Clinical Study Protocol for PENTILULA: A Phase 1/2 Study Assessing [ 177 Lu]Lu-Pentixather for Relapsed or Refractory CXCR4-Positive Acute Leukemia

C-X-C chemokine receptor type 4 (CXCR4) inhibition may represent a new therapeutic strategy for patients with acute leukemia (AL), not only by increasing chemosensitivity but also by preventing relapse through disruption of residual leukemic cell interactions with the bone marrow niche. Radiolabeled CXCR4 ligands are available for PET imaging ([68Ga]Ga-pentixafor) and radiopharmaceutical therapy (RPT) ([177Lu]Lu-pentixather/[90Y]Y-pentixather). Early clinical experience with CXCR4-targeted RPT, together with the reported feasibility of CXCR4-targeted PET in acute myeloid leukemia, supports the development of theranostic approaches targeting the CXCR4/C-X-C motif chemokine ligand 12–defined leukemia-initiating cell niche. The objective of this study is to determine the maximum tolerated dose (MTD) of a single infusion of [177Lu]Lu-pentixather in patients with relapsed/refractory AL (including both acute myeloid leukemia and acute lymphoblastic leukemia). Methods: PENTILULA is an investigator-initiated, first-in-human, prospective phase 1/2 study based on a standard 3 + 3 dose-escalation design with 5 levels and 3–6 patients per level. Key inclusion criteria include patients with relapsed/refractory AL with CXCR4-positive leukemic cells. The primary endpoint is the incidence and evaluation of dose-limiting toxicities (DLTs) and determination of the MTD. DLTs will be assessed 4–6 wk after RPT and include grade 3 or higher nonhematologic toxicity, prolonged grade 4 pancytopenia with hypocellular bone marrow, and excessive renal or hepatic radiation absorbed dose. The MTD is defined as the highest level at which fewer than one third of patients experience a DLT. In a subset of patients, [68Ga]Ga-pentixafor PET/MRI will be performed to explore the predictive value of theranostic PET imaging on CXCR4 expression, dosimetry, and treatment response. Conclusion: This first-in-human clinical study is ongoing, having reached the fifth and final activity level. [177Lu]Lu-pentixather is being used to definitively establish the MTD and preliminary efficacy of this CXCR4-targeted approach in this high-risk population with limited therapeutic options.