Extending PRRT: Targeted Alpha-Emitter Radionuclide Therapy of NETs

Conference Correspondent  - Healing NET Summit 2018

Currently, clinical studies with peptide receptor radionuclide therapy (PRRT) have tested the following isotopes: 111Indium, 90Yttrium, , 177Lutetium, 213Bismuth, 225Actinium. These isotopes exert their therapeutic properties by emitting either alpha or beta particles to destroy tumors. Alpha particles have the advantage of a shorter range in tissue than beta particles, allowing a more focused application of radiation to tumor tissue without collateral damage to normal tissue. Alpha-emitting radionuclides for targeted alpha-particle therapy (TAT) include 225Ac, 211At, and 212Pb. In terms of toxicity, 225Ac distributes to the liver where it decays to 221Fr, which redistributes to the small intestine or decays to 217At and rapidly to 213Bi, which distributes to the kidney or decays en route through the emission of 1 net alpha particle. This can cause transient liver function abnormality. 211At distributes to the thyroid gland, with no reported toxicity, and 212Pb distributes to the small intestine, potentially causing abdominal pain.

The first-in-human experience with 213Bi-DOTATOC TAT was conducted in 7 patients with progressive advanced neuroendocrine liver metastases refractory to treatment with 90Y/177Lu-DOTATOC, who were treated with an intra-arterial infusion of 213Bi-DOTATOC, and 1 patient with bone marrow carcinosis who was treated with a systemic infusion of 213Bi-DOTATOC.1 Hematologic, kidney, and endocrine toxicities were assessed according to Common Terminology Criteria for Adverse Events. Radiologic response was assessed with contrast-enhanced MRI and 68Ga-DOTATOC-PET/CT. More than 2 years of follow-up were available in 7 patients. The biodistribution of 213Bi-DOTATOC was evaluable with 440-keV gamma emission scans, and demonstrated specific tumor binding. Enduring responses were observed in all treated patients. Chronic kidney toxicity was moderate, and acute hematotoxicity was even less pronounced than with the preceding beta therapies. This study showed that TAT can induce remission of tumors refractory to beta radiation with favorable acute and mid-term toxicity at therapeutic effective doses. The results of this study have prompted a number of additional clinical studies with 225Ac-DOTATOC TAT in neuroendocrine tumors (NETs), the results of which are pending.2

A new study examining the dose tolerance of 212Pb-AR-RMX is starting in patients with NETs. Led by Dr. Ebrahim Delpassand of Excel Diagnostics, this study is the first approved protocol to examine TAT in NET patients. 212Pb-AR-RMX is a somatostatin analogue that is modified to carry the alpha emitter. The study is currently enrolling as a Phase 1 trial to determine dosing. This study is a collaboration between Excel Diagnostics, MadioMedix, and AREVA Med.

References

  1. Kratochwil C, et al. Eur J Nucl Med Mol Imaging. 2014;41:2106-2119.
  2. Makvandi M, et al. Targ Oncol. 2018. https://doi.org/10.1007/s11523-018-0550-9.
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Last modified: April 6, 2018