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


CONCLUSIONS
At this dose and schedule, L-alanosine was ineffective in patients with advanced MTAP-deficient tumors.
Kindler
Hedy Lee
HL
University of Chicago, 5841 South Maryland Avenue, MC2115, Chicago, IL, 60637-1460, USA. hkindler@medicine.bsd.uchicago.edu
Burris
Howard A
HA
Sandler
Alan B
AB
Oliff
Ira Anton
IA
D000225:Adenine / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000368:Aged; D000409:Alanine / Q000009:adverse effects / Q000031:analogs & derivatives / Q000627:therapeutic use; D000964:Antimetabolites, Antineoplastic / Q000378:metabolism / Q000627:therapeutic use; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology*; D011683:Purine-Nucleoside Phosphorylase / Q000172:deficiency* / Q000378:metabolism
D000964:Antimetabolites, Antineoplastic; C000082:alanosine; D011683:Purine-Nucleoside Phosphorylase; C021784:5'-methylthioadenosine phosphorylase; D000225:Adenine; D000409:Alanine