Phase I trial of 40-kd branched pegylated interferon alfa-2a for patients with advanced renal cell carcinoma Journal Article
| Authors: | Motzer, R. J.; Rakhit, A.; Ginsberg, M.; Rittweger, K.; Vuky, J.; Yu, R.; Fettner, S.; Hooftman, L. |
| Article Title: | Phase I trial of 40-kd branched pegylated interferon alfa-2a for patients with advanced renal cell carcinoma |
| Abstract: | Purpose: Pegylated (40 kd) interferon alfa-2a (IFNα2a) (PEGASYS, Hoffman-La Roche, Nutley, NJ; PEG-IFN) is a modified form of recombinant human IFNα2a with sustained absorption and prolonged half-life after subcutaneous administration. A phase I study of PEG-IFN with pharmacokinetic and pharmacodynamic evaluations was conducted in previously untreated patients with advanced renal cell carcinoma (RCC). Patients and Methods: Twenty-seven patients were enrolled onto cohorts of three or six patients. PEG-IFN was administered on a weekly basis by subcutaneous injection. The dose was escalated from 180 μg/wk to a maximum of 540 μg/wk in 90-μg increments. Serial venous blood samples were drawn to assess concentrations of PEG-IFN and two immunologic surrogates, neopterin and 2′-5′ oligoadenylate synthetase (OAS). Results: The maximum-tolerated dose was determined as 540 μg/wk, because two patients experienced dose-limiting toxicity within 28 days of starting treatment. One developed serum grade 3 ALT elevation, and a second developed grade 3 fatigue. Six patients were treated at 450 μg/wk without dose-limiting toxicity. Over the course of treatment, the side-effect profile was mostly mild to moderate in intensity. Adverse events included fatigue, fever, headache, myalgia, nausea, and decreased appetite. Five patients (19%) achieved a partial response. The mean maximum serum concentration increased from 5.0 to 27 ng/mL, and mean area under the curve increased from 247 to 2,981 ng/h/mL, with dose escalation from 180 μg/wk to 540 μg/wk. Serum concentration of PEG-IFN was sustained at close to peak during the dasing interval, and steady-state was achieved in approximately 5 weeks. The immunologic surrogates, neopterin and OAS, were induced at all doses with a sustained concentration profile similar to PEG-IFN. Conclusion: PEG-IFN is a modified form of IFNα2a with distinct pharmacokinetic advantages and immunomodulatory and antitumor activity for patients with advanced RCC. A dose of 450 μg/wk by subcutaneous administration was determined as a suitable dose for further study. PEG-IFN is more convenient to administer than IFNα and has potential for increased efficacy, less toxicity, or both. The efficacy and toxicity of PEG-IFN will be further assessed in clinical trials and compared with IFNα. © 2001 by American Society of Clinical Oncology. |
| Keywords: | adult; cancer chemotherapy; clinical article; controlled study; treatment outcome; aged; middle aged; clinical trial; fatigue; advanced cancer; area under the curve; drug efficacy; antineoplastic agents; anorexia; protein blood level; controlled clinical trial; liver toxicity; steady state; nausea; myalgia; antineoplastic activity; drug effect; dose-response relationship, drug; kidney carcinoma; kidney neoplasms; fever; alanine aminotransferase; carcinoma, renal cell; immunomodulation; headache; drug blood level; phase 1 clinical trial; injections, subcutaneous; polyethylene glycols; recombinant alpha2a interferon; interferon alfa-2a; humans; human; male; female; priority journal; article; neopterin; 2',5' oligoadenylate synthetase |
| Journal Title: | Journal of Clinical Oncology |
| Volume: | 19 |
| Issue: | 5 |
| ISSN: | 0732-183X |
| Publisher: | American Society of Clinical Oncology |
| Date Published: | 2001-03-01 |
| Start Page: | 1312 |
| End Page: | 1319 |
| Language: | English |
| PUBMED: | 11230473 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Export Date: 21 May 2015 -- Source: Scopus |
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