Pegylated interferon alfa-2b treatment for patients with solid tumors: a phase I/II study.

PURPOSE: The efficacy of interferon alfa has been established in treating advanced melanoma and renal cell carcinoma (RCC) patients. We conducted a phase I/II study to determine the maximum-tolerated dose (MTD), the safety and tolerability, and the preliminary efficacy of once-weekly pegylated interferon alfa-2b (IFNalpha-2b) in patients with advanced solid tumors (primarily RCC). PATIENTS AND METHODS: To determine the MTD, 35 patients with a variety of advanced solid tumors received 0.75 to 7.5 micro g/kg/wk of pegylated IFNalpha-2b by subcutaneous injection for 12 weeks. An additional 35 previously untreated RCC patients received 6.0 and 7.5 micro g/kg/wk for up to 12 weeks. Patients with a response or stable disease after 12 weeks were eligible for the extension protocol and were treated for up to 1 year or until disease progression. RESULTS: The MTD for pegylated IFNalpha-2b at 12 weeks was 6.0 micro g/kg/wk. One year of 6.0 micro g/kg/wk was well tolerated with appropriate dose modification; no grade 3 or 4 fatigue occurred, and safety was comparable with that with nonpegylated IFNalpha-2b. The most common nonhematologic adverse events included mild to moderate nausea, anorexia, and fatigue. Six patients had grade 3 or 4 hematologic toxicity. Twenty-nine patients continued on the extension protocol. Four patients had a complete response, and five patients had a partial response. Among 44 previously untreated RCC patients, the objective response rate was 14%. Median survival for all RCC patients was 13.2 months. CONCLUSION: Pegylated IFNalpha-2b was active and well tolerated in patients with metastatic solid tumors, including RCC, at doses up to 6.0 micro g/kg/wk.

Clinical EPR: unique opportunities and some challenges.

Electron paramagnetic resonance (EPR) spectroscopy has been well established as a viable technique for measurement of free radicals and oxygen in biological systems, from in vitro cellular systems to in vivo small animal models of disease. However, the use of EPR in human subjects in the clinical setting, although attractive for a variety of important applications such as oxygen measurement, is challenged with several factors including the need for instrumentation customized for human subjects, probe, and regulatory constraints. This article describes the rationale and development of the first clinical EPR systems for two important clinical applications, namely, measurement of tissue oxygen (oximetry) and radiation dose (dosimetry) in humans. The clinical spectrometers operate at 1.2 GHz frequency and use surface-loop resonators capable of providing topical measurements up to 1 cm depth in tissues. Tissue pO2 measurements can be carried out noninvasively and repeatedly after placement of an oxygen-sensitive paramagnetic material (currently India ink) at the site of interest. Our EPR dosimetry system is capable of measuring radiation-induced free radicals in the tooth of irradiated human subjects to determine the exposure dose. These developments offer potential opportunities for clinical dosimetry and oximetry, which include guiding therapy for individual patients with tumors or vascular disease by monitoring of tissue oxygenation. Further work is in progress to translate this unique technology to routine clinical practice.

A phase I, dose-escalation study of cyclical weekly oral temozolomide and weekly PEG-interferon alpha-2b in patients with refractory or advanced solid tumours.

BACKGROUND: Temozolomide (TMZ) is an oral alkylating agent used in the treatment of central nervous system neoplasms and metastatic melanoma. Preclinical and clinical data suggested that combining TMZ with interferon alpha-2b (IFN-alpha-2b) may result in increased anti-tumour efficacy. METHODS: This was a phase I, dose-escalation study to define the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of cyclical oral TMZ (days 1-7 and 15-21) in combination with pegylated IFN-alpha-2b (PEG-IFN-alpha-2b) in patients with advanced solid tumours. RESULTS: We treated 19 patients (10 female and nine male), median age 58 years (range: 41-79 years). Ten patients tolerated TMZ at 100 mg/m² on days 1-7 and 15-21 plus PEG-IFN-alpha-2b at 1.5 mcg/kg/week on 28-day cycles which was the MTD of the combination. The pharmacokinetic parameters of PEG-IFN-alpha-2b were not altered by TMZ, at the MTD. CONCLUSION: The MTD of cyclical oral TMZ was 100 mg/m² on days 1-7 and 15-21 when combined with weekly subcutaneous PEG-IFNα-2b at 1.5 mcg/kg/week on 28 days cycles. The PK of PEG-IFN-alpha-2b appeared consistent with those when it is used as monotherapy.

Phase I/II trial of outpatient PEG-interferon with interleukin-2 in advanced renal cell carcinoma: a cytokine working group study.

A phase I/II trial was undertaken to determine the maximum tolerated dose of polyethylene glycol interferon-alpha-2b (PEG-IFN) with interleukin-2 (IL-2), and to evaluate the efficacy and toxicity in patients with metastatic renal cell carcinoma. Patients initially received subcutaneous PEG-IFN, 3.0 mcg/kg/wk, combined with IL-2, but owing to unexpected toxicity a revised phase I schedule ensued. Patients received 1.0, 1.5, 2.0, or 3.0 mcg/kg/wk of PEG-IFN on days 1, 8, 15, and 22; subcutaneous IL-2 was given at a dose of 5 x 10 IU/m2 every 8 hours x 3 on day 1, followed daily at 5 x 10 IU/m2 days 2, 3, 4, and 5 of week 1, then 5 times per week for 3 weeks, followed by 2 weeks off. The maximum tolerated dose of PEG-IFN was 2.0 mcg/kg/wk. Fifty-four patients were enrolled. Frequent grade III/IV cardiac and neurologic toxicities led to an expanded phase I trial. Eleven serious events in 33 patients in the phase II portion led to early termination. No patient died from treatment. The overall response rate in 53 evaluable patients was 30.2% (95% confidence interval 20.5-39.9), with 2 complete responses and 14 partial responses and at least 1 response at each dose level. The median duration of response was 11 months (range, 2 to 65+ mo); median survival was 20 months (range, 2 to 71+ mo); median time to progression was 4 months. Despite clinical efficacy, the study was closed prematurely owing to excess toxicity. Although all serious adverse events resolved, this degree of toxicity is unacceptable for an outpatient treatment regimen.