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Safety, tolerability, and pharmacokinetics of single and multiple doses of intravenous cixutumumab (IMC-A12), an inhibitor of the insulin-like growth factor-I receptor, administered weekly or every 2 weeks in patients with advanced solid tumors

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Summary

Background: Type 1 insulin-like growth factor receptor (IGF-IR) signaling is often dysregulated in cancer. Cixutumumab, a fully human IgG1 monoclonal antibody, blocks IGF-IR and inhibits downstream signaling. The current study determined the recommended dose, safety, and pharmacokinetic (PK) profile of weekly or every-2-week dosing of cixutumumab. Patients and Methods: Two open-label, multicenter phase I studies evaluated weekly (3–15 mg/kg) or every-2-weeks (6–15 mg/kg) dosing of cixutumumab in patients with advanced solid tumors. Serial blood samples for PK were collected up to 168–336 h (day 8–15) following the first administration of cixutumumab. Efficacy was evaluated as best overall tumor response. Results: A total of 24 and 16 patients were enrolled in the weekly and every-2-week dosing studies, respectively. Treatment-emergent adverse events (≥10 %) included hyperglycemia, fatigue, anemia, nausea, and vomiting. Severe adverse events (AE) were infrequent; one serious AE (grade 3 electrocardiogram QT prolongation) was deemed possibly cixutumumab-related (10 mg/kg every-2-weeks). One death occurred due to disease progression (6 mg/kg weekly cohort). Maximum serum concentrations increased with dose. A maximum tolerated dose was not identified; pre-determined target serum minimum concentrations (60 μg/mL) were achieved with ≥6 mg/kg weekly and ≥10 mg/kg every-2-week dosing. Cixutumumab terminal elimination half-life is approximately a week (individual range, t1/2 = 4.58–9.33 days based upon 10 mg/kg every 2 weeks). Overall, stable disease was achieved in 25 % of all patients. Conclusions: Cixutumumab was associated with favorable safety and PK profiles. A dosing regimen of 10 mg/kg every 2 weeks was recommended for subsequent disease-focused clinical trials.

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Acknowledgments

The authors would like to acknowledge Chastity Bradley, PhD, Medical Communication Consultants, for medical writing assistance and Lisa R Ferguson-Sells, Eli Lilly and Company, for her critical review of the manuscript.

Funding

This work (CP13-0501 [NCT00785538] and CP13-0502 [NCT00785941]) was supported by Eli Lilly and Company, Bridgewater, NJ.

Conflict of interest statement

C.S. Higano and J. Berlin have conducted research sponsored by the company. S. Tang, A. Dontabhaktuni, J.D. Schwartz, and J. Cosaert are or were employees of Eli Lilly and Company and own Eli Lilly and Company stock. All remaining authors have declared no conflicts of interest.

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Author notes

  1. P. LoRusso

    Present address: Yale Cancer Center, New Haven, USA

  2. J. D. Schwartz

    Present address: Stemline Therapeutics, Inc., New York, USA

Authors and Affiliations

  1. Departments of Medicine and Urology, University of Washington and Fred Hutchinson Cancer Research Center, Seattle, USA

    C. S. Higano

  2. Vanderbilt Ingram Cancer Center, Vanderbilt University, Nashville, USA

    J. Berlin

  3. Pinnacle Oncology Hematology, Scottsdale, USA

    M. Gordon

  4. Karmanos Cancer Institute, Wayne State University, Detroit, USA

    P. LoRusso

  5. Eli Lilly and Company, Bridgewater, USA

    S. Tang, A. Dontabhaktuni, J. D. Schwartz & J. Cosaert

  6. Rutgers Cancer Institute of New Jersey, New Brunswick, USA

    J. M. Mehnert

  7. University of Washington, Seattle Cancer Care Alliance, 825 Eastlake Ave, E., Seattle, WA, 98109-1023, USA

    C. S. Higano

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Key message

These open-label, phase I studies evaluated the safety, tolerability, and pharmacokinetic profile of cixutumumab dosed weekly and every 2 weeks in patients with advanced solid tumors. Cixutumumab therapy was safe, tolerable, and demonstrated evidence of disease control. The dosing regimen established here (10 mg/kg every 2 weeks) has been used in subsequent phase II disease-focused trials.

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Higano, C.S., Berlin, J., Gordon, M. et al. Safety, tolerability, and pharmacokinetics of single and multiple doses of intravenous cixutumumab (IMC-A12), an inhibitor of the insulin-like growth factor-I receptor, administered weekly or every 2 weeks in patients with advanced solid tumors. Invest New Drugs 33, 450–462 (2015). https://doi.org/10.1007/s10637-015-0217-7

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  • DOI: https://doi.org/10.1007/s10637-015-0217-7

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