Meemansa Sood, Larissa Lachi Silva, Fariba Khanshan, Peter McCormack, Lars Blumenstein, Yu-Yun Ho
Novartis Pharma AG, Basel, Switzerland
Introduction: [177Lu]Lu-DOTA-TATE (Lutathera®) is an approved drug used for the treatment of somatostatin receptor-positive (SSTR-positive) advanced gastroenteropancreatic neuroendocrine tumors (GEP-NETs) in adults. There is an unmet need of treatment options in adolescent patients (12 to <18 yr) with advanced GEP-NETs and Pheochromocytomas and Paragangliomas (PPGL). In order to address this unmet need and accelerate the access of [177Lu]Lu-DOTA-TATE as a potential treatment for adolescent patients, Novartis proposed extrapolation of the clinical efficacy already established in adults to the adolescent population. This extrapolation was made by comparing either the plasma exposure of [177Lu]Lu-DOTA-TATE or the cumulative radioactive dose already established in adults and exploring this dose/regimen with respect to kidney and bone marrow (BM) dosimetry thresholds. The hypothesis behind this full efficacy extrapolation is that adolescents can be treated with the same dose as adults with advanced GEP-NET, (7.4 GBq for 4 cycles every 8 weeks) without significant risk of exceeding pre-defined external beam radiation therapy (EBRT) thresholds of 29 Gy for kidney and 2 Gy for bone marrow dosimetry.
Objectives: The objectives included dose determination and justification of full adult dose of 7.4 GBq over 4 cycles of [177Lu]Lu-DOTA-TATE in the adolescent population (12 to <18 yr) with GEP-NET or PPGL. Full efficacy extrapolation approach with safety as the primary factor using modeling and simulation aims to confirm comparable exposure, and exposure-dosimetry relationship for kidney and BM and applicability of flat dosing between adults and adolescents. The ongoing phase 2 NETTER-P study (NCT04711135) will evaluate the exposure, safety and dosimetry of [177Lu]Lu-DOTA-TATE in adolescent patients with (SSTR+) GEP-NET and PPGL.
Methods: Modeling and simulation were used to explore adolescent-specific factors (renal function, body weight, age) on both exposure and dosimetry and to determine the dose for adolescent population. Empirical models based on creatinine clearance and dose as predictors were used to predict kidney and BM, dosimetry for adults. Scenario simulations based on the dosimetry models were performed using Simulx to predict the median dosimetry values and the probability of the median to exceed the EBRT thresholds for kidney and BM in a simulated adolescent population. It is assumed that the dosimetry values for the full treatment (four cycles) is 4 times the dosimetry measurements at the first dose. The exposure-dosimetry model for adult data was further updated to include the adolescent data in order to compare the exposure-dosimetry relationship between the two populations.
Results: Adult model for dosimetry applied to an adolescent population without risk factors resulted in a 7.4 GBq dose administered on 4 cycles having a median kidney and BM dosimetry values ≤29 Gy and ≤2 Gy respectively. Comparable kidney and BM dosimetry and exposure-dosimetry relationship between adults and adolescents was observed, with similar probabilities of kidney and BM dosimetry remaining ≤29 Gy and ≤2 Gy EBRT thresholds, respectively. Neither exposure nor kidney and BM dosimetry were clinically relevantly impacted by patients’ age and body weight, indicating the appropriateness of flat dosing in adolescent population and similar dosing to adult population.
Conclusions: The predicted median values from simulations based on adult data for kidney and BM dosimetry models for specific values of creatinine clearance remained below the threshold values of 29 Gy for kidney and 2 Gy for BM, after 4 cycles of 7.4 GBq. Based on the comparable exposure, and exposure-dosimetry relationship between adults and adolescent and no clinically relevant impact of patients age and body weight on exposure and exposure-dosimetry, the same adult dose can be administered to the adolescent population. This modeling work thereafter justifies the dose for adolescents to be 7.4 GBq for 4 cycles every 8 weeks.
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Reference: PAGE 32 (2024) Abstr 11239 [www.page-meeting.org/?abstract=11239]
Poster: Drug/Disease Modelling - Oncology