A phase II open-label study of recombinant human interleukin-12 in patients with stage IA, IB, or IIA mycosis fungoides.

BACKGROUND: Interleukin-12 (IL-12) increases Th(1) cytokines, natural killer (NK) cells, and cytotoxic T-cell activities. Progression of mycosis fungoides is associated with Th(2) cytokines produced by a clonal proliferation of epidermotropic T-helper cells. OBJECTIVE: To determine the safety and efficacy of subcutaneous recombinant human IL-12 (rhIL-12) in early mycosis fungoides (MF; stage IA-IIA) in a multi-center, open label clinical trial. METHODS: rhIL-12 was administered biweekly (100 ng/kg for 2 weeks; 300 ng/kg thereafter). A modified severity-weighted assessment tool (SWAT) and the longest diameter of 5 index lesions measured efficacy. RESULTS: Twenty-three MF patients (stage IA, 12 patients; IB, 9; and IIA, 2) had previously received >3 therapies. Ten of 23 patients (43%) achieved partial responses (PR); 7 (30%) achieved minor responses; and 5 (22%) had stable disease. The duration of PRs ranged from 3 to more than 45 weeks. Twelve (52%) ultimately progressed with mean time to progressive disease of 57 days (range, 28-805). Ten completed 6 months of therapy; 1 completed 24 months. Of patients not completing 6 months of therapy, 6 progressed and 6 others discontinued because of adverse events or withdrew consent. Seventeen patients had treatment-related adverse events that were generally mild or moderate in severity, including asthenia, headache, chills, fever, injection site reaction, pain, myalgia, arthralgia, elevated aspartate and alanine aminotransferase levels, anorexia, and sweating. One patient in PR died of hemolytic anemia, possibly exacerbated by rhIL-12 treatment. LIMITATIONS: The original company was purchased during the conduct of the trial and rhIL-12 is currently unavailable. The quality of life data were not available for inclusion. CONCLUSION: Twice-weekly subcutaneously administered rhIL-12 (100 ng/kg escalated to 300 ng/kg) showed antitumor activity with a response rate of 43% in refractory patients. It was relatively well-tolerated in early-stage MF.

Phase 1 study of the intravesical administration of recombinant human interleukin-12 in patients with recurrent superficial transitional cell carcinoma of the bladder.

Superficial transitional cell carcinoma (STCC) of the bladder is usually managed with intravesical bacille Calmette-Guerin. Recombinant human interleukin-12 (rhIL-12) is a heterodimeric cytokine that induces T-cell and natural killer cell proliferation/activation and production of IFNgamma. It has demonstrated preclinical in vivo bladder antitumor activity and no systemic toxicity. This phase 1 study evaluated intravesical rhIL-12 administration in patients with STCC (Tis, Ta, or T1) who had failed at least one prior intravesical therapy or had at least two recurrences of low-grade tumors. Eligible patients had adequate hematologic, renal, and hepatic function and Karnofsky performance status at least 70%. Cohorts of three patients received 5, 20, 50, 100, and 200 microg rhIL-12 (treated n = 15). Each patient received intravesical rhIL-12 weekly for 6 weeks, with a 2-hour bladder dwell. No patient experienced moderate, severe, or life-threatening systemic toxicity. Treatment-related adverse events included dysuria, urinary frequency, urinary urgency, asthenia, pain, hematuria, bladder spasms, and chills. Specific AE incidences were not dose-related. Among 12 patients without visible pretreatment lesions, 7 remained disease-free and 5 experienced recurrence of STCC within the 4-week follow-up period. Three patients with pretreatment Tis or Ta/T1 lesions had persistent disease at posttreatment follow-up. No patients with persistent tumor manifested antitumor response to rhIL-12. Two-hour dwell urine samples and 24- to 30-hour postdose serum samples showed negligible induction of IFNgamma. In summary, intravesical rhIL-12 was well tolerated by patients with recurrent STCC but showed no clinically relevant evidence of antitumor or immunologic effects.