flotetuzumab (MGD006) / MacroGenics - LARVOL DELTA

PEPN1812: Flotetuzumab for the Treatment of Pediatric Recurrent or Refractory Acute Myeloid Leukemia (clinicaltrials.gov) - P1 | N=16 | Active, not recruiting | Sponsor: Children's Oncology Group | Trial completion date: Sep 2024 ➔ Sep 2025

Trial completion date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Pediatrics • CD123 • IL3RA

Post-transplant Flotetuzumab for AML (clinicaltrials.gov) - P1 | N=3 | Completed | Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Recruiting ➔ Completed | N=16 ➔ 3 | Trial completion date: Dec 2027 ➔ Jun 2024 | Trial primary completion date: Dec 2025 ➔ Jun 2024

Enrollment change • Post-transplantation • Trial completion • Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Transplantation • IL3RA

Flotetuzumab for Relapsed Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS) Following Allogeneic Hematopoietic Cell Transplantation (Allo-HCT) (clinicaltrials.gov) - P2 | N=11 | Terminated | Sponsor: Washington University School of Medicine | Trial completion date: Mar 2026 ➔ Jul 2024 | Active, not recruiting ➔ Terminated; The sponsor is no longer supporting the drug

Trial completion date • Trial termination • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • Transplantation

Flotetuzumab for Relapsed Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS) Following Allogeneic Hematopoietic Cell Transplantation (Allo-HCT) (clinicaltrials.gov) - P2 | N=11 | Active, not recruiting | Sponsor: Washington University School of Medicine | Recruiting ➔ Active, not recruiting | N=25 ➔ 11 | Trial completion date: Jun 2029 ➔ Mar 2026 | Trial primary completion date: Jul 2028 ➔ Mar 2024

Enrollment change • Enrollment closed • Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • Transplantation

OUTCOMES WITH IMMUNE-BASED THERAPIES FOR TP53 MUTATED ACUTE MYELOID LEUKEMIA: A SYSTEMATIC REVIEW AND META-ANALYSIS (EHA 2024) - "Immune therapies were Magrolimab 4 (40%), Durvalumab 1 10%),Nivolumab 1 (10%), Flotetuzumab 1 (10%), Pembrolizumab 1 (10%), CLL1-CD33 CAR-T 1 (10%), and APVO436 1(10%). Non-allogeneic transplant immune-based therapies show encouraging response rates, offering a potential treatmentoption for patients with TP53 mutated AML for whom options are limited. Prospective randomized studies withreasonable long follow up are needed to establish the efficacy of immune-based therapies in this difficult to treat population."

IO biomarker • Retrospective data • Review • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CD33 • TP53

Flotetuzumab for Relapsed Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS) Following Allogeneic Hematopoietic Cell Transplantation (Allo-HCT) (clinicaltrials.gov) - P2 | N=25 | Recruiting | Sponsor: Washington University School of Medicine | Trial completion date: Dec 2027 ➔ Jun 2029 | Trial primary completion date: Jan 2026 ➔ Jul 2028

Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • Transplantation

Flotetuzumab as a salvage immunotherapy in advanced CD123-positive hematological malignancies, a phase 1 pilot study. (PubMed, Leuk Lymphoma) - "Responses only occurred in Cohort B, with a partial response in one patient with Hodgkin's lymphoma and morphological complete remission in the bone marrow in one patient with blastic plasmacytoid dendritic cell neoplasm. In conclusion, flotetuzumab had a manageable safety profile in advanced CD123-positive hematological malignancies."

IO biomarker • Journal • Metastases • P1 data • Acute Lymphocytic Leukemia • Hematological Disorders • Hematological Malignancies • Hodgkin Lymphoma • Leukemia • Lymphoma • Neutropenia • Oncology • Thrombocytopenia • CD123 • IL3RA

Flotetuzumab for the Treatment of Relapsed or Refractory Advanced CD123-Positive Hematological Malignancies (clinicaltrials.gov) - P1 | N=13 | Active, not recruiting | Sponsor: City of Hope Medical Center | Trial completion date: Nov 2023 ➔ May 2026 | Trial primary completion date: Nov 2023 ➔ May 2026

Metastases • Trial completion date • Trial primary completion date • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • B Acute Lymphoblastic Leukemia • Chronic Myeloid Leukemia • Hairy Cell Leukemia • Hematological Disorders • Hematological Malignancies • Hodgkin Lymphoma • Leukemia • Lymphoma • Myelodysplastic Syndrome • Oncology • T Acute Lymphoblastic Leukemia • IL3RA • PD-L1

Spatial Technologies Reveal the Immune Landscape of Pediatric Acute Myeloid Leukemia (ASH 2023) - P1/2 | "Moreover, we acquired an additional dataset of pre-treatment immune-related gene expression profiling obtained from the BM of 30 flotetuzumab-treated (CD3 x CD123 bispecific antibody) refractory/relapsed (R/R) adult AML patients (NCT02152956; Vadakekolathu et al., 2020) for TIDE-based immune deconvolution (Jiang et al., 2018)...Lastly, for the first time, we identified TLS-like aggregates in the BM of AML patients, which have been associated with immunotherapy response in many cancers (Schumacher & Thommen, 2022). Additional studies to further characterize the function and relevance of these lymphoid aggregates are ongoing."

Clinical • IO biomarker • Tumor mutational burden • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Pediatrics • Rhabdomyosarcoma • Sarcoma • Solid Tumor • CD123 • CD8 • IL3RA • KMT2A • TMB

Spatially Resolved Transcriptomics Unveils Unique T-Cell Dysfunctional States and Prognostic Gene Expression Signatures in TP53-Mutated Acute Myeloid Leukemia (ASH 2023) - "We have previously shown that TP53 abnormalities are associated with a pro-inflammatory and immunosuppressive tumor microenvironment (TME), including high CD274 and FoxP3 expression, with dysfunctional natural killer (NK)/CD8+ T-cell states and with response to flotetuzumab, a CD123 × CD3 bispecific T-cell engager...Conclusions Spatial gene programs of leukemia stemness, T-cell dysfunction and immune suppression are enriched in TP53-m AML. It remains to be determined whether TP53-m AML with a pre-existing but ineffective T-cell response may be amenable to T cell-targeting immunotherapies."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CD123 • CD3D • CD4 • CD8 • CDCP1 • FOXP3 • IL1B • IL3RA • PD-L1 • PRDM1 • S100A8 • S100A9 • TP53 • ZEB2

PEPN1812: Flotetuzumab for the Treatment of Pediatric Recurrent or Refractory Acute Myeloid Leukemia (clinicaltrials.gov) - P1 | N=16 | Active, not recruiting | Sponsor: Children's Oncology Group | N=47 ➔ 16 | Trial completion date: Oct 2023 ➔ Sep 2024

Enrollment change • Trial completion date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Pediatrics • CD123 • IL3RA

Modeling Flotetuzumab‑Associated Cytokine Release Syndrome (CRS) in AML Using In Vitro and In Vivo Preclinical Models (SOHO 2023) - "The in vitro killing assay shows that T-cells from the spleens of immune competent C57/Bl6 hCD123eHOM mice bind to both FLZ and hCD123 on transduced murine leukemia cells. Co- culture with T-cells + target cells + FLZ showed killing at 24 hours compared to controls. T-cell activation and proliferation were noted based on cell surface markers."

Cytokine release syndrome • IO biomarker • Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CD123 • CD8 • IL3RA

Flotetuzumab for the Treatment of Relapsed or Refractory Advanced CD123-Positive Hematological Malignancies (clinicaltrials.gov) - P1 | N=13 | Active, not recruiting | Sponsor: City of Hope Medical Center | Recruiting ➔ Active, not recruiting | N=40 ➔ 13

Enrollment change • Enrollment closed • Metastases • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • B Acute Lymphoblastic Leukemia • Chronic Myeloid Leukemia • Hairy Cell Leukemia • Hematological Disorders • Hematological Malignancies • Hodgkin Lymphoma • Leukemia • Lymphoma • Myelodysplastic Syndrome • Oncology • T Acute Lymphoblastic Leukemia • IL3RA • PD-L1

"It failed in MDS, FLAG or CLIA kinda regimens , else flotetuzumab bi specific or MDM2i trial navtemadlin/ milademetan/ siremadlin MIRROS trial failed though" (@RenoHemonc)

[VIRTUAL] Targeting p53 in MDS (SOHO 2021) - P1, P1b, P1b/2, P2, P3 | "Lastly, a 2nd generation oral agent (APR-548) will enter the clinic in 2021...These data support the planned Phase 3 open-label study of azacitidine + magrolimab versus azacitidine + venetoclax in unfit AML patients and versus induction chemotherapy in fit patients with a primary endpoint of OS in the non-intensive group (NCT04778397). Other novel HMA combinations have recently had high ORR/CR rates as frontline therapy, which include sabatolimab and pevonedistat, although unclear molecular subset data in TP53 mutant patients...Specifically, PDL1 has been shown to be upregulated on TP53 mutant hematopoietic stem cells and bone marrow blasts.17,18 Importantly, TP53 mutant AML patients have been strongly associated with an adverse immune microenvironment and potentially may be an optimal molecular subset for novel immunomodulatory agents.19 In this regard the bispecific agent flotetuzumab targeting CD123 has had activity in TP53 mutant relpased..."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Myelodysplastic Syndrome • Oncology • CD123 • TP53

Interim results from a phase 1 first-in-human study of flotetuzumab, a CD123 x CD3 bispecific DART molecule, in AML/MDS (ESMO 2017) - P1; "...Flotetuzumab (MGD006/S80880), a novel CD123 x CD3 bispecific DART protein, is designed to target CD123+ cells for elimination by T cells...A LID strategy and early use of tocilizumab ameliorated this toxicity and limits corticosteroid use...To date flotetuzumab has an acceptable safety profile and demonstrated early evidence of anti-leukemic activity."

Clinical • P1 data • Acute Myelogenous Leukemia • Myelodysplastic Syndrome

A Phase 1, First-in-Human, Dose-Escalation Study of MGD024, a CD123 x CD3 Bispecific Dart® Molecule, in Patients with Relapsed or Refractory CD123-Positive (+) Hematologic Malignancies (ASH 2022) - P1 | "Of note, the CD123-directed therapy tagraxofusp has now become the standard of care (SoC) for blastic plasmacytoid dendritic cell neoplasm (BPDCN) (Pemmaraju NEJM 2019)...This new construct permits intermittent intravenous (IV) dosing due to a longer half-life (Alderson ASH 2021) compared with the first-generation DART molecule flotetuzumab, a continuous-infusion molecule that showed preliminary single-agent activity in refractory acute myeloid leukemia (AML) (Uy Blood 2021)...Secondary objectives include pharmacokinetics, immunogenicity, preliminary assessment of MGD024 clinical activity, and preliminary evaluation of safety/efficacy of tocilizumab in the management of MGD024-induced CRS...Response evaluation is determined using modified European LeukemiaNet (ELN) 2017 criteria for ALM and ALL; International Working Group (IWG) 2006 criteria for MDS; Lugano 2014 criteria for cHL; ELN 2020 criteria for CML; 2017 consensus criteria for HCL; IWG-Myeloproliferative..."

Clinical • P1 data • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Chronic Myeloid Leukemia • Hairy Cell Leukemia • Hematological Malignancies • Hodgkin Lymphoma • Inflammation • Lymphoma • Myelodysplastic Syndrome • Myeloproliferative Neoplasm • CD123

[VIRTUAL] Immune Senescence and Exhaustion Correlate with Response to Flotetuzumab, an Investigational CD123×CD3 Bispecific Dart® Molecule, in Acute Myeloid Leukemia (ASH 2020) - P1/2 | "In conclusion, features of IES were associated with response to FLZ. T-cell functional rejuvenation by FLZ could benefit patients with R/R AML by counteracting pre-existing immune dysfunction."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Immune Modulation • Inflammation • Leukemia • Oncology • CD123 • CD38 • CD8 • GBP1 • HAVCR2 • ICOS • IFIH1 • IFNG • LAG3 • NKG2D • PD-L1 • PTPRC

Lead-in Dose Optimization to Mitigate Cytokine Release Syndrome in AML and MDS Patients Treated with Flotetuzumab, a CD123 x CD3 Dart® Molecule for T-Cell Redirected Therapy (ASH 2017) - P1; "...Flotetuzumab (MGD006/S80880) is a novel CD123 x CD3 bispecific DART® protein being tested in a Phase 1 study of patients with relapsed/refractory acute myeloid leukemia (AML) and myelodysplastic syndrome...Two lead-in dose (LID) strategies, in conjunction with early intervention with tocilizumab, were assessed for their ability to mitigate CRS...CRS is commonly observed with T-cell-directing therapies. Two-step LID showed effectiveness in limiting IRR/CRS events and circulating cytokines over a single-step LID. Ability to predict which patients may develop CRS would be helpful when administering T-cell-activating therapies."

Clinical • Acute Myelogenous Leukemia • Biosimilar • Myelodysplastic Syndrome • Ophthalmology

Preliminary Results of a Phase 1 Study of Flotetuzumab, a CD123 x CD3 Bispecific Dart® Protein, in Patients with Relapsed/Refractory Acute Myeloid Leukemia and Myelodysplastic Syndrome (ASH 2017) - P1; "...Flotetuzumab (MGD006/S80880) is a novel T-cell redirecting (CD123 x CD3) bispecific DART® protein being tested in a phase 1 study in patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS)...Flotetuzumab in R/R AML and MDS demonstrated evidence of anti-leukemic activity (ORR 43%) with a manageable safety profile. This program advances an immune-activating agent in treating AML and continues to enroll patients in cohort expansion (24 AML and 24 MDS patients at the MTDS) in the US and Europe. clinicaltrials.gov NCT02152956."

Bispecific • Clinical • P1 data • Acute Myelogenous Leukemia • Biosimilar • Myelodysplastic Syndrome

Preliminary Translational Results from an Ongoing Phase 1 Study of Flotetuzumab, a CD123 x CD3 Dart®, in AML/MDS: Rationale for Combining Flotetuzumab and Anti-PD-1/PD-L1 Immunotherapies (ASH 2017) - P1; "...Translational studies were performed in an ongoing phase 1 study in patients with AML and MDS treated with flotetuzumab (MGD006/S80880), a novel CD123 x CD3 bispecific DART® protein, to assess the potential role of combining PD-1/PD-L1 inhibitors with flotetuzumab...Flotetuzumab has shown evidence of activity against CD123+ AML blasts in vivo, associated with an increase in T-cell infiltration and activation in the bone marrow, with enhanced IFNɣ secretion, which in turn may lead to upregulation of PD-1 on T cells and PD-L1 expression by the AML blasts. Synergistic cytotoxicity was observed after treatment of AML cell lines with both flotetuzumab and CPI in vitro. Furthermore, AML cells in patients that progressed on flotetuzumab or with residual disease tend to be PD-L1 positive."

Checkpoint inhibition • P1 data • Acute Myelogenous Leukemia • Biosimilar • Hematological Malignancies • Hodgkin Lymphoma • Leukemia • Lymphoma • Myelodysplastic Syndrome • Oncology • Ophthalmology

Safety and Activity of Flotetuzumab in Pediatric and Young Adult Patients with Relapsed/Refractory Acute Myeloid Leukemia: Results from the COG PEPN1812 Phase 1 Trial (ASH 2022) - P1 | "We report the safety, RP2D, and preliminary activity of the CD123xCD3 bispecific antibody flotetuzumab in children with r/r AML. Despite the frequent occurrence of mild CRS and CLS, flotetuzumab was determined to be safe and tolerable at the RP2D of 500 ng/kg/day (DL1) with an overall response rate (CR + PR) of 20% in children and AYAs with r/r AML. This study supports the potential of CD123-targeting immunotherapies in pediatric patients with AML and provides rationale for future phase 2/3 investigation."

Clinical • IO biomarker • P1 data • Acute Myelogenous Leukemia • Anesthesia • Bone Marrow Transplantation • Hematological Malignancies • Inflammation • Pediatrics • Transplantation • CD123

Management of AML in the elderly (PubMed, Bull Cancer) - "In recent years, many molecules have shown very interesting efficacy, often targeted therapies whose indication is based on a specific mutation profile (gilteritinib, ivosidenib), or mutation-independent (venetoclax), but also drugs whose indication is based on a specific biomarker (tamibarotene) or on new generation immunotherapies targeting macrophages (magrolimab) or other immune effectors while targeting leukemic cells resulting in forced immunological synapse (flotetuzumab) or activation of lymphocyte effectors associated with inhibition of the AML cells' stem signature in their microenvironment (cusatuzumab sabatolimab). All of these new strategies are discussed in this review, as well as the challenges of this frail population, which has benefited in recent months from all the major advances in the field, questioning in a second phase the modification of practices in younger patients."

IO biomarker • Journal • Review • Acute Myelogenous Leukemia • Hematological Malignancies • Immunology • Leukemia • Oncology

CD123 a Therapeutic Target for Acute Myeloid Leukemia and Blastic Plasmocytoid Dendritic Neoplasm. (PubMed, Int J Mol Sci) - "Some of these agents have shown promising results at the clinical level, including tagraxofusp (CD123 conjugated with diphtheria toxin) for the treatment of BPDCN and IMGN632 (anti-CD123 drug-conjugate), and flotetuzumab (bispecific anti-CD123 and anti-CD3 monoclonal antibody) for the treatment of AML. However, the therapeutic efficacy of CD123-targeting treatments is still unsatisfactory and must be improved through new therapeutic strategies and combined treatments with other antileukemic drugs."

Journal • Review • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Infectious Disease • Leukemia • Oncology • Pediatrics • CD123

Flotetuzumab and other T-Cell Immunotherapies Upregulate MHC Class II Expression on Acute Myeloid Leukemia Cells. (PubMed, Blood) - "Finally, we report that FLZ-induced MHC-II upregulation is mediated by IFN-γ. In conclusion, we provide evidence that T-cell immunotherapies targeting relapsed AML can kill AML via both MHC-independent mechanisms and by an MHC-dependent mechanism through local release of IFN-γ and subsequent upregulation of MHC-II expression."

IO biomarker • Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Transplantation • CD123 • CD33 • IFNG