PHASE-I EVALUATION OF INTRAVENOUS RECOMBINANT HUMAN INTERLEUKIN-12 INPATIENTS WITH ADVANCED MALIGNANCIES

A Phase I dose escalation trial of i.v. administered recombinant human interleukin 12 (rhIL-12) was performed to determine its toxicity, max imum tolerated dose (MTD), pharmacokinetics, and biological and potent ial antineoplastic effects. Cohorts of four to six patients with advan ced cancer, Karnofsky performance greater than or equal to 70%, and no rmal organ function received escalating doses (3-1000 ng/kg/day) of rI L-12 (Genetics Institute, Inc.) by bolus i.v. injection once as an inp atient and then, after a 2-week rest period, once daily for five days every 3 weeks as an outpatient. Therapy was withheld for grade 3 toxic ity (grade 4 hyperbilirubinemia or neutropenia), and dose escalation w as halted if three of six patients experienced a dose-limiting toxicit y (DLT). After establishment of the MTD, eight more patients were enro lled to further assess the safety, pharmacokinetics, and immunobiology of this dose. Forty patients were enrolled, including 20 with renal c ancer, 12 with melanoma, and 5 with colon cancer; 25 patients had rece ived prior systemic therapy. Common toxicities included fever/chills, fatigue, nausea, vomiting, and headache. Fever was first observed at t he 3 ng/kg dose level, typically occurred 8-12 h after rhIL-12 adminis tration, and was incompletely suppressed with nonsteroidal anti-inflam matory drugs. Routine laboratory changes included anemia, neutropenia, lymphopenia, hyperglycemia, thrombocytopenia, and hypoalbuminemia. DL Ts included oral stomatitis and liver function test abnormalities, pre dominantly elevated transaminases, which occurred in three of four pat ients at the 1000 ng/kg dose level. The 500 ng/kg dose level was deter mined to be the MTD. This dose, administered by this schedule, was ass ociated with asymptomatic hepatic function test abnormalities in three patients and an onstudy death due to Clostridia perfringens septicemi a but was otherwise well tolerated by the 14 patients treated in the d ose escalation and safety phases. The T-1/2 elimination of rhIL-12 was calculated to be 5.3-9.6 h. Biological effects included dose-dependen t increases in circulating IFN-gamma, which exhibited attenuation with subsequent cycles. Serum neopterin rose in a reproducible fashion reg ardless of dose or cycle. Tumor necrosis factor ex was not detected by ELISA. One of 40 patients developed a low titer antibody to rhIL-12 L ymphopenia was observed at all dose levels, with recovery occurring wi thin several days of completing treatment without rebound lymphocytosi s. There was one partial response (renal cell cancer) and one transien t complete response (melanoma), both in previously untreated patients. Four additional patients received all proposed treatment without dise ase progression. rhIL-12 administered according to this schedule is bi ologically and clinically active at doses tolerable by most patients i n an outpatient setting. Nonetheless, additional Phase I studies exami ning different schedules and the mechanisms of the specific DLTs are i ndicated before proceeding to Phase II testing.