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

Venepalli, Neeta K. MD, MBA*; Emmadi, Rajyasree MD; Danciu, Oana C. MD*; Chowdhery, Rozina MD*; Cabay, Robert J. MD; Gaitonde, Sujata MD; Aardsma, Nathan MD; Kothari, Rajul MD; Liu, Li C. PhD§; Fischer, James H. PharmD; Zaidi, Ayesha MBBS; Russell, Meredith J. BS; Dudek, Arkadiusz Z. MD, PhD*,#,**

American Journal of Clinical Oncology: November 2019 - Volume 42 - Issue 11 - p 862–869
doi: 10.1097/COC.0000000000000611
Original Articles: Experimental Therapeutics

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.

*Department of Medicine, Division of Hematology/Oncology

Departments of Pathology


§Division of Epidemiology and Biostatistics School of Public Health

Department of Pharmacy Practice, College of Pharmacy

Oncology Clinical Trials Office, University of Illinois at Chicago, Chicago, IL

#IGF Oncology LLC

**HealthPartners Regions Cancer Care Center, St Paul, MN

A.Z.D. has received research funding from Millennium Pharmaceuticals, Merck, Eli Lilly, and consulting honoraria from Biothera. A.Z.D. serves as Chief Medical Officer for Vanquish Oncology, TTC Oncology, IGF Oncology, and Martell Diagnostic Laboratories. J.H.F. has received reimbursement from IGF Oncology for performing the pharmacokinetic analysis. IGF Oncology and the University of Illinois Cancer Center have provided funding for this project. The other authors declare no conflicts of interest.

Reprints: Neeta K. Venepalli, MD, MBA, Department of Medicine, Division of Hematology/Oncology, University of Illinois at Chicago, 840 South Wood Street, 820-E CSB, Chicago, IL 60612. E-mail:

Online date: October 16, 2019

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