The Journal of clinical endocrinology and metabolism · 2025
A Phase I/II Trial of Sapanisertib in Advanced Anaplastic and Radioiodine Refractory Differentiated Thyroid Carcinoma.
Клиническое исследование I фазыКлиническое исследование II фазыКонтролируемое клиническое исследованиеСтатьяМногоцентровое исследованиеНазвание и аннотация: Перевод в очереди
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Sehgal Kartik, Serritella Anthony, Liu Mofei, ONeill Anne, Nangia Chaitali, Pappa Theodora, Demeure Michael J, Worden Francis P, Haddad Robert I, Lorch Jochen
Аннотация
BACKGROUND: There are limited therapeutic options for patients with recurrent/metastatic anaplastic thyroid carcinoma (ATC) and radioiodine refractory (RAIR) differentiated thyroid carcinoma (DTC) refractory to multikinase inhibitors. This multicenter trial evaluated sapanisertib, a next-generation oral kinase inhibitor of mTOR complexes 1/2, in ATC and RAIR DTC.
METHODS: A safety run-in phase I was followed by nonrandomized phase II trial in ATC, with an exploratory cohort in RAIR DTC. The primary endpoint was the proportion of patients with ATC who were without disease progression at 4 months. Safety and survival outcomes were key secondary endpoints.
RESULTS: Forty-six patients (20 ATC, 26 DTC) were enrolled including 40 (18 ATC, 22 DTC) who received recommended phase II dose of 5 mg daily. Eleven percent [2/18, 95% confidence interval (CI): 1.4-34.7%] of patients with ATC were progression-free at 4 months; 22.2% (4/18) had stable disease as best response. Enrollment in the ATC cohort stopped early with 18 patients out of the proposed 23 due to overall futility. One confirmed partial response (4.5%, 1/22) occurred in RAIR DTC, with stable disease in 63.6% (14/22) patients. Median progression-free survival was 1.6 (95% CI: 0.9-2.8) months and 7.8 (2.0-not reached) months in ATC and DTC, respectively. Grade 3 treatment-related adverse events occurred in 30% of patients who received the phase II dose, with the most common being anorexia, nausea, diarrhea, fatigue, skin rash, and hyperglycemia. Genomic alterations in the PI3K/AKT/mTOR pathway were not associated with response or progression-free survival.
CONCLUSION: Sapanisertib monotherapy did not meet the primary endpoint of this trial (proportion progression-free at 4 months) in ATC and did not show clinically meaningful activity. Clinical trials with alternative therapeutic strategies are needed.
METHODS: A safety run-in phase I was followed by nonrandomized phase II trial in ATC, with an exploratory cohort in RAIR DTC. The primary endpoint was the proportion of patients with ATC who were without disease progression at 4 months. Safety and survival outcomes were key secondary endpoints.
RESULTS: Forty-six patients (20 ATC, 26 DTC) were enrolled including 40 (18 ATC, 22 DTC) who received recommended phase II dose of 5 mg daily. Eleven percent [2/18, 95% confidence interval (CI): 1.4-34.7%] of patients with ATC were progression-free at 4 months; 22.2% (4/18) had stable disease as best response. Enrollment in the ATC cohort stopped early with 18 patients out of the proposed 23 due to overall futility. One confirmed partial response (4.5%, 1/22) occurred in RAIR DTC, with stable disease in 63.6% (14/22) patients. Median progression-free survival was 1.6 (95% CI: 0.9-2.8) months and 7.8 (2.0-not reached) months in ATC and DTC, respectively. Grade 3 treatment-related adverse events occurred in 30% of patients who received the phase II dose, with the most common being anorexia, nausea, diarrhea, fatigue, skin rash, and hyperglycemia. Genomic alterations in the PI3K/AKT/mTOR pathway were not associated with response or progression-free survival.
CONCLUSION: Sapanisertib monotherapy did not meet the primary endpoint of this trial (proportion progression-free at 4 months) in ATC and did not show clinically meaningful activity. Clinical trials with alternative therapeutic strategies are needed.