Early phase clinical trials of 211At-meta-astatobenzylguanidine for children with neuroblastoma and adults with advanced neuroendocrine cancers

University Of Pennsylvania, Philadelphia PA

Investigators

Abstract

PROJECT SUMMARY An important hallmark of many neuroendocrine cancers, particularly neuroblastoma (NB) and pheochromocytoma/paraganglioma (PPGL), is expression of the norepinephrine transporter (NET). NET facilitates the uptake of catecholamines into vesicles. The guanethidine analog meta-iodobenzylguanidine (MIBG) is a substrate for NET and, when synthesized with radioactive iodine (I) isotopes 123I and 131I, has been approved by the FDA for imaging of NB and PPGL and, with 131I, for the therapy of PPGL. In relapsed/refractory NB, 131I-MIBG has the highest reported single agent response rate. While MIBG is safe and effective, toxicity is a limiting factor in adults. Additionally, complete remissions are rare in adult patients with PPGL. NB is typically treated at much higher administered activity per patient mass than adults can tolerate (the approved administered activity in adults is 296 MBq/kg whereas in children with neuroblastoma the standard administered activity is 666 MBq/kg). Children often receive 131I-MIBG in combination with other treatments and stem cell support. Complete remissions with combination therapy in NB are common, but unfortunately relapsed disease is common. A putative mechanism for relapse is the presence of micrometastatic disease, particularly in the marrow, that is very difficult to target with the b- particles emitted by 131I-MIBG; b- travel up to millimeters in tissue and have low linear energy transfer. (LET) and so deposit very little energy in microscopic sites of disease. The high mass amount of MIBG given in low specific activity formulations of 131I-MIBG result in common infusion reactions in adults. Finally, the high abundance of high energy g rays from 131I result in radiation safety and logistical challenges. The a-particle-emitting halogen 211At can be used to synthesize 211At-MABG, which has biodistribution and cancer uptake kinetics nearly identical to 131I-MIBG. Through extensive in vitro and in vivo pre-clinical studies, we have shown that 211At-MABG is safe and effective. Only standard precautions are needed with 211At, and no other significant radiation safety precautions. Additionally, the exceptionally high specific activity of 211At-MABG will prevent pharmacologic effects with the potential for improved target to background ratio. Finally, the high LET, relative biological effectiveness (RBE), and short path length of a-particles allows cytotoxicity to be maintained down to microscopic disease. Our overarching hypothesis is that 211At-MABG will improve upon 131I-MIBG in the treatment of neuroendocrine cancers with less off-target toxicity and greater potential to eradicate microscopic sites of disease. This should result in higher rates of durable disease control. Additionally, treatment will be more readily given due to a much lower external radiation exposure. Finally, 211At can be cyclotron produced and is therefore less subject to supply chain constraints facing nuclear reactor-produced isotopes like 131I. Building upon our pre-clinical experience we propose to test 211At-MABG in pediatric and adult patients.