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NATL. CANCER INSTITUTE "SECOND GENERATION" INTERLEUKIN-2/LAK CLINICAL TESTING PROTOCOLS WILL INCLUDE TREATMENT WITH IL-2 ALONE IN ADVANCED CANCER PATIENTS

Executive Summary

The National Cancer Institute is initiating "second generation" studies with interleukin-2 (IL-2) and lympyhokine activated killer (LAK) cells that will include clinical testing of IL-2 alone in prospectively randomized cancer patients, according to NCI investigator Steven Rosenberg. The IL-2 trial will focus on treating patients with renal cell carcinoma, melanoma and colorectal cancer, Rosenberg told the Board of Scientific Counselors to NCI's Division of Cancer Treatment (DCT) on May 29. Under the new regimen, one group of patients will receive both LAK cells and IL-2 and another will get only high doses of IL-2, he said. The current protocol used by NCI involves the administration of 100,000 units of IL-2/kg along with LAK cells three times a day. Rosenberg has reported testing 300,000 unit doses of IL-2/kg alone three times daily in a small group of patients. Asked by board member Robert Goodman, University of Pennsylvania, if there are enough data to justify randomized trials using only IL-2, Rosenberg said that "dramatic responses" to IL-2 treatment have been observed and that "all of the animal models predict that more is better." NCI also is planning to conduct two randomized adjuvant studies evaluating the LAK-cell therapy. One study would enroll patients with stage-two melanoma who are disease free after lymph node dissection. A second would involve colorectal cancer patients with completely resected liver metastases or who appear clinically disease free, Rosenberg reported. Pilot Studies Currently Underway To "Confirm and Extend" Rosenberg LAK Findings As of April 25, Rosenberg and his colleagues had treated 82 patients at the NIH Clinical Center. Of the 55 who could be evalutated, 21, or 38% have shown an "objective response" to the IL-2/LAK treatment, Rosenberg said. "We've seen responses now in five different histologies," said Rosenberg, including colorectal cancer (4 of 17 patients responded), melanoma (6 of 14) and metastatic renal cancer, which appears to be "unusually susceptible" to the treatment, with 9 of 10 patients responding. NCI also is beginning to retreat patients who have responded to the IL-2/LAK therapy, said Rosenberg. The institute's future efforts will include studies of LAK cells in vitro and the use of "allogenic" LAK cells, he added. In a separate report on the institute's intramural biological response modifiers program, Associate Program Director Dan Longo said BRMP has been conducting small pilot studies to "confirm and extend" Rosenberg's findings with LAK cells, and to explore improvements of the therapy and minimize its toxicity. One BRMP pilot study is assessing the effect steroids have on dose-limiting toxicity. In 10 patients receiving both steroids and IL-2/LAK, said Longo, "dose-limiting toxicities are the same [with steroids], but the time it takes to get to [the] dose-limiting" stage is longer. If steroids are omitted during the administration of IL-2, the median number of doses that may be delivered before dose-limiting toxicity is reached is "a little more" than 9 doses; with steroids, the median number of doses is more than 13, Longo reported. DCT biologics evaluation branch chief Michael Hawkins reported that, as of May 22, a total of 35 patients had been enrolled in an NCI-funded, six-center IL-2/LAK trial. The study is expected to enroll a total of 300 patients at a cost of $2.5 mil. in fiscal 1986. Cetus is providing NCI with the IL-2 free of charge ("The Pink Sheet" Feb. 10, T&G-2). Of the 35, 28 have renal cell carcinoma and seven have malignant melanoma. It is too early to evaluate tumor response in most of the patients, according to Hawkins. However, he said, some toxicity data have been obtained. Of 23 patients who completed the LAK portion of the protocol, Hawkins reported, 71% required a transfusion due to anemia, 63% had hypotension requiring pressors and 67% had desquamating rash. According to DCT investigation drug branch chief Daniel Hoth, beginning in July the extramural centers will expand their studies to include IL-2/LAK treatment of three other tumors -- breast, nonsmall-cell lung, and non-Hodgkin's lymphoma. The extramural trial centers also will study retreatment tolerance, he said.

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