Safety and clinical effect of subcutaneous human interleukin-21 in patients with metastatic melanoma or renal cell carcinoma: a phase I trial.

PURPOSE: 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). EXPERIMENTAL DESIGN: 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. RESULTS: 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. CONCLUSION: 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.

Regulatory approvals in a large multinational clinical trial: the ESPRIT experience.

While accepted as serving an important function to safeguard human subjects, the process of obtaining regulatory approvals to conduct clinical trials is generally regarded as cumbersome and time-consuming. For large multinational trials, U.S. federally sponsored human subject research abroad involves specific U.S. regulatory requirements, in addition to those of the host country, that act as further hurdles. These requirements may include obtaining an Assurance of Protection for Human Subjects from the Office of Human Research Protection of the U.S. Department of Health and Human Services, maintaining specific Ethics Committee/Institutional Review Board (EC/IRB) composition, and incorporating mandated elements in informed consents, all of which may differ from local policies and guidelines. Specific examples of issues that led to delays in regulatory approvals for sites participating in the multinational clinical trial entitled Evaluation of Subcutaneous Proleukin in a Randomized International Trial (ESPRIT) are presented here. While the goal of these requirements is to protect the rights and welfare of human subjects, they may create substantial delays and engender resentment over the notion of lack of respect for individual country sovereignty. Substudies within ESPRIT have been undertaken to obtain feedback from EC/IRB chairpersons, site personnel responsible for processing the required assurances, ESPRIT investigators, and study participants regarding aspects of current U.S. regulatory requirements related to human subject protection and ethical issues in multinational research. The purpose of these substudies is to compare the attitudes and experiences across countries regarding important ethical issues associated with conducting ESPRIT. One objective of the substudies is to gather additional insight to the impact of U.S. regulatory processes. Another is to help to inform the debate about how to best maximize the rights and welfare of clinical trial participants without delaying the initiation of research, while respecting the importance of national sensitivities.