Phase I/II trial of a novel regimen of GM-CSF, IL-2 and pegylated interferon-alpha2b (PEG-Intron) for stage IV melanoma and renal cell carcinoma (RCC)

Abstract

7573 Background: This phase I/II trial was done to assess toxicity and anti-tumor effects of subcutaneous (SC) GM-CSF, IL-2 & PEG-IFN-α2b for stage IV melanoma (MEL) and RCC. Due to reported activity of GM-CSF in MEL, and its biologic effects (esp. on dendritic cells), it was added. Preliminary data in RCC suggests activity and reduced toxicity of pegylated IFNs. Methods: Phase I used a modified Fibonacci design. GM-CSF was escalated first, over 2 dose levels (125 & 250 μg/m2). IL-2 was then escalated from 3 to 5 MU/m2. Initially, the PEG-IFN dose was 1.5 μg/kg; later it was increased to 3.0 μg/kg, due to recent data. GM-CSF was given SC d 1–12. IL-2 was given SC d 3–5, 8–12 & 15–19, and PEG-IFN was given SC on d 17 & 24 q 35 d. A correlative study was done to measure changes in PBM subsets during treatment, and is reported separately. Results: 16 pts (8 MEL; 8 RCC) have been enrolled, with 15 evaluable for toxicity and 14 for tumor response. All planned dose levels were tested, without any dose-limiting toxicity. 6 patients had grade 3 non-hematologic toxicity, with 3 being fatigue; of note was that 2/3 pts had fatigue with non-pegylated IFN (due to a shortage of PEG-Intron). The other grade 3 toxicities were one episode each of reversible hypotension of uncertain cause in cycle 3, hyperglycemia and depression. There was 1 episode of transient grade 3 neutropenia. There was no grade 4 toxicity or treatment-related mortality. Other toxicities were 2 grade 2 injection site reactions and eosinophilia in 1 pt. No ORs were observed, but 1 MEL pt had a skin lesion regress, with biopsy-proven immune cell infiltrates. This pt, and 2 others had SD for >3 mo, while other pts experienced early PD. Conclusions: This 3-cytokine, SC regimen was shown to be safe and well-tolerated. Evidence of biologic activity was seen in 1 patient, and 3 patients had disease stabilization. Changes in immune cell subsets populations were observed (reported separately). A phase II dosing schedule was established and enrollment to complete the 1st stage of phase II is ongoing. Supported in part by Schering-Plough. No significant financial relationships to disclose.