A phase I study of R1507, a human monoclonal antibody IGF-1R (insulin-like growth factor receptor) antagonist given weekly in patients with advanced solid tumors

A78 Background: Signaling through the insulin-like growth factor 1 receptor (IGF-1R) is important for growth, survival and migration potential for many cancers. R1507, a human anti-IGF-1R monoclonal antibody, was explored in this phase I dose escalation study in patients with advanced malignant solid tumors or lymphoma to assess the safety, tolerability, pharmacokinetics and anti-tumor activities. Materials and Methods: Multiple ascending doses of R1507 were administered as a weekly 1-hour infusion until development of dose-limiting toxicity (DLT) or progressive disease. Inclusion criteria: ECOG PS 0-1; adequate hematologic, hepatic, and renal function; CD4 count >200/µl. Exclusion criteria: infection, immunosuppressives, diabetes mellitus, and uncontrolled intercurrent illness. DLT was defined as >grade 3 non-hematologic toxicity (except cardiac toxicity or hypersensitivity reaction >grade 2), or >grade 3 hematologic toxicity ≥7 days. PK: blood was collected following dosing on weeks 1 and 7 for non-compartmental analysis and dosing confirmation. Response was assessed by RECIST every 6 weeks. Results: 34 patients (pts) were enrolled in 3 dose levels: 1 (n= 6), 3 (n=6), and 9 mg/kg (n=22). The 9 mg/kg dose was expanded for further efficacy and toxicity evaluation. Median age was 55 yrs (range 18-74), M:F 23:11. Safety: drug-related adverse events (AE) included fatigue (n=3); anorexia and weight loss (n=2 each); rash, nausea, diarrhea, abdominal pain, musculoskeletal pain, muscular weakness, headache, dizziness, tremor, dry eyes, ear discomfort/deafness and hypophosphatemia (n=1 each). Of the 34 patients on trial, 30 (88%) had no drug-related toxicity ≥ grade 2. No adverse events of hyperglycemia were reported; however glucose tolerance test changed from negative to positive in 2/17 patients at week 7. Two serious AE, cerebrovascular accident and hyperbilirubinemia, were possibly attributed to study drug at 9 mg/kg. PK: Clearance was 846 mL/Day (CV =18.3%), 759 mL/Day (CV=17.9%) and 586 mL/Day (CV=33.9%) in the 1, 3 and 9 mg/kg groups respectively. Vd = 3.88 L (CV=28.3%), 4.88 L (CV=22.3%) and 4.19 L (CV=30.3%) for the 1, 3 and 9 mg/kg group respectively. T1/2 increased from 3.4 to 6.2 days. At the end of week 7, the median Css,min was 18.1, 57.2 and 162.5 ug/mL for the 1, 3 and 9 mg/kg groups respectively. Clearance decreased while the Vd remained stable thus T1/2 increased with increasing doses. Activity: Four of 8 evaluable Ewing’s sarcoma patients had confirmed ongoing partial responses (PR, n= 2) for 24-27+ weeks or stable disease (n= 2) for 12-18+ weeks. PRs were noted in the 1 mg/kg and 9 mg/kg cohorts. Overall 10 pts showed stable disease (median duration 18 weeks, range 12-48+). Seven pts remain on study (range 2-52+ weeks) with Ewing’s sarcoma (4), leiomyosarcoma, osteosarcoma, and desmoplastic tumor (1 each).Conclusions: No DLT or MTD were identified. The recommended phase II dose on this weekly schedule is 9 mg/kg. Higher doses are not being tested, as the trough concentration at this dose exceeds the target level identified in preclinical xenograft models necessary for IGF1R inhibition. Encouraging activity noted in sarcoma has prompted initiation of a phase II trial.