Jeffrey S. Weber

Phase I trial of subcutaneous interleukin-6 in patients with advanced malignancies.

PURPOSE Based on preclinical evidence in murine models that interleukin-6 (IL-6) mediates regression of metastatic tumors, we performed a phase I study of recombinant human IL-6 in patients with refractory advanced malignancies to determine its pharmacokinetics, toxicities, and possible immunologic and antitumor effects. PATIENTS AND METHODS Recombinant IL-6 was administered as a single subcutaneous dose daily for 7 days, with 7 days off therapy followed by another 7 days of IL-6. Doses were escalated in cohorts of three patients starting at 3 micrograms/kg/d, provided that toxicity at the preceding dose level was not dose-limiting. Dose-limiting toxicity was defined as grade III or IV major organ toxicity that did not resolve to grade II or less in 24 hours after stopping IL-6, using the National Cancer Institute Common Toxicity Criteria. Patients were treated with 3, 10, and 30 micrograms/kg/d IL-6 subcutaneously. RESULTS Three patients each were treated at the 3- and 10-micrograms dose levels. Two of five patients treated with 30 micrograms/kg/d IL-6 subcutaneously had grade III major organ toxicity that required IL-6 therapy to be discontinued. All patients experienced fever, chills, and minor fatigue. Significant increases in C-reactive protein (CRP), fibrinogen, platelet counts, and lymphocyte IL-2 receptor levels were seen in patients at the 10- and 30-micrograms/kg dose levels. Decreases in albumin and hemoglobin were observed, particularly at the 30-micrograms/kg dose level. The half-life (T1/2 beta) was 4.2 hours, with a peak IL-6 level at 5 hours. No antitumor responses were seen. CONCLUSION A safely tolerated dose of daily subcutaneous IL-6 is 10 micrograms/kg, with hepatotoxicity and cardiac arrhythmia being the dose-limiting toxicities at 30 micrograms/kg. Phase II trials of IL-6 administered subcutaneously daily for at least 7 days for two cycles with an intervening week of rest are recommended for phase II trials. However, patients with extensive replacement of liver by tumor and abnormal liver functions should receive IL-6 therapy with caution.

Randomized comparison of high-dose and low-dose intravenous interleukin-2 for the therapy of metastatic renal cell carcinoma: an interim report.

PURPOSE A randomized prospective study was performed to compare the efficacy and toxicity of high-dose intravenous bolus interleukin-2 (IL-2) and a lower-dose intravenous bolus regimen for the treatment of metastatic renal cell carcinoma (RCC). PATIENTS AND METHODS Between March 1991 and April 1993, 125 patients with metastatic RCC were randomized to receive IL-2 by intravenous bolus every 8 hours at either 720,000 IU/kg (high-dose) or 72,000 IU/kg (low-dose) to the maximum-tolerated number of doses (or a maximum of 15 doses). After approximately 7 to 10 days, both treatment groups were re-treated with a second identical cycle of therapy. Those patients who were stable or responding to treatment 5 to 6 weeks later went on to receive re-treatment with another course (two cycles) of therapy. Response rates and toxicity were determined for the two treatment arms. RESULTS One hundred twenty-five patients received a total of 208 courses of therapy. Sixty patients were randomized to receive low-dose, and 65 to receive high-dose IL-2. There were no treatment-related deaths in either arm. There was a greater incidence of grade III or IV thrombocytopenia, malaise, and hypotension in patients who received high-dose IL-2, while patients who received low-dose IL-2 had significantly more infections. Three percent of treatment courses with low-dose IL-2 required vasopressor support, compared with 52% of courses with high-dose IL-2. Patients who received low-dose IL-2 had a 7% complete response (CR) and an 8% partial response (PR) rate, and patients who received high-dose IL-2 had a 3% CR and a 17% PR rate. CONCLUSION Low-dose intravenous bolus IL-2 represents an effective regimen for the treatment of metastatic RCC, with preliminary results comparable to those observed with high-dose IL-2. Low-dose IL-2 can be administered with significantly fewer complications, reduced use of vasopressor support, and fewer admissions to an intensive care unit (ICU).

The use of interleukin-2 and lymphokine-activated killer cells for the treatment of patients with non-Hodgkin's lymphoma.

PURPOSE The study was undertaken to assess whether immunotherapy regimens with bolus high-dose interleukin-2 (IL-2) alone or with lymphokine-activated killer (LAK) cells are active in previously treated, relapsed patients with non-Hodgkins lymphoma. PATIENTS AND METHODS Nineteen patients with low- or intermediate-grade lymphomas were treated with bolus high-dose IL-2 alone (11 patients) or IL-2 with LAK cells (eight patients). IL-2 was administered by intravenous bolus infusion at 720,000 IU/kg every 8 hours. Eight patients had low-grade histologies; 11 patients were intermediate-grade. Eighteen patients had received second- or third-generation combination chemotherapy, and eight had also received radiation. All 19 relapsed after a median of two chemotherapy regimens. RESULTS Four responses were observed, three partial and one complete, in patients with follicular histologies who received IL-2 with LAK cells. Response durations were 10, 16, 16, and 26 months, and three responders were re-treated after relapse with subsequent disease control for an additional 16, 39+, and 2+ months, respectively. CONCLUSION High-dose, bolus IL-2-based immunotherapy with LAK cells may be an effective treatment for patients with non-Hodgkins lymphoma and merits further testing with larger numbers of patients in phase II trials.

Renal dysfunction associated with the administration of high-dose interleukin-2 in 199 consecutive patients with metastatic melanoma or renal carcinoma.

PURPOSE To describe the incidence and management of renal dysfunction associated with the use of high-dose interleukin-2 (IL-2) (as is currently approved) in the treatment of cancer patients. PATIENTS AND METHODS One hundred ninety-nine consecutive patients with metastatic renal carcinoma or melanoma were treated with intravenous bolus infusions of IL-2 alone (720,000 IU/kg) every 8 hours. RESULTS Patients received 310 courses (589 cycles) of therapy and most experienced oliguria, hypotension, and weight gain; 13% of cycles were discontinued due to increased serum creatinine levels. Creatinine values (mean pretherapy, 1.2 mg/dL) increased during therapy and peaked (mean, 2.7 mg/dL) approximately 1 day after discontinuation of the second cycle of IL-2. Off therapy, toxicities reversed promptly and creatinine values returned to baseline. Higher peak creatinine values occurred in patients with renal carcinoma (v melanoma), older patients, males (v females), and those who had undergone prior nephrectomy. These same patient subsets received fewer doses of IL-2, but clinical responses were not associated with creatinine values or number of IL-2 doses administered. Urinalyses showed the appearance of protein, bilirubin, RBCs, WBCs, and granular casts during therapy, which cleared completely on follow-up evaluation. CONCLUSION High-dose IL-2 can be safely administered to cancer patients. The associated renal dysfunction is transient and without evidence of intrinsic long-term renal damage. Practical guidelines for patient management have been identified.

A Phase I Trial of Intravenous Interleukin-6 in Patients with Advanced Cancer

Eighteen patients were treated with escalating doses of recombinant, Escherichia coli-derived human interleukin-6 (IL-6) intravenously every 8 h. Therapy was given for two cycles of 7 days each separated by a week off therapy. Fevers and chills were observed in most patients. Mild renal and liver function abnormalities were noted at higher doses of IL-6. Dose-limiting toxicity was reached at 30 micrograms/kg i.v. every 8 h due to reversible neurotoxicity, but significant rapidly reversible anemia and hyperglycemia were seen at lower doses. Platelet counts, white blood cell counts, and acute phase reactant levels were substantially elevated. No antitumor responses were seen. A maximum tolerated dose of 10 micrograms/kg i.v. every 8 h for two 7-day cycles is recommended for future phase II trials.

A randomized double-blinded comparison of the antiemetic efficacy of ondansetron and droperidol in patients receiving high-dose interleukin-2

Emesis and nausea are common toxicities seen during high-dose interleukin-2 (IL-2) therapy (720,000 IU/kg i.v. every 8 h). A growing list of randomized studies have documented the efficacy of ondansetron, a potent antagonist of the 5-hydroxytryptamine3 receptor, in preventing acute chemotherapy-induced emesis and nausea. However, no study has evaluated the efficacy of ondansetron in preventing IL-2-induced emesis and nausea. This double-blinded, randomized trial was performed to compare the antiemetic and antinausea efficacy of ondansetron with that of droperidol, a butyrophenone, in patients receiving high-dose IL-2 on protocols at the National Cancer Institute. Ondansetron or droperidol was given intravenously, 30 min prior to the first dose of IL-2 and then every 8 h for the duration of IL-2 treatment. No significant differences were seen between the two agents in complete freedom from emesis (p2 = 0.51), level of nausea (p2 = 0.17), antiemetic treatment failure (p2 = 0.89), and time to first emetic episode (p2 = 0.44). Equivalent doses of IL-2 were administered on each arm of the study, with a similar incidence of liver dysfunction (p2 = 0.15) and diarrhea (p2 = 0.64). Finally, there was no significant difference in the response rates to metastatic disease in either arm of the antiemetic study (p2 = 0.67), and these response rates were similar to those in other patients treated under immunotherapy protocols in the Surgery Branch of the National Cancer Institute with high-dose IL-2. We conclude that droperidol is equally effective in preventing emesis and controlling nausea when compared with ondansetron for patients receiving high-dose IL-2.