magrolimab (GS-4721)

P1, N=0, Withdrawn, National Cancer Institute (NCI) | N=33 --> 0 | Suspended --> Withdrawn

P1, N=82, Active, not recruiting, National Cancer Institute (NCI) | Suspended --> Active, not recruiting

P3, N=378, Terminated, Gilead Sciences | Trial completion date: Jul 2025 --> Apr 2024 | Active, not recruiting --> Terminated | Trial primary completion date: Jul 2025 --> Apr 2024; Study was terminated due to futility

P3, N=258, Terminated, Gilead Sciences | Active, not recruiting --> Terminated; Study discontinued due to futility.

P1/2, N=0, Withdrawn, Novartis Pharmaceuticals | N=63 --> 0 | Not yet recruiting --> Withdrawn

P1, N=34, Completed, Gilead Sciences | Phase classification: P1b --> P1

P2, N=54, Completed, Gilead Sciences | Active, not recruiting --> Completed

Bispecific antibodies and SIRPα/Fc fusion proteins appear to balance the efficacy and safety of treatment. We review the latest clinical research advances and discuss the opportunities and challenges associated with CD47-based immunotherapy for hematological malignancies.

P2, N=135, Active, not recruiting, Gilead Sciences | Recruiting --> Active, not recruiting

P2, N=230, Active, not recruiting, Gilead Sciences | Recruiting --> Active, not recruiting

GenSci059 selectively binds to CD47, effectively blocks the CD47/SIRPα axis signaling pathway and enhances the phagocytosis effects of macrophages toward tumor cells. This monoclonal antibody demonstrates potent antitumor activity and exhibits a favorable safety profile, positioning it as a promising and effective therapeutic option for cancer.

P2, N=57, Suspended, M.D. Anderson Cancer Center | Recruiting --> Suspended

P2, N=135, Recruiting, Gilead Sciences | Trial primary completion date: Feb 2024 --> Mar 2025

P1, N=24, Suspended, University of California, San Francisco | Recruiting --> Suspended

P1, N=33, Suspended, National Cancer Institute (NCI) | Recruiting --> Suspended

P1, N=1, Active, not recruiting, National Cancer Institute (NCI) | Trial primary completion date: Feb 2026 --> Mar 2024

P2, N=0, Withdrawn, Uwe Platzbecker | N=108 --> 0 | Not yet recruiting --> Withdrawn

P2, N=90, Active, not recruiting, Gilead Sciences | Recruiting --> Active, not recruiting | N=144 --> 90

P1, N=1, Active, not recruiting, National Cancer Institute (NCI) | Recruiting --> Active, not recruiting | N=76 --> 1 | Trial completion date: Jun 2028 --> Feb 2027

P1/2, N=88, Active, not recruiting, National Cancer Institute (NCI) | Suspended --> Active, not recruiting

P1, N=82, Suspended, National Cancer Institute (NCI) | Trial completion date: Jun 2026 --> Dec 2032 | Trial primary completion date: Jun 2026 --> Dec 2032

P1, N=44, Suspended, City of Hope Medical Center | Initiation date: Dec 2023 --> Jun 2024 | Not yet recruiting --> Suspended

P2, N=230, Recruiting, Gilead Sciences

P2, N=153, Active, not recruiting, Gilead Sciences

P1/2, N=88, Recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2023 --> Dec 2025 | Trial primary completion date: Dec 2023 --> Dec 2025

P2, N=144, Recruiting, Gilead Sciences

P1/2, N=178, Active, not recruiting, Gilead Sciences | Phase classification: P1b/2 --> P1/2 | Trial completion date: Aug 2024 --> May 2024 | Trial primary completion date: Aug 2024 --> May 2024

P2, N=106, Active, not recruiting, Gilead Sciences | Recruiting --> Active, not recruiting

P1/2, N=88, Recruiting, National Cancer Institute (NCI) | Suspended --> Recruiting | Phase classification: P1b/2 --> P1/2

Furthermore, genetic associations with inflammatory bone marrow signatures suggest the need for tailored platforms in defined AML subtypes. The eagerly anticipated results of trials investigating magrolimab, an anti-CD47 antibody targeting the "do not eat me" signal in p53-mutated AML, should shed further light on the potential of these evolving immunotherapeutic approaches.

Notably, azacitidine + venetoclax, azacitidine + sabatolimab, and azacitidine + magrolimab have shown exciting results in large, single-arm studies and have completed accrual in placebo-controlled, double-blind studies with OS as a primary endpoint. We all eagerly await the results of these studies.

P1, N=33, Recruiting, National Cancer Institute (NCI) | Initiation date: Dec 2023 --> Mar 2024

Magrolimab is a fully humanized IgG4 anti-human CD47 antibody, with high activity in FL when combined with rituximab (Advani NEJM 2018). The primary objective is safety, with secondary endpoints of overall response rate, duration of response, and PFS. Exploratory objectives include the identification of a molecular signature that predicts response to magrolimab and obinutuzumab, and correlation of response with circulating tumor DNA levels.

P2, N=57, Recruiting, M.D. Anderson Cancer Center | Not yet recruiting --> Recruiting | Initiation date: Feb 2024 --> Nov 2023

P2, N=108, Not yet recruiting, Uwe Platzbecker | Initiation date: Oct 2023 --> Jan 2024

Since 2017, we have seen eleven novel Food & Drug Administration (FDA)-approved medications for AML, all of which extend beyond the classical cytarabine-based cytostatic chemotherapy...However, despite these translational efforts, we currently have no immune-based therapies for AML on the market, with the exception of gemtuzumab ozogamicin. In this focused review, we discuss molecular target validation and the most relevant clinical updates for immune-based experimental therapeutics including anti-CD47 monoclonal antibodies, CAR-T therapies, and bispecific T cell engagers. We highlight barriers to the clinical translation of these therapies in AML, and we propose solutions to optimize the manufacturing and delivery of the most novel immune-based therapies in the pipeline.

We validated the translational utility of this orthotopic humanized model by evaluating the safety and efficacy of an immunotherapy antibody, magrolimab...In conclusion, this orthotopic humanized mouse model of Ewing sarcoma represents an improved platform for evaluating immunotherapy in bone and soft tissue sarcoma, such as Ewing sarcoma. With careful design and optimization, this model is generalizable for other bone malignancies.

The evaluated regimens in MORPHEUS-UC were tolerable. However, response rates for the combinations did not meet the criteria for further development in platinum-experienced locally advanced or mUC.

Patients 1 and 3 received treatment with CD47AB (Magrolimab), 5'-Azacitidine (Aza), and Venetoclax (Ven); Patient 2 received IMGN632 (CD123-targeting ADC), Aza and Ven. Patient 4 received p97 Inhibitor CB-5339; Patient 5 received CD47 inhibitor (ALX148), Aza, Ven... This study establishes a genotype-phenotype connection through single-cell proteogenomic profiling of TP53-mutated AML, describing the clonal evolution and immunophenotypic dynamics during treatment while proposing a potential mechanism of resistance.

Among the most promising MM SOC agents is monoclonal antibodies (mAb) such as the CD38 antibody daratumumab, which significantly improved the management of newly diagnosed and relapsed/refractory MM...We further verified HOSU-53 efficacy using the disseminated MM1.S luciferase CDX model and found a significant prolonged survival in the HOSU-53 cohort (median survival53-days) compared to vehicle (median survival28-days) that was further enhanced with isatuximab combination resulting in superior survival benefit (median survival 69-days)...Currently there is significant clinical interest in CD47 antibody therapy such as magrolimab for both solid tumors and hematological malignancies...In summary, we show compelling survival benefit for HOSU-53 as a monotherapy which is further enhanced when combined with anti-CD38 or anti-CD47 therapies. HOSU-53 is expected to enter phase 1 clinical trials in 2024 and our data is supportive for its expansion into MM.

CD47 expression on RBCs was shown to interfere with pre-transfusion laboratory testing in patients treated with the anti-CD47 mAb, Hu5F9-G4 (Velliquette et al. Here we demonstrate that interference with blood compatibility testing is dependent upon the type of CD47-blocking agent. Decoy receptors such as Maplirpacept, unlike anti-CD47 mAb, do not interfere with blood group serologic testing, which may confer a significant clinical advantage by negating the need for additional approaches to prevent interference.

Through single cell transcriptomic profiling of TP53-mutated AML patients treated with the triplet combination of AVM on protocol we identified erythroid differentiation and oxidative phosphorylation as possible intrinsic resistance mechanisms. Additionally, non-responders exhibited a dysfunctional T cell state prior to treatment, while relapses were associated with development of CD8 dysfunction. Overall, this data provides valuable insight into the mechanisms of response and resistance to magrolimab-based therapy.