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Phase I Trial of Concurrent Twice-Weekly Recombinant Human Interleukin-12 Plus Low-Dose IL-2 in Patients With Melanoma or Renal Cell Carcinoma

Jared A. Gollob, Korina G. Veenstra, Robert A. Parker, James W. Mier, David F. McDermott, Daniel Clancy, Linda Tutin, Henry Koon, Michael B. Atkins

From the Division of Hematology/Oncology and the Biometrics Center, Beth Israel Deaconess Medical Center, Harvard Medical School Boston, MA.

Address reprint requests to Jared A. Gollob, MD, Duke University Medical Center, DUMC Box 3441, Durham, NC 27710; email: gollo001{at}mc.duke.edu.

Purpose: To maintain interferon gamma (IFN) induction by recombinant human interleukin-12 (rhIL-12) and enhance its activity against melanoma and renal cell cancer, a regimen of twice-weekly intravenous (IV) rhIL-12 was modified to include concurrent low-dose subcutaneous (SC) IL-2 in a phase I dose escalation study.

Patients and Methods: Patients received 6-week cycles of twice-weekly IV rhIL-12 at doses of 300 to 500 ng/kg. Midway through cycle 1, low-dose SC IL-2 was added. The IL-2 was escalated from 0.5 to 6.0 MU/m². Grade 3 elevations of hepatic ALT, AST, or alkaline phosphatase were not considered dose-limiting unless values were more than 10 times normal. During cycle 1, patients underwent immune monitoring to assess the effect of IL-2 on lymphocyte activation and cytokine production induced by rhIL-12.

Results: Twenty-eight patients were enrolled onto the study. The maximum-tolerated dose (MTD) was 500 ng/kg rhIL-12 plus 3 MU/m² IL-2. Toxicities related to the addition of IL-2 at the MTD included fever or chills, anemia, fatigue, nausea or vomiting, and orthostatic hypotension. At the MTD, IL-2 significantly augmented IFN and IFN-inducible protein-10 production by rhIL-12 and led to a three-fold expansion of natural killer cells. There was one major clinical response (partial response) as well as two pathologic responses; all occurred in melanoma patients. Stable disease for three to six cycles was only observed at or above the MTD in melanoma and renal cell cancer patients.

Conclusion: The addition of concurrent low-dose IL-2 to rhIL-12 is well tolerated, restores and maintains immune activation by rhIL-12, and has clinical activity. This regimen should be further investigated in phase II studies in untreated patients with melanoma or renal cell cancer and in other rhIL-12–responsive malignancies.

Supported by National Institutes of Health (NIH) grant K23RR15541, the David A. Stulberg Career Investigator Award from the Kidney Cancer Association, NIH grant M01-RR01032, the Beth Israel Deaconess General Clinical Research Center, and by a grant from Chiron Corp.

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