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Phase 1B Study of Subcutaneously Administered Interleukin 2 in Combination with 13-cis Retinoic Acid as Maintenance Therapy in Advanced Cancer¹

Unità Operativa di Oncologia, Ospedale Civile di Avezzano, 67051 Avezzano [F. R., S. D. F., G. S., A. C.]; Fondazione "Carlo Ferri," 00015 Monterotondo [F. R., M. R., S. R.]; Chiron Italia, 43301 Milano [L. F.]; and Oncologia Chirurgica, Università Degli Studi di L’Aquila, 67100 L’Aquila [S. R.], Italy

At present, no therapeutic strategy is available to maintain responses achieved in patients treated with chemotherapy. This Phase IB study was aimed at identifying the optimal biological dose of chronic maintenance therapy using s.c. interleukin (IL) 2 and oral 13-cis retinoic acid (RA) in patients with either tumor stabilization or response to chemotherapy. IL-2 has no cross-resistance with chemotherapy and improves cancer-related lymphocytopenia, a factor that determines poor prognosis, whereas RA has immunomodulatory properties, potentially synergistic with IL-2. Eighteen patients with advanced solid tumor who achieved a response or stable disease as a result of standard chemotherapy, received RA (0.5 mg/kg) and IL-2 5 days/week for two cycles of 3 weeks/month for up to 1 year. Three doses of IL-2 were used: 9.0, 4.5, and 1.8 x 10⁶ IU/day. Monitoring consisted in a weekly blood differential count and a bimonthly assessment of tumor markers, CD4+, CD8+, and natural killer cells. Patients were evaluated for toxicity, response maintenance, time to progression, and survival.

Patients chronically treated with 9 and 4.5 x 10⁶ IU of IL-2 developed dose-limiting toxicity grade III or IV, consisting of fever, fatigue, thrombocytopenia, mucositis, and local cutaneous reaction. No grade III or IV toxicity was observed with the 1.8 x 10⁶ IU dose, considered as the optimal biological dose. Fifty courses of IL-2 were administered (median, 3 per patient). An increase in total lymphocyte number, CD4:CD8 ratio and natural killer cell count was observed at all of the three dose levels with respect to baseline values. Two patients with a partial response to chemotherapy achieved a complete response after 6 and 7 months, respectively, of IL-2 + RA maintenance therapy. Median time to progression and overall survival were, respectively, 8.1 and 13.7 months (range, 2–48.8+ months). Low-dose IL-2 + RA as maintenance therapy after chemotherapy is, therefore, feasible and well tolerated and improves immunological parameters known to have a prognostic value in cancer.

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