Safety and Clinical Effect of Subcutaneous Human Interleukin-21 in Patients with Metastatic Melanoma or Renal Cell Carcinoma: A Phase I Trial

This phase I study in patients with metastatic melanoma (MM) and renal cell carcinoma (RCC) evaluated the safety and maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of s.c. treatment of human recombinant interleukin 21 (IL-21). Phase I dose-escala...

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Bibliographic Details
Published in:	Clinical cancer research Vol. 16; no. 21; pp. 5312 - 5319
Main Authors:	SCHMIDT, Henrik, BROWN, Janet, MOURITZEN, Ulrik, SELBY, Peter, FODE, Kirsten, SVANE, Inge Marie, COOK, Graham P, HAL MOLLERUP, David, GEERTSEN, Poul F
Format:	Journal Article
Language:	English
Published:	Philadelphia, PA American Association for Cancer Research 01-11-2010
Subjects:	Adult Aged Aged, 80 and over Antineoplastic agents Biological and medical sciences Carcinoma, Renal Cell - drug therapy Dermatology Dose-Response Relationship, Drug Female Humans Injections, Subcutaneous Interleukins - administration & dosage Interleukins - adverse effects Interleukins - pharmacokinetics Kidney Neoplasms - drug therapy Kidneys Male Maximum Tolerated Dose Medical sciences Melanoma - drug therapy Melanoma - metabolism Melanoma - pathology Middle Aged Neoplasm Metastasis Nephrology. Urinary tract diseases Pharmacology. Drug treatments Recombinant Proteins - administration & dosage Recombinant Proteins - adverse effects Recombinant Proteins - pharmacokinetics Skin Neoplasms - drug therapy Skin Neoplasms - metabolism Skin Neoplasms - pathology Tumors of the skin and soft tissue. Premalignant lesions Tumors of the urinary system Kidney disease Human Urinary system disease Carcinoma Subcutaneous Toxicity Patient Malignant tumor Metastasis Kidney cancer Malignant melanoma Interleukin 21 Phase I trial Grawitz tumor Advanced stage Subcutaneous administration Safety Cancer
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Summary:	This phase I study in patients with metastatic melanoma (MM) and renal cell carcinoma (RCC) evaluated the safety and maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of s.c. treatment of human recombinant interleukin 21 (IL-21). Phase I dose-escalation trial with treatment of three to six patients at each dose level, escalating from 3 to 300 μg/kg. Treatment was administered s.c. on an outpatient basis 3 days per week for 8 or 16 weeks. Twenty-six patients entered the study. Recombinant IL-21 was generally well tolerated, and dose-limiting toxicities (DLT) were first seen at dose levels of 200 and 300 μg/kg. The following four DLTs were observed in three patients: increased transaminases, increased hyperbilirubinemia, hypersensitivity reaction, and lethargy. The MTD was declared to be 200 μg/kg, although five of seven patients at the 300 μg/kg dose level experienced no DLTs. A treatment-related effect on soluble CD25 was observed at all dose levels and increased with dose level. Furthermore, higher doses induced interferon-γ, perforin, and granzyme B mRNA expression in peripheral blood, and granzyme B protein expression in both CD8(+) T cells and natural killer cells, consistent with the activation of cytotoxic lymphocytes. Three patients, one patient with MM and two with RCC, obtained a partial response. Outpatient treatment with s.c. administered IL-21 was tolerated and had dose-dependent pharmacodynamics. rIL-21 showed antitumor activity in patients with MM and RCC.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23
ISSN:	1078-0432 1557-3265
DOI:	10.1158/1078-0432.CCR-10-1809