Phase I study of fulvestrant in combination with 177 Lu-DOTATATE for advanced pancreatic neuroendocrine tumors.

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TPS649 Background: Peptide receptor radionuclide therapy (PRRT), using 177 Lu-DOTATATE, improves progression-free survival (PFS) in advanced well-differentiated pancreatic NETs, but objective response rates (ORR) range from approximately 18% – 43% (Zhang, Jie et al., 2020), which necessitates further improvement. Preclinical data has shown that Estrogen Receptor Alpha or ESR1, a transcription factor involved in Homologous Recombination (HR) DNA repair, is present in pNET samples (Jeffy, Brandon D et al., 2005), that NET cells are estrogen-receptive (Schwarz, Jason L. et al., 2023) and that ESR1 inhibition with Fulvestrant radiosensitizes pNET cells and decreases transcription of HR-related genes (Schwarz, Jason L. et al., 2023). We propose a Phase I study to evaluate the safety and preliminary efficacy of Fulvestrant in combination with 177 Lu-DOTATATE for advanced metastatic pNETs. Methods: This is an investigator-initiated phase I study of Fulvestrant in combination with 177 Lu-DOTATATE for patients with well-differentiated somatostatin receptor-expressing advanced pancreatic neuroendocrine tumors. A total of 19-25 patients (pts) will be enrolled in Stage 1 (safety run-in, 6-12 pts) and Stage 2 (dose-expansion, 13 pts). If clinically significant or unresolved Grade 3 or higher toxicities are observed in ≥2 of 6 patients in Stage 1, an additional 6 patients will be enrolled and treated at reduced dose. Enrollment will continue to Stage 2 if ≤1 patient experience clinically significant or unresolved Grade 3 or higher toxicities related to combination treatment. A total sample size of 19 from Stage 1 + Stage 2 will provide 82% power to detect a difference between ORR 30% and ORR 55% at a one-sided alpha of 0.10. PRRT with 177 Lu-DOTATATE will be administered 7.4 GBq (200mCi) IV (and 3.7GBq/100mCi for reduced dose cohort) every 8 weeks for a total of 4 cycles. Fulvestrant will be administered 500mg IM on cycle 1 days 1, 15 and 29, and on days 1 and 29 of every cycle thereafter, for a total of 9 doses. The primary endpoint is to assess the safety and efficacy of Fulvestrant in combination with 177 Lu-DOTATATE for advanced pNETs based on ORR. Secondary endpoints include PFS and overall survival. Clinical trial information: NCT06663072 .

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