vibecotamab (XmAb14045) / Xencor, UT MD Anderson Cancer Center - LARVOL DELTA

NCI-2022-02215: A Phase II Study of Vibecotamab (XmAb14045) for MRD- Positive AML and MDS After Hypomethylating Agent Failure (clinicaltrials.gov) - P2 | N=42 | Active, not recruiting | Sponsor: M.D. Anderson Cancer Center | Recruiting ➔ Active, not recruiting

Enrollment closed • Minimal residual disease • Acute Myelogenous Leukemia • Myelodysplastic Syndrome • IL3RA

INCA035784, A NOVEL, EQUIPOTENT T CELL–REDIRECTING ANTIBODY FOR PATIENTS WITH MYELOPROLIFERATIVE NEOPLASMS CARRYING DIFFERENT TYPES OF CALRETICULIN MUTATIONS (EHA 2025) - "INCA035784 does not bind to wtCALR when a stress agent such as doxorubicin induces its translocation to the cell surface...INCA035784 induced minimal levels of CRS-associated cytokines from HD PBMCs, HD T cells, and patient-derived PBMCs vs other T cell-engaging antibodies such as mosunetuzumab and vibecotamab, targeting CD20 and CD123, respectively... Overall, INCA035784 activates T cells in the presence of mutCALR complexed with TPOR on the cell surface. By binding to a unique, conserved epitope on the mutCALR N-domain, INCA035784 can target the diverse mutCALR variants found across the MPN patient population. INCA035784 also exhibits a low-risk profile with respect to cytokine induction."

Clinical • Myeloproliferative Neoplasm • Oncology • CALR • CD123 • CD34 • CD69 • IL2RA • IL3RA • MPL

Bispecific antibodies in immunotherapy for acute leukemia: latest updates from the 66th annual meeting of the American society of hematology, 2024. (PubMed, Front Oncol) - "Blinatumomab plus standard chemotherapy or in combination with other treatments, such as Mini-Hyper-CVD and Inotuzumab Ozogamicin, improved disease-free survival (DFS) in B-ALL. In AML and related conditions, novel BsAbs like AFM28 (CD123xCD16A) and Vibecotamab (CD123xCD3) showed promising efficacy in heavily pretreated R/R AML and in MDS/CMML following the failure of treatment with hypomethylating agents (HMA). The meeting underscored the transformative potential of BsAbs, especially in ALL-focused trials, with ongoing research aiming to evaluate their safety and efficacy in broader patient populations and combination regimens. This summary highlights the latest progress in BsAb-based immunotherapy presented at the ASH 2024 meeting, held from December 7-10 in San Diego, California."

IO biomarker • Journal • Review • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Chronic Myelomonocytic Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • IL3RA

CSF1R-targeting T cell engaging bispecific antibodies for Acute Myeloid Leukemia treatment (ITOC 2025) - "Background The potential of T-cell engaging bispecific antibodies (TCEs) is illustrated by the success of targeting CD19 (Blinatumomab) and CD20 (Epcoritamab, Glofitamab, Mosuenetuzumab) in relapsed and refractory B-cell non-Hodgkin lymphoma. However, in AML, TCEs targeting CD33 (JNJ-67571244, AMG330) and CD123 (Vibecotamab) have shown low efficacy and high toxicity...Consistent with our single-cell RNA sequencing-based target analysis, the CSF1R-TCE exhibited a superior safety profile than the CD33-TCE while maintaining anti-tumor activity. CSF1R-targeting TCEs may represent a novel immunotherapeutic approach for AML with high translative potential."

Acute Myelogenous Leukemia • B Cell Non-Hodgkin Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CD123 • CD33 • CD34 • CSF1R • IL3RA

CSF1R Targeting T Cell Engaging Bispecific Antibodies Enable Safe and Efficient Immunotherapies in Acute Myeloid Leukemia (ASH 2024) - "While the use of T cell engaging bispecific antibodies (TCE) targeting B cell lineage antigens such as CD19 (Blinatumomab) or CD20 (Epcoritamab, Glofitamab, Mosuenetuzumab) have induced strong and long-lasting response rates in B cell malignancies (Falchi, Vardhana et al...Early clinical trials of CD33-TCE (JNJ-67571244, AMG330) or CD123-TCE (Vibecotamab) have shown modest clinical activity (response rates ranging between 0 to 16,6%) and a high degree of treatment-emergent adverse events (TEAE) (Ravandi, Bashey et al...In summary, we could show the safety and efficacy of CSF1R-TCB in preclinical in vitro and in vivo models and demonstrate the superior safety profile of CSF1R-TCB compared to CD33-TCB in CB-humanized mouse models. In cell line-derived xenograft models of AML, CSF1R-TCB induced anti-leukemia activity, warranting further preclinical and clinical investigations."

IO biomarker • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • CCL3 • CD123 • CD20 • CD33 • CD34 • CSF1R • CSF2 • IL2 • IL3RA • IL6

Updated Results from a Phase II Study of Vibecotamab, a CD3-CD123 Bispecific T-Cell Engaging Antibody, for MDS or CMML after Hypomethylating Failure and in MRD-Positive AML (ASH 2024) - "In the MDS/CMML cohort (16 MDS, 3 CMML), 9 pts (47%) received ≥2 prior lines of therapy, 11 pts (58%) had prior venetoclax exposure, and 2 pts (11%) had prior stem cell transplant (SCT). The protocol has now been amended for vibecotamab to be given indefinitely to responders. The clinical activity of vibecotamab, including in high-risk pts and its lack of clinically significant myelosuppression provide rationale to combine it with other agents in AML, MDS, and CMML."

Minimal residual disease • P2 data • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Chronic Myelomonocytic Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • CD123 • IL3RA • TP53

Vibecotamab shows promise in high-risk leukemia and myeloid diseases (Newswise) - P2 | N=42 | NCT05285813 | "The Phase II study treated 37 patients with low-blast myeloid diseases from two groups: one with myelodysplastic syndrome (MDS) or chronic myelomonocytic leukemia (CMML), and the other with measurable residual disease (MRD)-positive acute myeloid leukemia (AML). In the MDS/CMML group, 68% of patients responded to vibecotamab. Among patients with MRD-positive AML, 28% achieved MRD negativity, with some responses ongoing for over two years. All responses were observed after the first cycle of therapy."

P2 data • Acute Myelogenous Leukemia • Chronic Myelomonocytic Leukemia • Myelodysplastic Syndrome

Phase 1 Study of Vibecotamab Identifies an Optimized Dose for Treatment of Relapsed/Refractory Acute Myeloid Leukemia (Cancer Network) - P1 | N=120 | NCT02730312 | Sponsor: Xencor, Inc. | "A phase 1 clinical trial, published in the journal Blood Advances, has found the optimal dosing schedule with a tolerable safety profile in patients with relapsed/refractory (R/R) acute myeloid leukemia (AML)....Vibecotamab showed preliminary antileukemic activity, with a total of 10 responders achieving complete remission (CR), CR with incomplete hematologic recovery (CRi), or morphologic leukemia-free state (MLFS), resulting in an overall response rate (ORR) of 9.0%. The incidence and grade of CRS were highest during the first dose and weekly step-up dosing. Peak levels of the cytokine IL-6 correlated with higher priming doses and weekly dosing step-ups."

P1 data • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

A Phase II Study of Vibecotamab, a CD3-CD123 Bispecific T-Cell Engaging Antibody, for MDS or CMML after Hypomethylating Failure and in MRD-Positive AML (ASH 2023) - "Conclusion Vibecotamab was safe and active in low-blast, high-risk myeloid diseases, with a response rate of 64% in MDS/CMML after HMA failure and 25% in MRD-positive AML. The clinical activity of vibecotamab, including in pts with prior venetoclax exposure and/or HSCT, and its lack of clinically significant myelosuppression provide rationale to combine it with other agents in AML, MDS, and CMML."

Minimal residual disease • P2 data • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Cardiovascular • Chronic Myelomonocytic Leukemia • Congestive Heart Failure • Heart Failure • Myelodysplastic Syndrome • Transplantation • CD123 • IL3RA • TP53

MD Anderson Research Highlights: ASH 2023 Special Edition (Newswise) - P2 | N=40 | NCT05285813 | "In a Phase II trial led by Nicholas Short, M.D., and presented by Daniel Nguyen, M.D., Ph.D., researchers evaluated vibecotamab in 11 patients with myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) after failure of hypomethylating agents, as well as in 12 patients with measurable residual disease (MRD)-positive AML. Vibecotamab had a response rate of 64% in patients with MDS/CMML, while 25% of patients with MRD-positive AML achieved MRD negativity. Ten (44%) patients experienced grade 2 infusion reactions and one (4%) experienced a grade 3 infusion reaction. This study suggests vibecotamab is safe and merits further investigation as part of a combination therapy for patients with AML, MDS and CMML."

P2 data • Acute Myelogenous Leukemia • Chronic Myelomonocytic Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

Phase 1 study of vibecotamab identifies an optimized dose for treatment of relapsed/refractory acute myeloid leukemia. (PubMed, Blood Adv) - P1 | "Response was associated with lower baseline blast count in blood and bone marrow (<25%) suggesting potential benefit. This trial was registered at www.clinicaltrials.gov as #NCT02730312."

Journal • P1 data • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CD123 • IL3RA

A phase II study of vibecotamab, a CD3-CD123 bispecific T-cell engaging antibody, for MRD-positive AML and MDS after hypomethylating agent failure. (ASCO 2023) - P2 | "The trial is actively accruing at MD Anderson Cancer Center. Clinical trial information: NCT05285813."

Minimal residual disease • P2 data • Acute Myelogenous Leukemia • Chronic Myelomonocytic Leukemia • Myelodysplastic Syndrome • CD123

Plasmacytoid dendritic cell neoplasms. (PubMed, Blood Res) - "Recent advances in molecular biology and genetics have led to the development of targeted agents, such as tagraxofusp (a recombinant fusion protein targeting CD123), anti-CD123 CAR-T cells, XmAb14045, and IMGN632. Lastly, this review provides a comprehensive overview of pDC neoplasms."

IO biomarker • Journal • Review • Chronic Myelomonocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • Transplantation • CD123 • CD4 • NCAM1 • NRP1 • TCF4

Preclinical Characterization of NGM936, a Novel Bispecific T Cell Engager Targeting ILT3 for the Treatment of Acute Myeloid Leukemia with Monocytic Differentiation (ASH 2022) - "In both whole blood cytokine release assays and in TDCC assays in which cytokine secretion was measured after target engagement, induction of TNF-α, IL-6, IFN-γ, and IL-2 by NGM936 was considerably lower than that induced by a vibecotamab biosimilar (CD123 x CD3). Finally, NGM936 induced a dose-dependent depletion of circulating tumor cells in a xenograft model in which irradiated, immunodeficient NSG mice were engrafted with human PBMCs and human ILT3+ AML cells. NGM936 thus represents a promising new treatment strategy for monocytic AML, with the potential to eliminate monocytic leukemia cells while minimizing the myelotoxicity associated with ablation of healthy bone marrow."

Preclinical • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • Transplantation • CD123 • CD34 • CTCs • IFNG • IL2 • IL6 • TNFA

A Phase II Study of Vibecotamab (XmAb14045) for MRD- Positive AML and MDS After Hypomethylating Agent Failure (clinicaltrials.gov) - P2 | N=40 | Recruiting | Sponsor: M.D. Anderson Cancer Center | Not yet recruiting ➔ Recruiting | Initiation date: Sep 2022 ➔ May 2022

Enrollment open • Minimal residual disease • Trial initiation date • Acute Myelogenous Leukemia • Myelodysplastic Syndrome

A Phase II Study of Vibecotamab (XmAb14045) for MRD- Positive AML and MDS After Hypomethylating Agent Failure (clinicaltrials.gov) - P2 | N=40 | Not yet recruiting | Sponsor: M.D. Anderson Cancer Center

Minimal residual disease • New P2 trial • Acute Myelogenous Leukemia • Myelodysplastic Syndrome

PH 1 Study to Evaluate Safety and Tolerability of XmAb14045 in Patients With CD123-expressing Hematologic Malignancies (clinicaltrials.gov) - P1 | N=120 | Completed | Sponsor: Xencor, Inc. | Recruiting ➔ Completed | Trial completion date: Feb 2023 ➔ Sep 2021 | Trial primary completion date: Feb 2022 ➔ Sep 2021

Trial completion • Trial completion date • Trial primary completion date • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • B Acute Lymphoblastic Leukemia • Chronic Myeloid Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology

Xencor Reports Third Quarter 2021 Financial Results and Announces Encouraging Preliminary Data from Ongoing Phase 1 Study of Potency-reduced IL15-Fc Cytokine, XmAb306 (Businesswire) - "Portfolio Highlights and Upcoming Data Presentations: Vibecotamab (CD123 x CD3): The Company was notified that Novartis is terminating its rights with respect to the vibecotamab program, which will be effective February 2022. The Company does not intend any further internal development of vibecotamab."

Discontinued • Licensing / partnership • Oncology

Targeting CD123 in BPDCN: an emerging field. (PubMed, Expert Rev Hematol) - "We review the history of CD123 research regarding BPDCN, recent advances including FDA approval of tagraxofusp (formerly SL-401) for BPDCN, and ongoing clinical studies utilizing novel therapeutic strategies to target CD123...Several other promising strategies for targeting CD123 in BPDCN are currently under investigation, including antibody-drug conjugates, T-cell engagers, and CAR-T cellular therapeutics. These CD123 targeted approaches may soon become standard of care for patients with this difficult to treat malignancy."

IO biomarker • Journal • Hematological Disorders • Hematological Malignancies • Oncology • CD123

Complete Responses in Relapsed/Refractory Acute Myeloid Leukemia (AML) Patients on a Weekly Dosing Schedule of XmAb14045, a CD123 x CD3 T Cell-Engaging Bispecific Antibody: Initial Results of a Phase 1 Study (ASH 2018) - P1; "CRS was the most common toxicity but was generally manageable with premedications. The study is ongoing with further optimization of dose, schedule, and premedication regimen for CRS anticipated during accrual to dose escalation cohorts in Part B. ClinicalTrials.gov Identifier: NCT02730312"

Clinical • P1 data • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Biosimilar • Chronic Myeloid Leukemia • Hematological Disorders • Hematological Malignancies • Immunology • Leukemia • Neutropenia • Oncology • Transplantation

[VIRTUAL] Complete Responses in Relapsed/Refractory Acute Myeloid Leukemia (AML) Patients on a Weekly Dosing Schedule of Vibecotamab (XmAb14045), a CD123 x CD3 T Cell-Engaging Bispecific Antibody; Initial Results of a Phase 1 Study (ASH 2020) - "Vibecotamab demonstrated evidence of antileukemic activity in heavily pretreated patients with relapsed/refractory AML treated at the ≥0.75 µg/kg doses cohorts, with a 14% response rate. CRS was the most common toxicity but was generally manageable with premedications. The study is ongoing with further optimization of dose and schedule."

Clinical • P1 data • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • B Acute Lymphoblastic Leukemia • Cardiovascular • Chronic Myeloid Leukemia • Hematological Malignancies • Hypotension • Leukemia • Oncology • Transplantation • CD123

PH 1 Study to Evaluate Safety and Tolerability of XmAb14045 in Patients With CD123-expressing Hematologic Malignancies (clinicaltrials.gov) - P1; N=145; Recruiting; Sponsor: Xencor, Inc.; Trial completion date: Feb 2021 ➔ Feb 2023; Trial primary completion date: Aug 2020 ➔ Feb 2022

Clinical • Trial completion date • Trial primary completion date • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • B Acute Lymphoblastic Leukemia • Chronic Myeloid Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology

Xencor and MD Anderson Enter Strategic Collaboration to Advance Investigational XmAb Drug Candidates (Businesswire) - "Xencor, Inc…and The University of Texas MD Anderson Cancer Center today announced a strategic collaboration to study investigational treatments for patients with a variety of cancer types. The parties will collaborate to design and execute additional clinical studies with Xencor’s portfolio of XmAb® drug candidates, including novel bispecific antibodies and engineered cytokines. Xencor is committing to funding and supporting these studies over an initial five-year term."

Licensing / partnership • Oncology

Xencor Reports Third Quarter 2020 Financial Results (Businesswire) - "In the coming weeks, we will present additional clinical data from some of these programs, including updated results from the Phase 1 studies of XmAb20717 at SITC, and vibecotamab at ASH....Tidutamab (SSTR2 x CD3): Xencor plans to initiate an additional clinical study in patients with Merkel cell carcinoma and small cell lung cancer...in early 2021...Xencor plans to initiate additional clinical studies evaluating vibecotamab in 2021....Plamotamab (CD20 x CD3): Patient enrollment continues in the Phase 1 study in non-Hodgkin lymphoma and chronic lymphocytic leukemia, with planned expansion cohorts expected to open in 2021....New data from three preclinical-stage programs, including the IL-12-Fc cytokine program...will also be presented at the SITC Annual Meeting in November 2020....The European Marketing Authorization Application for tafasitamab is currently under review, and MorphoSys expects a decision in the second half of 2021."

Clinical data • European regulatory • New trial • P1 data • Preclinical • Chronic Lymphocytic Leukemia • Lung Cancer • Merkel Cell Carcinoma • Non Small Cell Lung Cancer • Non-Hodgkin’s Lymphoma • Oncology • Small Cell Lung Cancer

Xencor Presents Updated Data from the Phase 1 Study of Vibecotamab in Acute Myeloid Leukemia at the 2020 ASH Annual Meeting (Businesswire) - P1, N=145; NCT02730312; Sponsor: Xencor; "The efficacy analysis included 54 evaluable patients who received a dose of at least 0.75 mcg/kg, completed at least the first cycle of treatment and had at least one post-treatment disease assessment. Two patients achieved complete remission (CR), and three patients achieved a CR with incomplete hematologic recovery. Additionally, two patients reached a morphologic leukemia-free state, and one patient experienced partial remission, as assessed by the investigator. The overall response rate (ORR) was 15% (n=8/54). Biomarker analyses suggest that low baseline leukemic burden and low PD-1 expression on CD4+ and CD8+ T cells are independent predictors of response."

Biomarker • P1 data • Acute Myelogenous Leukemia • Hematological Malignancies • Oncology