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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.

AbstractBACKGROUND:
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.
AuthorsC S Higano, J Berlin, M Gordon, P LoRusso, S Tang, A Dontabhaktuni, J D Schwartz, J Cosaert, J M Mehnert
JournalInvestigational new drugs (Invest New Drugs) Vol. 33 Issue 2 Pg. 450-62 (Apr 2015) ISSN: 1573-0646 [Electronic] United States
PMID25749986 (Publication Type: Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)
Chemical References
  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Agents
  • cixutumumab
  • Receptor, IGF Type 1
Topics
  • Adult
  • Aged
  • Antibodies, Monoclonal (administration & dosage, adverse effects, pharmacokinetics)
  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Agents (administration & dosage, adverse effects, pharmacokinetics)
  • Area Under Curve
  • Female
  • Half-Life
  • Humans
  • Male
  • Maximum Tolerated Dose
  • Metabolic Clearance Rate
  • Middle Aged
  • Neoplasms (drug therapy)
  • Receptor, IGF Type 1 (antagonists & inhibitors)

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