Phase I study of the safety and efficacy of atiprimod, a novel azaspirine, for patients with advanced cancer

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13050 Background: Atiprimod (N-N-diethl-8,8-dipropyl-2-azaspiro [4.5] decane-2-propanamine) is an oral cationic azaspirane that suppresses angiogenesis by inhibiting both bFGF and VEGF induced proliferation and migration. Atiprimod has been shown to down-regulate multiple growth factors involved in tumor progressions and metastases, including IL-6, TNF-α, and VEGF. Methods: This is an ongoing, single-center, open-label, ascending dose (modified Fibonacci) Phase I trial of oral atiprimod in patients with advanced cancers (3+3 design). Atiprimod was given orally for 14 days every 28-day cycle. The primary objectives are to identify the MTD and to evaluate the safety of atiprimod; the secondary objectives include measuring PK and describing efficacy. Data from these patients enrolled are presented here. Results: Fourteen patients have been treated to date with 60 mg tablets (N = 3), 60 mg capsules (N = 3), 90 mg capsules (N = 3) and 120 mg capsules (N = 5). The most common side effects, which occurred in over half the patients, were related to the gastrointestinal system, and include nausea (11), diarrhea (7), vomiting (4) abdominal pain (2) and dyspepsia (2). These events were generally low-grade, occurred primarily during days of active drug administration and tended to resolve during off-drug days. Less common adverse events were sinus headaches, and elevated serum transaminases, alkaline phosphatase and creatinine. One patient who received prolonged therapy (7 months) developed fever and multi-organ failure of unclear etiology. One patient with uterine leiomyosarcoma experienced a DLT (syncope and hypotension) at 120 mg/day, and that dose level is therefore being expanded up to 6 patients. One patient with midgut carcinoid tumor and liver metastasis achieved a partial remission lasting 2+ months (50% decrease in maximum diameter by RECIST). Three patients (carcinoid = 2 and thymoma = 1) had stable disease for four, four and six months, respectively. Conclusions: Preliminary data indicate that atiprimod was reasonably tolerated, with predominantly gastrointestinal side effects. There is early evidence of anti-tumor activity in carcinoid tumors. Dose escalation continues. [Table: see text]