CD38-SADA Pretargeted Radioimmunotherapy (PRIT) with Lutetium 177 (Lu177)-DOTA in Adult Patients with Relapsed or Refractory Non-Hodgkin Lymphoma: A First-in-Human Phase 1 Trial

Introduction

Despite significant progress in the treatment of relapsed or refractory non-Hodgkin lymphoma (NHL), there remains an unmet medical need for targeted therapies. Numerous studies have established the radiosensitivity of NHL and the rationale for therapeutic intervention targeting CD38, a glycoprotein expressed on some hematopoietic cells and hematological malignancies, including NHL of both B-cell and T-cell lineage (Salles et al. Clin Lymphoma Myeloma Leuk. 2019;19:275-84; Mantei and Wood. Cytometry B Clin Cytom. 2009;76:315-20; Espinet et al. Clin Cancer Res. 2014;20:1007-19; Zaja et al. Am J Hematol. 2017;92:E1-E2; Wang et al. Cytometry B Clin Cytom. 2020;98:28-35). Adoption of conventional 1-step radioimmunotherapy for NHL has nevertheless been limited. CD38-SADA PRIT employs a 2-step approach with CD38-SADA, a self-assembling and disassembling bispecific fusion protein with high-binding affinity for the CD38 antigen and select radionuclides chelated to tetraxetan (“DOTA”). CD38-SADA is linked to a p53-derived tetramerization domain that drives the self-assembly of CD38-SADA tetramers, which in a concentration- and time-dependent manner disassemble to form low-molecular-weight monomers. In the initial step of CD38-SADA PRIT, nonradiolabeled CD38-SADA tetramers are infused and localized to CD38-expressing cells, while disassembled monomers are excreted through the kidneys. During the second “payload delivery” step, the radionuclide-chelated DOTA complex is infused and binds to the pretargeted CD38-SADA on CD38+ tumor cells and causes radiation-induced cytotoxicity. In preclinical models, CD38-SADA PRIT with Lu177-DOTA has demonstrated robust anti-tumor efficacy.

Methods

Trial 1201 (NCT05994157) is a phase 1, first-in-human, dose-escalation, open-label, multicenter trial investigating the safety and tolerability of CD38-SADA PRIT with Lu177-DOTA in adults with relapsed or refractory NHL. Part A includes dose escalation of the CD38-SADA bispecific fusion protein to define the optimal safe dose of the CD38-SADA protein, the administration interval between CD38-SADA and Lu177-DOTA, and the Lu177-DOTA dose for tumor imaging. In Part B, dose escalation of Lu177-DOTA will establish the optimal therapeutic dose of the radioactive payload. For each part, the escalation is based on a 3+3 trial design of 4 planned dose levels. Trial 1201 will include adult patients with relapsed, progressive, or refractory NHL (B-cell, T-cell, and natural killer cell lymphomas) after at least 2 prior lines of therapy and with CD38+ tumors. Patients with central nervous system involvement or >40% bone marrow involvement are ineligible. Primary endpoints include tumor imaging during Part A and occurrence of dose-limiting toxicities during both Parts A and B. Safety endpoints include number and severity of adverse events and will be summarized by trial part and cohort. Efficacy endpoints include best overall response, duration of response, and survival. Response will be assessed in accordance with the Lugano 2014 criteria (Cheson et al. J Clin Oncol. 2014;32:3059-68). Additional objectives include dosimetry, pharmacokinetics, and immunogenicity of CD38-SADA data. The study is actively enrolling at sites in the United States.