Phase 1 trial of PARP inhibitor combined with 177Lu-DOTA-Octreotate Peptide Receptor Radionuclide Therapy (PRRT) in patients with metastatic neuroendocrine tumor - PARLuNET

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Introduction: 177Lu-DOTA-Octreotate (177Lu-DOTATATE) is an effective treatment for patients with grade 1 and 2 NET. However, strategies are required to optimize treatment efficacy and outcomes. Combining a DNA-repair modifying agent could further enhance radiation efficacy. Pre-clinical data supports that a PARP inhibitor (PARPi) combined with PRRT significantly enhances NET cell death and animal survival compared to 177Lu-DOTATATE alone. This combination strategy aims to enhance radiation efficacy from PRRT.

Aim(s): Primary objectives: To establish the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of talazoparib (PARPi) + 177Lu-DOTATATE in patients with progressive NET. Secondary objectives: Assessment of safety, RECIST 1.1, molecular imaging responses, PFS and OS. Exploratory: To assess DNA-damage and repair in circulating lymphocytes using γ-H2AX.

Materials and methods: Patients with grade 2 progressive metastatic pancreatic NET requiring PRRT for clinical progression will be recruited into this single center study at Peter MacCallum Centre Center (ENETS Center of Excellence). Patients will receive 1 cycle of 177Lu-DOTATATE alone followed by 3 cycles of 177Lu-DOTATATE combined with 5 days of talazoparib. Cycle duration is 8 weeks. A Bayesian optimal interval (BOIN) design will be used to find the MTD in this dose escalation study, considering a fixed dose of 177Lu-DOTATATE and 4 dose levels of talazoparib. Maximum sample size is 24 patients who commence cycle 2.

Conference: 18th Annual ENETS Concerence (2021)

Presenting Author: Kong G

Authors: Kong G, Hatzimihalis A, Hogg A, Bressel M, Hicks R,

Keywords: PRRT, PARP inhibitor, combination therapy, NET, pancreatic, phase 1,