- |||||||||| sabatolimab (MBG453) / Novartis
Stimulus MDS-US Trial in Progress: Evaluating Sabatolimab in Combination with Hypomethylating Agents (HMAs) in Patients with Intermediate-, High-, or Very High–Risk Myelodysplastic Syndrome (MDS) (ENMCC - Hall D) - Nov 4, 2022 - Abstract #ASH2022ASH_2631;
P1b, P2
Primary end points are incidence and severity of adverse events (AEs) and serious AEs. Secondary endpoints are complete remission (CR) rate (according to International Working Group for the Prognosis for MDS), progression-free survival, overall survival, leukemia-free survival, percentage of patients with CR, marrow CR and/or partial remission, duration of CR, time to CR, and percentage of patients with improvement in red blood cell/platelet transfusion independence.
- |||||||||| ALLG AMLM26 Phase 1B/2 Study Investigating Novel Therapies to Target Early Relapse and Clonal Evolution As Pre-Emptive Therapy in AML (INTERCEPT): A Multi-Arm, Precision-Based, Recursive, Platform Trial (ENMCC - Hall D) - Nov 4, 2022 - Abstract #ASH2022ASH_2286;
Where no specific targeted treatment is available, patients will be randomly allocated to non-targeted therapies, if more than one applicable arm exists, to arms including sabatolimab, sabatolimab + azacitidine, ASTX727 + VEN or LDAC + VEN...Key secondary endpoints will be nadir MRD response, MRD clearance rate, median time to and duration of MRD response, relapse-free survival, overall survival and quality of life measures. Exploratory objectives will include analysis of drug resistance mechanisms and correlates of response.
- |||||||||| Review, Journal: Updates on the Management of Acute Myeloid Leukemia. (Pubmed Central) - Oct 15, 2022
On the other hand, for "unfit patients", azacitidine-venetoclax has been consolidated as a frontline treatment, while other combinations with magrolimab or ivosidenib are in development...New immunotherapies or targeted therapies, such as Menin inhibitors or sabatolimab, represent an opportunity in this situation. Future directions will probably come from combinations of different targeted therapies ("triplets") and maintenance strategies guided by measurable residual disease.
- |||||||||| Jakafi (ruxolitinib) / Novartis, Incyte
Trial completion date: ADORE: Platform Study of Novel Ruxolitinib Combinations in Myelofibrosis Patients (clinicaltrials.gov) - Oct 12, 2022
P1/2, N=47, Active, not recruiting,
Future directions will probably come from combinations of different targeted therapies ("triplets") and maintenance strategies guided by measurable residual disease. Trial completion date: Oct 2024 --> Jun 2024
- |||||||||| sabatolimab (MBG453) / Novartis, magrolimab (GS-4721) / Ono Pharma, Gilead
P3 data, Review, Journal, IO biomarker: Current status of phase 3 clinical trials in high-risk myelodysplastic syndromes: pitfalls and recommendations. (Pubmed Central) - Oct 11, 2022
Despite initial encouraging results, two registration trials from 2021 and 2022 have not been successful in improving outcomes when compared with single-agent hypomethylating agents. Here, I summarise the current status of ongoing phase 3 trials for patients with untreated high-risk myelodysplastic syndromes and provide some suggestions for future designs.
- |||||||||| sabatolimab (MBG453) / Novartis
Journal: Characterization of sabatolimab, a novel immunotherapy with immuno-myeloid activity directed against TIM-3 receptor. (Pubmed Central) - Oct 6, 2022
Sabatolimab was shown to (i) enhance T-cell killing and inflammatory cytokine production by dendritic cells (DCs); (ii) facilitate the phagocytic uptake of TIM-3-expressing target cells; and (iii) block the interaction between TIM-3 and its ligands PtdSer/galectin-9. Taken together, our results support both direct anti-leukemic effects and immune-mediated modulation by sabatolimab, reinforcing the notion that sabatolimab represents a novel immunotherapy with immuno-myeloid activity, holding promise for the treatment of myeloid cell neoplasms.
- |||||||||| sabatolimab (MBG453) / Novartis, siremadlin (HDM201) / Novartis
Trial completion date, Trial primary completion date, Combination therapy: HDM201 in Combination With MBG453 or Venetoclax in Patients With Acute Myeloid Leukemia (AML) or High-risk Myelodysplastic Syndrome (MDS) (clinicaltrials.gov) - Oct 6, 2022
P1, N=80, Recruiting,
Taken together, our results support both direct anti-leukemic effects and immune-mediated modulation by sabatolimab, reinforcing the notion that sabatolimab represents a novel immunotherapy with immuno-myeloid activity, holding promise for the treatment of myeloid cell neoplasms. Trial completion date: Dec 2022 --> Apr 2023 | Trial primary completion date: Dec 2022 --> Apr 2023
- |||||||||| sabatolimab (MBG453) / Novartis
Galectin-9 drives TIM-3+ natural killer cell dysfunction in head and neck squamous cell carcinoma (Hall C) - Oct 6, 2022 - Abstract #SITC2022SITC_825;
Galectin-9-induced effects on cytotoxicity can be abrogated using the clinical-grade anti-TIM-3 blocking antibody, MBG453...This may be due to higher intratumoral galectin-9 protein expression in HPV+ HNSCC lesions, as well as higher frequencies of circulating and tumor-infiltrating TIM-3+ NK cells in HPV+ patients. Conclusions Our data stress the importance of TIM-3 in the context of NK cells and suggest that targeting the TIM-3/galectin-9 pathway may be a cogent immunotherapeutic strategy to reinvigorate NK cell effector function in HPV+ HNSCC patients.
- |||||||||| sabatolimab (MBG453) / Novartis, spartalizumab (PDR001) / Novartis
Enrollment closed, Combination therapy: Trial of Anti-Tim-3 in Combination With Anti-PD-1 and SRS in Recurrent GBM (clinicaltrials.gov) - Oct 4, 2022
P1, N=16, Active, not recruiting,
Conclusions Our data stress the importance of TIM-3 in the context of NK cells and suggest that targeting the TIM-3/galectin-9 pathway may be a cogent immunotherapeutic strategy to reinvigorate NK cell effector function in HPV+ HNSCC patients. Recruiting --> Active, not recruiting
- |||||||||| sabatolimab (MBG453) / Novartis, emavusertib (CA-4948) / Curis, Dr. Reddy's, magrolimab (GS-4721) / Ono Pharma, Gilead
Journal: EXABS-140-MDS Immune Therapy Approaches in MDS. (Pubmed Central) - Sep 29, 2022
Study sponsored by Novartis Pharmaceuticals Corporation. No abstract available
- |||||||||| sabatolimab (MBG453) / Novartis, nisevokitug (NIS793) / Novartis, Ilaris (canakinumab) / Novartis
Trial completion date, Trial primary completion date: Phase Ib Study of Select Drug Combinations in Patients With Lower Risk MDS (clinicaltrials.gov) - Sep 21, 2022
P1, N=90, Recruiting,
Active, not recruiting --> Terminated; Business reasons Trial completion date: Feb 2024 --> Sep 2024 | Trial primary completion date: Feb 2024 --> Sep 2024
- |||||||||| sabatolimab (MBG453) / Novartis
Trial completion date, Trial initiation date, Trial primary completion date: A Study of Sabatolimab and Magrolimab-based Treatment in AML or Higher Risk MDS Participants (clinicaltrials.gov) - Sep 6, 2022
P1/2, N=63, Not yet recruiting,
Trial completion date: Feb 2024 --> Sep 2024 | Trial primary completion date: Feb 2024 --> Sep 2024 Trial completion date: Jul 2027 --> Oct 2029 | Initiation date: Sep 2022 --> Dec 2024 | Trial primary completion date: Jul 2027 --> Oct 2029
- |||||||||| sabatolimab (MBG453) / Novartis, magrolimab (GS-4721) / Ono Pharma, Gilead
Review, Journal, Checkpoint inhibition, Tumor Mutational Burden, PD(L)-1 Biomarker, IO biomarker: Immune Checkpoint Inhibition in Acute Myeloid Leukemia and Myelodysplastic Syndromes. (Pubmed Central) - Jul 29, 2022
Randomized trials are currently ongoing to confirm the efficacy of these agents. In this review, we will present the current progress and future directions of immune checkpoint inhibition in AML and MDS.
- |||||||||| sabatolimab (MBG453) / Novartis, magrolimab (GS-4721) / Ono Pharma, Gilead
Review, Journal: New Frontiers in Monoclonal Antibodies for the Targeted Therapy of Acute Myeloid Leukemia and Myelodysplastic Syndromes. (Pubmed Central) - Jul 29, 2022
Sabatolimab, an inhibitor of T-cell immunoglobulin and mucin domain-containing protein 3 (TIM3), which disrupts its binding to galectin-9, has shown promising results in AML/MDS, enhancing the effector functions of lymphocytes and triggering tumor cell death...These novel mAbs are currently under investigation for use as monotherapy or in combination with hypomethylating agents, BCL2 inhibitors, and chemotherapy in various clinical trials at different phases of development. Here, we review the main molecular targets and modes of action of novel mAb-based immunotherapies, which can represent the future of AML and higher risk MDS treatment.
- |||||||||| Immune Therapy Approaches in MDS (Level 4, Grand Ballroom G-L) - Jul 26, 2022 - Abstract #SOHO2022SOHO_65;
Its aberrant expression on leukemic blasts stem cells (LSCs) and blasts but not on that of normal hematopoietic stem cells make this an attractive therapeutic target.5,6 Binding of the high affi nity anti-TIM3 IgG4 antibody sabatolimab to TIM3 results in phagocytic killing of LSCs and blasts and in combination with DNMT inhibitors have demonstrated safety, minimal immune toxicity and importantly early evidence of durable remissions in the phase 1b setting.7 Toxicities were predominantly expected cytopenias and mild GI intolerance (constipation, nausea)...An on-going phase 1/2 trial is evaluating tagraxofusp monotherapy in chronic myelomonocytic leukemia (N=38) reported tolerability including a 21% capillary leak syndrome (CLS) rate (11% grade 2 and 11% grade 3) and encouraging median overall survival of 15.6 months (95% CI, 8.1-17.5; range, 0.36-40.77).11 Based on strong preclinical evidence demonstrating tagraxofusp resistance was due to decreased expression of DPH1 which could be restored with azacitidine, a phase 1b trial of azacitidine and tagraxofusp in MDS/AML was launched...Targeting immunological dysfunctional pathways is a well-studied approach in MDS with prior successes with immunosuppressive therapies (ATG), immunomodulatory agents such as lenalidomide in 5q deletion MDS and luspatercept which limits TGF-beta signaling...Notably, among 7 patients with splicing mutated higher risk MDS there was 57% marrow CR rate including 1 with HI.15 This trial has plans to assess CA-4948 in combination with azacitidine or venetoclax...It remains a challenge to interpret small single arm studies and mixing populations that are truly resistant (HMA refractory) and treatment naïve, and different formulations of the same class of drugs and thus reliance on large phase 2/3 trials and importantly randomized trials will be most informative. A focus on identifying select disease subpopulations in these early trials (‘signal fi nding’ i.e. magrolimab with TP53 mutations or splicing mutations with IRAK4 inhibition) is an opportunity we cannot afford to miss.
- |||||||||| Treatment of Higher Risk MDS (Level 3, Room 343B) - Jul 26, 2022 - Abstract #SOHO2022SOHO_28;
P1b/2, P3
The Phase 2/3 North American Intergroup SWOG S1117 study randomized patients in an open label trial to azacitidine alone versus azacitidine plus lenalidomide or azacitidine plus vorinostat3...Pevonedistat, a fi rst-in-class, selective inhibitor of NEDD8- activating enzyme has been investigated with azacitidine in patients with myeloid malignancies with encouraging randomized phase 2 data with signifi cant improved CR rates (52% vs 27%) and improved EFS in HR-MDS patients5...The phase 1b/2 results showed the combination of azacitidine + APR-246 to be well tolerated with no dose-limiting toxicities and a recommended phase 2 dose of APR-246 as a fi xed dose of 4500mg days 1-4 in combination with AZA22...These data support the ongoing ENHANCE-2 phase 3 open-label study of azacitidine + magrolimab vs azacitidine + venetoclax in unfi t AML patients and versus induction chemotherapy in fi t patients with a primary endpoint of OS in the non-intensive group (NCT04778397)...Lastly, novel triplet HMA combinations are of high interest for TP53 mutant and wildtype patients including multiple combinations of HMA with venetoclax, sabatolimab and magrolimab...Notably, TP53 specifi c trials are urgently needed given clear differential outcomes. Ideally, future translational data will further elucidate the underpinnings driving the synergy and resistance mechanisms underlying these novel therapeutic strategies.
- |||||||||| sabatolimab (MBG453) / Novartis, spartalizumab (PDR001) / Novartis
Trial completion date, Trial primary completion date, Combination therapy: Study of PDR001 and/or MBG453 in Combination With Decitabine in Patients With AML or High Risk MDS (clinicaltrials.gov) - Jul 12, 2022
P1b, N=243, Active, not recruiting,
Ideally, future translational data will further elucidate the underpinnings driving the synergy and resistance mechanisms underlying these novel therapeutic strategies. Trial completion date: Jun 2022 --> Sep 2022 | Trial primary completion date: Jun 2022 --> Sep 2022
- |||||||||| sabatolimab (MBG453) / Novartis
SABATOLIMAB (MBG453) COMBINATION TREATMENT REGIMENS FOR PATIENTS WITH HIGHER-RISK MYELODYSPLASTIC SYNDROMES: THE MYELODYSPLASTIC SYNDROMES STUDIES IN THE STIMULUS IMMUNO-MYELOID CLINICAL TRIAL PROGRAM () - May 13, 2022 - Abstract #EHA2022EHA_1812;
P2, P3
STIMULUS-MDS2 ( NCT04266301) is an international, randomized, double-blind, placebo-controlled, ph III trial of sabatolimab + azacitidine (AZA) in pts with vH/H/IR-MDS or chronic myelomonocytic leukemia-2; the study has completed recruiting (N=530)...STIMULUS MDS-US (NCT04878432) is a US-based, open-label, single-arm, ph II trial of sabatolimab + HMA of investigator’s choice (AZA intravenous [IV] or subcutaneous, decitabine IV, or oral decitabine/cedazuridine) in pts with vH/H/IR-MDS...STIMULUS-MDS3 (NCT04812548) is an international, open-label, single-arm, ph II trial that explores triplet therapy of sabatolimab + AZA + BCL-2 inhibitor venetoclax (VEN) in pts with vH/HR-MDS...Results None. Conclusion None.
- |||||||||| LY3321367 / Eli Lilly, sabatolimab (MBG453) / Novartis, cobolimab (TSR-022) / GSK
Review, Journal, Checkpoint inhibition, IO biomarker: New Checkpoint Inhibitors on the Road: Targeting TIM-3 in Solid Tumors. (Pubmed Central) - Apr 19, 2022
However, the TIM-3 pathway is highly complex in terms of non-canonical signaling, broad expression by different immune cells and multiple ligands. Different anti-TIM-3 inhibitors are currently on research, either as monotherapy or in combination with other immunotherapies or chemotherapy, aiming to overcome resistance.
- |||||||||| sabatolimab (MBG453) / Novartis, spartalizumab (PDR001) / Novartis
Clinical, P1 data, Journal, Combination therapy, PD(L)-1 Biomarker, IO biomarker: Phase I/Ib clinical trial of Sabatolimab, an Anti-TIM-3 Antibody, Alone and in Combination With Spartalizumab, an Anti-PD-1 Antibody, in Advanced Solid Tumors. (Pubmed Central) - Apr 2, 2022
Sabatolimab plus spartalizumab was well tolerated and showed preliminary signs of antitumor activity. The RP2D for sabatolimab was selected as 800 mg Q4W (alternatively Q3W or Q2W schedules, based on modeling), with or without 400 mg spartalizumab Q4W.
- |||||||||| sabatolimab (MBG453) / Novartis, spartalizumab (PDR001) / Novartis
Trial completion date, Trial primary completion date, Combination therapy, IO biomarker, Metastases: Phase I-Ib/II Study of MBG453 as Single Agent and in Combination With PDR001 in Patients With Advanced Malignancies (clinicaltrials.gov) - Feb 22, 2022
P1/2, N=252, Active, not recruiting,
In addition, the expression and genomic alteration of TIM-3 and its ligand have prognostic values for certain cancers. Trial completion date: Mar 2022 --> Jul 2022 | Trial primary completion date: Mar 2022 --> Jul 2022
- |||||||||| sabatolimab (MBG453) / Novartis, nisevokitug (NIS793) / Novartis, Ilaris (canakinumab) / Novartis
Trial completion date, Trial primary completion date: Phase Ib Study of Select Drug Combinations in Patients With Lower Risk MDS (clinicaltrials.gov) - Feb 22, 2022
P1, N=90, Recruiting,
Trial completion date: Mar 2022 --> Jul 2022 | Trial primary completion date: Mar 2022 --> Jul 2022 Trial completion date: Nov 2023 --> Feb 2024 | Trial primary completion date: Nov 2023 --> Feb 2024
- |||||||||| sabatolimab (MBG453) / Novartis
Enrollment open: STIMULUS MDS-US : Sabatolimab Added to HMA in Higher Risk MDS (clinicaltrials.gov) - Feb 9, 2022
P2, N=90, Recruiting,
Trial completion date: Nov 2023 --> Feb 2024 | Trial primary completion date: Nov 2023 --> Feb 2024 Not yet recruiting --> Recruiting
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