Phase I trial of interferon α2b and liposome‐encapsulated all‐trans retinoic acid in the treatment of patients with advanced renal cell carcinoma

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Abstract
BACKGROUND: Studies suggest that retinoic acid (RA) can augment the antitumor effects of interferon‐based therapy in patients with advanced renal cell carcinoma (RC); however, this benefit has not been achieved convincingly using oral formulations of 13‐cis RA and all‐trans RA. Liposome‐encapsulated all‐trans RA (ATRA‐IV) has improved pharmacokinetics with increased and prolonged ATRA serum levels compared with oral retinoids.METHODS: Cohorts of 3–6 patients with progressive metastatic RC received a dose of 3 MU interferon α2b per day subcutaneously, which was escalated weekly to 5 MU and then to 10 MU, plus ATRA‐IV beginning at a dose of 90 mg/m2 intravenously three times per week (Monday, Wednesday, and Friday), with a planned escalation to a maximum of 140 mg/m2.RESULTS: Two of the initial five patients experienced Grade 3 leukopenia while receiving 3 MU interferon and 90 mg/m2 ATRA‐IV. Therefore, the trial was amended to begin ATRA‐IV at a dose of 15 mg/m2 three times per week with a planned escalation by 15 mg/m2 per cohort plus interferon‐α at a dose of 3 MU subcutaneously 5 days per week (Monday through Friday), which was escalated weekly to 5 MU and then to 10 MU. Twelve patients were treated on the revised schedule. Toxicity was mild and included Grade 2 anemia (n = 7 patients), leukopenia (n = 2 patients), nausea (n = 2 patients), fatigue (n = 2 patients), fever (n = 2 patients), hepatic toxicity (n = 1 patient), edema (n = 1 patient), neurocortical toxicity (n = 1 patient), headache (n = 1 patient), and infection (n = 1 patient). One patient developed hyperthyroidism, and one patient required admission for bacteremia from a line infection. Dose limiting toxicity was Grade 3 hepatic toxicity, which was observed at a dose of 30 mg/m2 ATRA‐IV in 2 of 6 patients. Only 2 of 12 patients agreed to a dose escalation up to 10 MU interferon‐α. Of 12 patients who were evaluable for response, 2 patients (17%) had a partial response in bone and lung, including 1 partial response of > 91 weeks' duration, at a dose of 15 mg/m2 ATRA‐IV three times per week and 5 MU interferon‐α. Five additional patients experienced stable disease, two of whom had disease progression in bone only.CONCLUSIONS: The acceptable toxicity profile and preliminary efficacy results suggest that this regimen warrants further evaluation. ATRA‐IV (15 mg/m2 TIW) and interferon‐α (3 MU Monday through Friday escalated weekly to 5 MU and to 7 MU) are recommended for further study in patients with advanced RC. Cancer 2002;95:1220–7. © 2002 American Cancer Society.DOI 10.1002/cncr.10809

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