Phase I trial of 40-kd branched pegylated interferon alfa-2a for patients with advanced renal cell carcinoma

R. J. Motzer, A. Rakhit, M. Ginsberg, K. Rittweger, Jacqueline Vuky, R. Yu, S. Fettner, L. Hooftman

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)1312-1319
Number of pages8
JournalJournal of Clinical Oncology
Volume19
Issue number5
StatePublished - Mar 1 2001
Externally publishedYes

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Renal Cell Carcinoma
Neopterin
Ligases
Fatigue
Pharmacokinetics
Serum
Maximum Tolerated Dose
peginterferon alfa-2a
Myalgia
Appetite
Subcutaneous Injections
Nausea
Area Under Curve
Headache
Half-Life
Fever
Clinical Trials
Therapeutics
interferon alfa-2a

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Motzer, R. J., Rakhit, A., Ginsberg, M., Rittweger, K., Vuky, J., Yu, R., ... Hooftman, L. (2001). Phase I trial of 40-kd branched pegylated interferon alfa-2a for patients with advanced renal cell carcinoma. Journal of Clinical Oncology, 19(5), 1312-1319.

Phase I trial of 40-kd branched pegylated interferon alfa-2a for patients with advanced renal cell carcinoma. / Motzer, R. J.; Rakhit, A.; Ginsberg, M.; Rittweger, K.; Vuky, Jacqueline; Yu, R.; Fettner, S.; Hooftman, L.

In: Journal of Clinical Oncology, Vol. 19, No. 5, 01.03.2001, p. 1312-1319.

Research output: Contribution to journalArticle

Motzer, RJ, Rakhit, A, Ginsberg, M, Rittweger, K, Vuky, J, Yu, R, Fettner, S & Hooftman, L 2001, 'Phase I trial of 40-kd branched pegylated interferon alfa-2a for patients with advanced renal cell carcinoma', Journal of Clinical Oncology, vol. 19, no. 5, pp. 1312-1319.
Motzer, R. J. ; Rakhit, A. ; Ginsberg, M. ; Rittweger, K. ; Vuky, Jacqueline ; Yu, R. ; Fettner, S. ; Hooftman, L. / Phase I trial of 40-kd branched pegylated interferon alfa-2a for patients with advanced renal cell carcinoma. In: Journal of Clinical Oncology. 2001 ; Vol. 19, No. 5. pp. 1312-1319.
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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.",
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T1 - Phase I trial of 40-kd branched pegylated interferon alfa-2a for patients with advanced renal cell carcinoma

AU - Motzer, R. J.

AU - Rakhit, A.

AU - Ginsberg, M.

AU - Rittweger, K.

AU - Vuky, Jacqueline

AU - Yu, R.

AU - Fettner, S.

AU - Hooftman, L.

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Y1 - 2001/3/1

N2 - 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.

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