Phase I study of flotetuzumab in AML and MDS patients – Oral abstract presented at ESMO 2017 by Vey et al.

Norbert Vey from the Institut Paoli-Calmettes, Marseille, France and colleagues presented interim data at the European Society for Medical Oncology (ESMO) 2017 congress (10^th September 2017 in Madrid, Spain),  from a phase I First-in-Human study of flotetuzumab (MGD006), a CD123 x CD3 bispecific Dual-Affinity Re-Targeting (DART®) molecule, in patients with Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS).¹

CD123, the Interleukin 3 α-chain receptor (IL3Rα), is differentially and significantly overexpressed in a majority (93%) of patients with AML and MDS. Binding of Interleukin 3 (IL-3) to CD123 can induce hematopoietic progenitor cell differentiation, proliferation and also up-regulation of anti-apoptotic proteins. Additionally, CD123 has been identified as a marker for Leukemic Stem Cells (LSCs)², which are a small population of stem cells that have properties of differentiation, self-renewal and homeostatic control, and which contribute to the maintenance and propagation of AML. In AML, a LSC reservoir can lead to disease resistance, relapse and often death in patients.³

Flotetuzumab is a humanized DART® molecule that is generated from antibodies to CD3 and CD123. Flotetuzumab acts to redirect T cells via CD3 to target blasts cells expressing CD123. This interaction can mediate, target-effector cell association, T- cell activation, proliferation and receptor diversification.² The proposed mechanism of action of flotetuzumab is shown in Figure 1.

Figure 1: Mechanism of action of flotetuzumab (reproduced with permission ^© 2017 MacroGenics, City)

In this phase 1 dose-escalation study (NCT02152956), the safety and the preliminary clinical activity of flotetuzumab was assessed in 47 patients (median age = 64 years) with Relapsed or Refractory (R/R) AML (n = 42) or intermediate-2/high-risk MDS (n = 5). The objectives of the study were to define the Maximal Tolerated Dose-Schedule and to optimize the management of Cytokine Release Syndrome using lead-in doses and anti-cytokine antibodies in order to minimize the use of corticosteroids

The key highlights of the study were:

• Design
  • Three-part study design consisting of single patient dose escalation, multi-patient dose escalation and expansion cohort
    • In the single patient dose escalation cohort, patients received doses of flotetuzumab ranging from 3–100 ng/kg/day
    • Defined base dose was 100 ng/kg/day
  • In the multi-patient dose escalation, all patients received a Lead-in-Dose (LID) of
    30 ng/kg/day for three days followed by 100 ng/kg/day for 4 days
    • In cycle 1, patients received flotetuzumab ranging from 300 ng/kg/day–1000 ng/kg/day on either a 4-day on/ 3-day off or 21 days continuous infusion
    • In cycle 2 and beyond, patients received flotetuzumab on a 4-day on/3-day off regimen
    • Data cut-off was on 1^st August 2017
  • Enrollment in the expansion cohort is ongoing
• Safety
  • Maximum Tolerated Dose/Schedule (MTDS); 500 ng/kg/day 7-day continuous infusion
  • Most common Treatment-Related Adverse Events (TAEs) were Infusion-Related Reaction (IRR)/ Cytokine Release Syndrome (CRS [36/47, ≥ grade 3, 12%]), Pyrexia (11/47), Chills (7/47) and hypotension (5/47)
  • Dose Limiting Toxicity (DLT) occurred at 700 ng/kg/day due to grade 3 IRR/CRS and myalgia
• Anti-leukemic activity in patients (n = 14) treated at ≥ 500 ng/kg/day
  • Anti-leukemic activity; 57% (8/14)
  • Objective Response Rate (ORR); 43% (6/14)
    • Complete Response (CR) rate; 28% (4/14)
    • One patient with Isocitrate Dehydrogenase 1 (IDH1) mutation achieved complete molecular response

The lead author, Norbert Vey, concluded by stating that flotetuzumab demonstrated “an acceptable safety profile” with an MTDS at 500 ng/kg/day 7-day continuous infusion. Infusion reactions were manageable with two lead-in doses and early use of tocilizumab. Additionally, flotetuzumab demonstrated an “encouraging initial anti-leukemic activity at ≥ 500 ng/kg/day”.

Flotetuzumab was granted Orphan Drug Designation by the US Food and Drug Administration (FDA) in January 2017.

Acknowledgement: This article was developed from slides kindly provided by Professor Norbert Vey (member of the AGP European Steering Committee). Figure 1 is reproduced with the kind permission of MacroGenics.