Study to Assess the Safety and Effectiveness of Novel Radiopharmaceutical Terbium-161 DOTATATE in Metastatic Neuroendocrine Tumors

Targeted radionuclide therapy (TRT) is a nuclear medicine technique that uses radiopharmaceuticals (RPs) with high affinity to receptors or antigens on the surface of tumor cells to achieve a therapeutic effect. TRT causes less collateral damage than external beam radiotherapy (EBRT) because the RPs are selectively taken up by tumors and their metastases, delivering high doses of radiation to cancer cells and minimizing doses to normal tissues.NETTER-1 and 2 trials have already established PRRT (Peptide Receptor Radionuclide Therapy) with Lutetium-177 (Lu-177) DOTATATE as first line TRT in metastatic well-differentiated gastro-enteropancreatic neuroendocrine tumors(GEP-NETs).

While Lu-177 as a radioisotope is safe and indigenously produced by BARC, the recent global shortage of this isotope has led to development of Terbium-161 (Tb-161). Terbium-161 belongs to the same family of Lanthanides as Lu-177 and offers the same physical characteristics.

The superiority of Tb-161 over Lu-177 evolves from its basic property of emission of Auger electrons (AE).(4) Most important characteristics of radioisotopes in Nuclear Medicine or Radiation Oncology are linear energy transfer and range; which are determinants of cell-damage to the target cell and normal cell, respectively. Compared to beta-emissions (as in Lu-177), AEs are most lethal to cancer cells when emitted near the cell nucleus and especially when incorporated into DNA. AEs cause DNA damage both directly and indirectly via water radiolysis. AEs can also kill targeted cancer cells by damaging the cell membrane and producing more targeted and lethal effects. Moreover, the important point is that since the range of delivery of this energy is relatively shorter as compared to beta-emitters, hence there is negligible bystander and crossfire effect, thereby causing no damage to surrounding cells.

Monte-Carlo simulations: Larauze et al assessed absorbed doses from simulations performed with CELLDOSE, which is a homemade Monte Carlo track-structure code for simulating the transport of electrons in water, based on differential and total interaction cross sections describing the elastic scattering, electronic excitation, and ionization. Absorbed doses to cell nuclei and cell membranes (with an intranuclear radionuclide location, only nuclear absorbed doses were assessed) were assessed. In this tumor cluster model, when all cells were targeted, and depending on the location of the radionuclide, Tb-161 delivered a 2- to 3-fold higher nuclear absorbed doses than Lu-177 but also 2- to 6-fold higher absorbed doses to cell membranes. Interaction of ionizing radiation with the cell membrane induces sphingomyelin hydrolysis to ceramide, initiating apoptosis.

Spoormans et al performed cellular dosimetry to quantify the absorbed dose to the cell nucleus and compared dose-response curves to evaluate differences in relative biological effectiveness in vitro, between Tb-161 and Lu-177. (7) Tb-161-DOTATATE and delivered a 3.6 times higher dose to the nucleus, respectively, than their Lu-177-labeled counterparts on saturated receptor binding. This increased nucleus-absorbed dose was mainly due to the additional emission of internal conversion electrons by Tb-161.

Verberg et al did a comparative dosimetric analysis of Lu-177 DOTATATE and Tb-161 DOTATATE by calculating the radiation absorbed dose to tumor as well as non-target organs of normal biodistribution, on adult human phantom models. The substitution of Lu-177 with Tb-161 results in an increase in the delivered dose per unit of activity to tumour tissue by 40% (in a 10 g tumour: 2.9 Gy/GBq and 4.1 Gy/GBq, respectively) as well as to dose-limiting non-target tissue (kidneys: 39%(0.73 Gy/GBq and 1.01 Gy/GBq, respectively), bone marrow: 42% (0.04 Gy/GBq and 0.06 Gy/GBq, respectively)

First-In-Human Studies: After qualifying through the cell survival and dosimetry studies, Baum et al used Tb-161 DOTATATE in 2 patients, one with paraganglioma and other with metastatic neuroendocrine tumor, both of whom were refractory to Lu-177 DOTATATE therapy. Patients formally consent to receive this treatment and Tb-161 DOTATATE was administered following the standard PRRT protocol. Post therapy SPECT/CT images were acquired which showed tracer localisation at the desired tumor locations. No adverse events and no changes in vital parameters were observed or reported by the patient during, immediately after or at follow-up review of the patient after administration of Tb-161-DOTATATE. According to the Common Terminology Criteria for Adverse Events, there were no clinically significant changes in the relevant laboratory values (hematological, renal, and hepatic panel) at the subsequent follow up of the patient after administration of Tb-161-DOTATATE.

Dept of Nuclear Medicine, TMH and ACTREC has already obtained approval from Atomic Energy Regulatory Board (AERB), and has treated 2 patients of metastatic NET on compassionate basis with Tb-161 DOTATATE, who were refractory to Lu-177 DOTATATE.

The investigators therefore would like to study the safety and efficacy of Tb-161 DOTATATE in patients in metastatic NET who have shown disease progression after treatment with Lu-177 DOTATATE PRRT.