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447 Interim results of a phase 1 study of the novel engineered toxin body TAK-169 in patients with relapsed or refractory multiple myeloma
  1. Shaji Kumar1,
  2. Admasu Mamuye2,
  3. Kristina Dabovic2,
  4. Jingyuan Wang2,
  5. Banmeet Anand2,
  6. Amy Yuet2,
  7. Bhagirathbhai Dholaria3 and
  8. Vivek Roy1
  1. 1Mayo Clinic, Rochester, MN, USA
  2. 2Molecular Templates, Inc., New York, NY, USA
  3. 3Vanderbilt University Medical Center, Tampa, FL, USA


Background Engineered toxin bodies (ETBs) are comprised of a proprietarily engineered and de-immunized Shiga-like Toxin-I A1 subunit genetically fused to an antibody-like binding domain. ETBs can force receptor internalization, induce potent cell-kill via enzymatic and permanent inactivation of ribosomes, and may not be subject to resistance mechanisms of other therapeutics. TAK-169 is a second-generation ETB targeting CD38 in hematologic malignancies including multiple myeloma (MM).

Methods This multicenter, open-label, phase 1 study is designed to evaluate the safety, tolerability, preliminary efficacy, pharmacokinetics, and pharmacodynamics of TAK-169 monotherapy in patients with relapsed or refractory MM (RRMM). The primary objective of the expansion phase (Part 2) is to provide a preliminary evaluation of the clinical activity of TAK-169 monotherapy in patients with RRMM. The starting dose of TAK-169 in Part 1 is 50 μg/kg IV once weekly. Subsequent planned dose levels are 100, 200, 335, 500, and 665 μg/kg (NCT04017130).

Results At the data cut-off in June 2021, 4 patients with a median age of 70 years were enrolled at the initial TAK-169 dose level of 50 µg/kg. All 4 patients were heavily pretreated with at least 5 previous lines of therapy. All patients have discontinued the study, 3 due to progressive disease and 1 due to a treatment-emergent adverse event (TEAE). The TEAE was asymptomatic grade 2 reversible myocarditis diagnosed by cardiac magnetic resonance imaging (MRI) and grade 3 hs-troponin elevation in the absence of ischemia, ECG, or echocardiographic abnormalities. Comparative baselines were not available for either the cardiac MRI or hs-troponin levels. No other cardiac TEAEs have been observed with any other patient. All other related TEAEs were either grade 1 or 2 events. All patients had quantifiable drug concentrations on Cycle 1 Day 1, with the mean elimination half-life calculated as 1 hour. The geometric mean of Cmax in the 4 patients was 1.73 nM, which is lower than the EC50 of 5 nM observed in MM cell-killing assays using patient bone marrow aspirates. Number of natural killer (NK) cells in peripheral blood for the 4 patients was reduced by a maximum of 56%, 85%, 88%, and 92% after the first dose. The patient with 56% reduction in NK cells had the lowest NK cell count at baseline, along with a low percentage of CD38+ NK cells.

Conclusions These data demonstrate that, at 50 mcg/kg, TAK-169 was engaging its target CD38, leading to robust NK-cell reductions. Dose escalation is ongoing.

Trial Registration Clinicaltrials.

gov identifier: NCT04017130

Ethics Approval Vanderbilt University Institutional Review Board (1313 21st Ave S, Suite 505. Nashville, TN 37232–4315) gave approval on 6/25/2021 (IRB #191752). Participants gave informed consent before taking part in the study.

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