF-MTX concentrations declined rapidly, with half-lives of 5.2 to 14 minutes for the initial distribution phase and 6.5 to 7.5 hours for the terminal elimination phase. Higher IGF-R1 expression did not correlate with better outcome.

Conclusions: IGF-MTX is well tolerated. IGF-MTX pharmacokinetics suggest rapid cellular uptake. The activity of IGF-MTX in Hodgkin lymphoma should be explored.

Publication types

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

MeSH terms

  • Adult
  • Aged
  • Disease-Free Survival
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Hematologic Neoplasms / drug therapy*
  • Hematologic Neoplasms / genetics
  • Hematologic Neoplasms / mortality
  • Humans
  • Illinois
  • Kaplan-Meier Estimate
  • Male
  • Maximum Tolerated Dose
  • Methotrexate / therapeutic use*
  • Middle Aged
  • Molecular Targeted Therapy
  • Neoplasms / drug therapy*
  • Neoplasms / genetics
  • Neoplasms / mortality
  • Patient Selection
  • Prognosis
  • Receptor, IGF Type 1 / genetics*
  • Risk Assessment
  • Survival Analysis


  • IGF1R protein, human
  • Receptor, IGF Type 1
  • Methotrexate