Pre-dosing with lilotomab prior to therapy with 177Lu-lilotomab satetraxetan significantly increases the ratio of tumor to red marrow absorbed dose in non-Hodgkin lymphoma patients

Abstract

Purpose177Lu-lilotomab satetraxetan is a novel anti-CD37 antibody radionuclide conjugate for the treatment of non-Hodgkin lymphoma (NHL). Four arms with different combinations of pre-dosing and pre-treatment have been investigated in a first-in-human phase 1/2a study for relapsed CD37+ indolent NHL. The aim of this work was to determine the tumor and normal tissue absorbed doses for all four arms, and investigate possible variations in the ratios of tumor to organs-at-risk absorbed doses.MethodsTwo of the phase 1 arms included cold lilotomab pre-dosing (arm 1 and 4; 40 mg fixed and 100 mg/m2 BSA dosage, respectively) and two did not (arms 2 and 3). All patients were pre-treated with different regimens of rituximab. The patients received either 10, 15, or 20 MBq 177Lu-lilotomab satetraxetan per kg body weight. Nineteen patients were included for dosimetry, and a total of 47 lesions were included. The absorbed doses were calculated from multiple SPECT/CT-images and normalized by administered activity for each patient. Two-sided Student’s t tests were used for all statistical analyses.ResultsOrgans with distinct uptake of 177Lu-lilotomab satetraxetan, in addition to tumors, were red marrow (RM), liver, spleen, and kidneys. The mean RM absorbed doses were 0.94, 1.55, 1.44, and 0.89 mGy/MBq for arms 1–4, respectively. For the patients not pre-dosed with lilotomab (arms 2 and 3 combined) the mean RM absorbed dose was 1.48 mGy/MBq, which was significantly higher than for both arm 1 (p = 0.04) and arm 4 (p = 0.02). Of the other organs, the highest uptake was found in the spleen, and there was a significantly lower spleen absorbed dose for arm-4 patients than for the patient group without lilotomab pre-dosing (1.13 vs. 3.20 mGy/MBq; p < 0.01).Mean tumor absorbed doses were 2.15, 2.31, 1.33, and 2.67 mGy/MBq for arms 1–4, respectively. After averaging the tumor absorbed dose for each patient, the patient mean tumor absorbed dose to RM absorbed dose ratios were obtained, given mean values of 1.07 for the patient group not pre-dosed with lilotomab, of 2.16 for arm 1, and of 4.62 for arm 4. The ratios were significantly higher in both arms 1 and 4 compared to the group without pre-dosing (p = 0.05 and p = 0.02). No statistically significant difference between arms 1 and 4 was found.ConclusionsRM is the primary dose-limiting organ for 177Lu-lilotomab satetraxetan treatment, and pre-dosing with lilotomab has a mitigating effect on RM absorbed dose. Increasing the amount of lilotomab from 40 mg to 100 mg/m2 was found to slightly decrease the RM absorbed dose and increase the ratio of tumor to RM absorbed dose. Still, both pre-dosing amounts resulted in significantly higher tumor to RM absorbed dose ratios. The findings encourage continued use of pre-dosing with lilotomab.Electronic supplementary materialThe online version of this article (10.1007/s00259-018-3964-9) contains supplementary material, which is available to authorized users.

FDG PET/CT parameters and correlations with tumor-absorbed doses in a phase 1 trial of 177Lu-lilotomab satetraxetan for treatment of relapsed non-Hodgkin lymphoma

“…From cell studies, the cell-killing effect of cold lilotomab appears to be limited [41], but the clinical translation is still to be determined. We have previously shown that pre-dosing with cold lilotomab results in lower absorbed doses to bone marrow and higher tumor-to-bone marrow absorbed dose ratios [42]. This demonstrates that the lilotomab pre-dosing alters biodistribution and probably renders more 177 Lulilotomab satetraxetan available for tumors.…”

Total Tumor Uptake and Absorbed Dose of 177Lu-Lilotomab Satetraxetan in a First in Human Trial for Relapsed Non-Hodgkin Lymphoma - Are We Hitting the Target?

“…Standard PK methods without molecular imaging based support assessed to theoretically calculate the amount of a pharmaceutical reaching the tumor volumes is not straight forward, mainly because of changes in biodistribution outside blood compartment as shown by Stokke et al [27]. Direct image-based measurement of the amounts accumulating in the tumor mass would be preferable for all treatments.…”

Phase 1/2a study of 177Lu-lilotomab satetraxetan in relapsed/refractory indolent non-Hodgkin lymphoma

“…A detailed description of the dosimetry methods has already been published. [23][24][25][26] Volumes taken from CT images and radioactivity in tumors and lumbar vertebrae 2 to 4 derived from SPECT were used for the calculations.…”

“…Some dosimetry and PK data have already been published for patients included in phase 1 of this study. [23][24][25][26] Figure 2 shows fused SPECT/CT images of activity at day 4 after 177 Lu-lilotomab satetraxetan administration for 5 representative patients, the correlation between absorbed dose in red marrow and tumor, and PK profiles for 177 Lu-lilotomab satetraxetan. Arms 1 and 4 showed the largest differences between tumor-and red marrow-absorbed dose.…”