This proposal seeks to explore the anti-tumor activity of IL-1alpha and chemotherapy. In preclinical studies, the antitumor effects of concomitantly administered Interleukin-1 and carboplatin (CBDCA) have been observed. As measured by the clonogenic cell survival assay IL- 1alpha significantly increases carboplatin (CBDCA)-induced tumor kill. Subsequent studies have demonstrated that IL-1alpha preferentially and significantly increases platinum levels in the tumor as compared to liver and kidney in animals treated with CBDCA alone. These antitumor effects have been encouraging enough to warrant expansion into clinical investigations. this current submission proposes to perform a series of clinical trials in which the feasibility, toxicity, pharmacology and efficacy of IL-1alpha administered in conjunction with CBDCA will be explored. To pursue this, a series of phase I and II clinical trials will be performed. To begin, the pharmacokinetics, dose-limiting toxicity and anti-tumor activity of IL-1alpha concomitantly administered with CBDCA will be explored at phase I trial. Once the maximally tolerated dose has been determined, a subsequent pilot trial will seek to determine the feasibility of administering IL-1alpha and CBDCA in preoperative patients. A phase IIb trial, performed as a multi- institutional trial with the Eastern Cooperative Oncology Group, will then evaluate the effects of IL-1alpha and CBDCA alone or in combination on local accumulation of chemotherapeutic agents, serum pharmacokinetics and pharmacodynamics, and tumor histology. The pilot and phase IIb trials will utilize patients with advanced, resectable squamous cell carcinoma of the head and neck. forty-eight hours prior to definitive surgery, patients will receive IL-1alpha alone or in combination with CBDCA at the dosages determined in the previous phase I trial. Alterations in the level of CBDCA will be assessed in blood, tumor and adjacent normal tissue. In parallel with these clinical trials a murine tumor model system will be used to characterize the antitumor activities of IL-1alpha in combination with CBDCA. These studies will focus on IL- 1alpha/CBDCA combination and determine whether, the interaction is synergistic by median dose effect, examine the CBDCA dose response, determine whether the IL-1alpha dose can be decreased, examine the effect of IL-1alpha on platinum-associated DNA in the tumor, examine time sequence studies and determine the efficacy of multiple combination dose treatments. It is hoped that by understanding and optimizing the antitumor effects noted with this combination, it might be possible to better exploit it allowing more effective and rational combinations to be developed.
Yu, W D; Chang, M J; Trump, D L et al. (1997) Interleukin-1alpha synergistic in vivo enhancement of cyclophosphamide- and carboplatin-mediated antitumor activity. Cancer Immunol Immunother 44:316-22 |
Chang, M J; Modzelewski, R A; Russell, D M et al. (1996) Interleukin 1 alpha and gamma-interferon induction of nitric oxide production from murine tumor-derived endothelial cells. Cancer Res 56:886-91 |
Modzelewski, R A; Davies, P; Watkins, S C et al. (1994) Isolation and identification of fresh tumor-derived endothelial cells from a murine RIF-1 fibrosarcoma. Cancer Res 54:336-9 |
Chang, M J; Yu, W D; Reyno, L M et al. (1994) Potentiation by interleukin 1 alpha of cisplatin and carboplatin antitumor activity: schedule-dependent and pharmacokinetic effects in the RIF-1 tumor model. Cancer Res 54:5380-6 |