James S. Sergi

Phase I trial of high-dose bolus interleukin-2 and interferon alfa-2a in patients with metastatic malignancy.

PURPOSE Based on preclinical evidence that the antitumor effects of the combination of interleukin-2 (IL-2) and interferon alfa (IFN alpha) are greater than those of either cytokine alone, we have performed a phase I trial of recombinant IL-2 (rIL-2) and recombinant human IFN alpha 2a (rHuIFN alpha 2a) in patients with refractory malignancies. This study was an extension of an earlier trial that identified reversible myelosuppression as the dose-limiting toxicity of this combination. The present trial used modified definitions of unacceptable toxicity to allow exploration of higher doses of rIL-2. PATIENTS AND METHODS Both rHuIFN alpha 2a 10.0 x 10(6) U/m2 intramuscularly (IM) and rIL-2 were administered three times weekly for 4 consecutive weeks. IL-2 was given by intravenous (IV) bolus injection at doses that were escalated in successive cohorts of four to six patients, provided that toxicity at the preceding dose level was acceptable. Unacceptable toxicity was defined as an elevation of the serum creatinine level to greater than 5 mg/dL, an elevation of the serum bilirubin level to greater than 5 mg/dL, dyspnea at rest, hypotension refractory to pressors, altered mental status, or other toxicities of grade 3 to 4, using the National Cancer Institute (NCI) Common Toxicity Criteria. The doses of rIL-2 administered were 4.0 x 10(6), 6.0 x 10(6), 8.0 x 10(6), 10.0 x 10(6), 12.0 x 10(6), 14.0 x 10(6), 18.0 x 10(6), 22.0 x 10(6), and 26.0 x 10(6) BRMP (Hoffman-LaRoche) U/m2. At a dose of rIL-2 10.0 x 10(6) BRMP U/m2, patients were also treated with doses of rHuIFN alpha 2a of 1.0 x 10(6) and 0.1 x 10(6) U/m2. RESULTS A total of 57 patients were treated. Intolerable side effects (hypotension, pulmonary, and CNS toxicity) were produced by rIL-2 26.0 x 10(6) BRMP U/m2 and rHuIFN alpha 2a 10.0 x 10(6) U/m2. Two of 21 patients with renal cell carcinoma showed objective responses, and five of 17 patients with malignant melanoma responded. Two of these responses in melanoma were complete and continue to be longlasting. CONCLUSIONS When given with rHuIFN alpha 2a 10.0 x 10(6) U/m2 as described above, the maximum-tolerated dose of rIL-2 is 22.0 x 10(6) BRMP U/m2. This dose of rIL-2 is equivalent to 50 to 60 MIU/m2, depending on the conversion factor used. Based on this experience and other trials, we favor phase II trials in renal cell carcinoma using an alternative dose schedule of this cytokine combination, in which rIL-2 is administered by continuous infusion. We suggest that phase II trials of this combination in patients with melanoma use an rIL-2 dose of 8.0 x 10(6) BRMP U/m2 by IV bolus injection three times weekly in combination with rHuIFN alpha 2a 10.0 x 10(6) U/m2 IM three times weekly.

Phase I study of WR-2721 and carboplatin

Because WR-2721 reduces the toxicity of cisplatin and carboplatin in preclinical systems, we have treated 35 patients in a phase I study of WR-2721 and carboplatin. As the plasma half-life of WR-2721 is short relative to that of carboplatin, WR-2721 was administered in two divided doses. This schedule produced acceptable toxicity in 24 patients treated with carboplatin 400 mg/m2 and escalating doses of WR-2721. In the subsequent 11 patients, WR-2721 was fixed at 740 mg/m2/dose and the dose of carboplatin was escalated. With WR-2721, grade 3-4 thrombopenia (platelets < 50 x 10(9)/l) was produced in 4/5 patients treated with carboplatin 625 mg/m2 and in 1/6 patients treated with carboplatin 500 mg/m2. Carboplatin pharmacokinetic parameters in 4 patients were similar to those reported for carboplatin alone. These results suggest that WR-2721 might increase the maximum tolerated dose of carboplatin from 400 to 500 mg/m2.

A phase I trial of 5-fluorouracil, folinic acid, and alpha-2a-interferon in patients with metastatic colorectal carcinoma.

The mechanisms of biochemical modulation of 5‐fluorouracil (5‐FU) cytotoxicity by folinic acid (FA) have been elucidated, and the clinical use of this combination has improved response rates and survival in patients with metastatic colorectal cancer. Recently, Phase II trials also showed potential synergism between alpha‐2a‐inter‐feron (rHuIFN‐α2a) and 5‐FU. Therefore, a Phase I trial of these three agents 5‐FU, FA, and rHuIFN‐α2a was conducted in patients with metastatic colorectal cancer. The drugs were given over 5 days, with dose escalation of either rHuIFN‐α2a or 5‐FU. Fifty‐five eligible patients were treated at eight dosing levels. The maximal tolerated dose (MTD) was as follows: 5‐FU 430 mg/m2/d intravenously (IV) on days 1 to 5, FA 200 mg/m2 IV on days 1 to 5, and rHuIFN‐α2a 4.0 × 106 U/m2/d subcutaneously on days 1 to 5. The dose‐limiting toxicities were mucositis and neutropenia. Objective responses were seen at most dosing levels, and overall 15 of 55 patients (27%; 95% confidence interval, 16% to 41%) responded (median duration, 6.5 months). A Phase II trial using the MTD is ongoing. Cancer 1992; 69:889–892.

Polyethylene glycol conjugated interleukin-2: Clinical and immunologic effects in patients with advanced renal cell carcinoma

SummaryRecombinant interleukin-2 (rIL-2) modified with monomethoxypolyethylene glycol (PEG IL-2) was utilized in patients with metastatic renal cell carcinoma in two separate multi-institutional trials. PEG IL-2 was administered as an I.V. bolus days 1, 8, 15, and 22 with cycles repeated every six weeks. The two trials employed different dose levels: A) 20x106 I.U./m2 day 1 followed by 12x106 I.U./m2 days 8, 15, 22; and B) 12x106 I.U./m2 days 1, 8, 15, 22. Thirty-five patients were entered and 31 were evaluable for response (A−15/18, B−16/17). Two of 31 patients had partial responses. Median therapy duration was four weeks (range 1–15), and dose reduction for grade III or IV toxicity was required in 14/35 patients (A-6/18, B-8/17). Toxicity (≥ grade III) seen included: hypotension 51%, dyspnea 17%, seizures 6%, and mental status changes 11%. No differences in response or toxicity between the two schedules were noted. Hematologic changes included lymphocytosis and eosinophilia in the majority of patients. PEG IL-2 given once weekly has significant toxicity, and may produce tumor regression in patients with renal cell carinoma.

Phase I trial of continuous infusion interleukin-2 and doxorubicin in patients with refractory malignancies

A phase I trial was performed to assess the immunomodulatory activities, maximum tolerated doses, and the toxicity of recombinant interleukin-2 (rIL-2) administered in combination with doxorubicin to patients with refractory malignancies. Therapy was administered to successive cohorts of four to six patients who were treated at three different dose levels (1A, 1B, 2A). Levels 1-2 refer to doxorubicin (40 or 60 mg/m2) given as an intravenous (i.v.) bolus on day 1, and levels A-B refer to rIL-2 (1.0 or 3.0 x 10(6) U/m2) given as a continuous i.v. infusion on days 2-5, 9-12, and 16-19. Cycles were repeated every 28 days. Seventeen patients were entered in the trial. Dose limiting toxicity consisted of neutropenia, and the maximum tolerated dose (MTD) of the combination was doxorubicin 40 mg/m2 and rIL-2 3.0 x 10(6) U/m2. No objective responses were observed. Lymphocytosis related to rIL-2 occurred and flow cytometry demonstrated significant increases in the following subsets: CD3+CD25+HLADr+ and CD11b-CD16c+CD8-. Natural killer cell activity and lymphokine-activated killer (LAK) cell precursors were increased in patients treated at dose levels 1A and 1B (40 mg/m2 doxorubicin), but no consistent changes in LAK activity were noted. No clinical responses were seen and the overall toxicity of this combination was moderate to severe. Administration of doxorubicin prior to rIL-2 does not enhance the immunologic effects of rIL-2.

IL-2 Based Combination Therapy of Malignant Disease: Summary of the Phase I Experience at the Cleveland Clinic

We have performed Phase I trials of rIL-2 in combination with IFNα or doxorubicin (DOX), based upon the independent activity of these agents and preclinical evidence of therapeutic synergy. In a Phase I trial of the combination of doxorubicin (DOX) and rIL-2, myelosuppression prevented dose escalation beyond the MTD of DOX 40 mg/m2 IV bolus day 1 and rIL-2 3.0 MU/m2/24 hr IV on days 2–5, 9–12, and 16–19. Significant increases in peripheral blood NK and LAK precursor activities were observed, but no clinical responses were produced in this patient population with largely gastrointestinal malignancies. In other Phase I studies, four week cycles of rIL-2 given by intravenous (IV) bolus injection three times weekly (TIW) have been administered in combination with rHuIFNα2a given intramuscularly (IM) TIW. With aggressive supportive care, the Maximum Tolerated Dose (MTD) of rIL-2 that could be given with rHuIFNα2a 10 MU/m2 IM TIW was 22.0 x 106 BRMP Units (MU)/m2 IV TIW. Dose limiting toxicities were CNS, pulmonary and cardiovascular. When given with rHuIFNα2a 10.0 MU/m2 TIW, the MTD of infusion rIL-2 was 3.0 MU/m2/24 hr x 5 days, weekly x 4. We have also treated pts with RCC and MM in Phase II trials of rIL-2 3.0 MU/m2/24 hrs D1–4 and rHuIFNα2a 5.0 MU/m2 SQ D1–4. Overall, 3/7 pts with RCC treated with infusion schedule rIL-2 and rHuIFNα2a have responded in our Phase I study, as opposed to 3/33 pts with RCC treated with bolus schedule rIL-2 and rHuIFNα2a. Of pts with MM, 6/23 pts have responded to bolus schedule rIL-2 and rHuIFNα2a while 0/3 have responded to infusion schedule rIL-2 with rHuIFNα2a in our Phase I studies. We have also entered patients on multi-center Phase II studies utilizing a somewhat less dose-intense schedule of infusion schedule rIL-2 and rHuIFNα2a. Among patients entered on these trials from the Cleveland Clinic, 3/11 pts with RCC have responded, while 2/10 pts with MM have responded. Further studies of the mechanisms by which responses are mediated are needed if IL-2 based therapies are to be improved.