A phase II multicenter study of L-alanosine, a potent inhibitor of adenine biosynthesis, in patients with MTAP-deficient cancer.

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Kindler HL, Burris HA 3rd, Sandler AB, Oliff IA

A phase II multicenter study of L-alanosine, a potent inhibitor of adenine biosynthesis, in patients with MTAP-deficient cancer.

Invest New Drugs. 2009 Feb;27(1):75-81. doi: 10.1007/s10637-008-9160-1. Epub 2008 Jul 11.

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18618081 [ View in PubMed
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Abstract

OBJECTIVE: Methylthioadenosine phosphorylase (MTAP)-deficient tumors are dependent on the de novo purine synthesis pathway. These cancers are potential targets for selective chemotherapy with inhibitors of de novo adenine synthesis such as L-alanosine [L-2-amino-3-(N-hydroxy-N-nitrosamino) propionic acid]. This phase II study was designed to evaluate the efficacy and safety of L-alanosine in patients with MTAP-deficient solid tumors. METHODS: Patients with mesothelioma, non-small cell lung cancer (NSCLC), soft tissue sarcoma, osteosarcoma, or pancreatic cancer whose tumors were MTAP deficient by immunohistochemistry were eligible. Patients received L-alanosine at a starting dose of 80 mg/m(2) by continuous intravenous infusion daily for 5 days every 21 days. Computed tomography scans or magnetic resonance imaging were performed every 3 cycles. RESULTS: 65 patients (16 mesothelioma, 13 NSCLC, 15 soft tissue sarcoma, 7 osteosarcoma, 14 pancreatic cancer) were enrolled at 19 centers; 55 were evaluable for response. There were no objective responses; 24% had s disease, including 2 patients with mesothelioma who had prolonged stable disease lasting 7.5 and 15.2 months, respectively. Grade 3/4 toxicities included mucositis 11%, fatigue 6%, nausea 3%, and renal failure 1.5%. CONCLUSION: At this dose and schedule, L-alanosine was ineffective in patients with advanced MTAP-deficient tumors.

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