A Phase 1, Open-label, Dose Finding Study of CC-95251 Alone and in Combination With Antineoplastic Agents in Subjects With Acute Myeloid Leukemia and Myelodysplastic Syndromes

The purpose of this study is to evaluate the safety, tolerability, and preliminary clinical activity of CC-95251 alone and in combination with antineoplastic agents in participants with relapsed or refractory acute myeloid leukemia and relapsed or refractory and treatment-naive higher risk melodysplastic syndromes.

Start Date19 Jan 2022

Sponsor / Collaborator

Bristol Myers Squibb Co.

NCT03783403 / TerminatedPhase 1

A Phase 1, Open-label, Dose Finding Study of CC-95251, a Monoclonal Antibody Directed Against SIRPα, Alone and in Combination With Cetuximab or Rituximab in Subjects With Advanced Solid and Hematologic Cancers

The purpose of this study is to evaluate the safety, tolerability, and preliminary clinical activity of CC-95251 as a single agent and in combination with cetuximab and rituximab in participants with advanced solid and hematologic cancers.

Start Date01 Mar 2019

Sponsor / Collaborator

Celgene Corp.

100 Clinical Results associated with Anzurstobart

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22 Feb 2024·Cancer research communications

Discovery and Preclinical Activity of BMS-986351, an Antibody to SIRPα That Enhances Macrophage-mediated Tumor Phagocytosis When Combined with Opsonizing Antibodies

Article

Author: Chan, Henry ; Fox, Brian A. ; Mavrommatis, Konstantinos ; Guzman, Roberto ; Dearth, Lawrence ; Mikolon, David ; Sivakumar, Pallavur ; Trout, Christina V. ; Cho, Ho ; Hariharan, Kandasamy ; Hadjivassiliou, Haralambos ; Adams, Preston ; Abbasian, Mahan

Abstract:

In normal cells, binding of the transmembrane protein CD47 to signal regulatory protein-α (SIRPα) on macrophages induces an antiphagocytic signal. Tumor cells hijack this pathway and overexpress CD47 to evade immune destruction. Macrophage antitumor activity can be restored by simultaneously blocking the CD47-SIRPα signaling axis and inducing a prophagocytic signal via tumor-opsonizing antibodies. We identified a novel, fully human mAb (BMS-986351) that binds SIRPα with high affinity. BMS-986351 demonstrated broad binding coverage across SIRPα polymorphisms and potently blocked CD47-SIRPα binding at the CD47 binding site in a dose-dependent manner. In vitro, BMS-986351 increased phagocytic activity against cell lines from solid tumors and hematologic malignancies, and this effect was markedly enhanced when BMS-986351 was combined with the opsonizing antibodies cetuximab and rituximab. A phase I dose-escalation/-expansion study of BMS-986351 for the treatment of advanced solid and hematologic malignancies is underway (NCT03783403).

Significance::

Increasing the phagocytotic capabilities of tumor-associated macrophages by modulating macrophage–tumor cell surface signaling via the CD47-SIRPα axis is a novel strategy. Molecules targeting CD47 have potential but its ubiquitous expression necessitates higher therapeutic doses to overcome potential antigen sink effects. The restricted expression pattern of SIRPα may limit toxicities and lower doses of the SIRPα antibody BMS-986351 may overcome target mediated drug disposition while maintaining the desired pharmacology.

News (Medical) associated with Anzurstobart

19 Apr 2023

·www.biospace.com

OSE Immunotherapeutics Presents Clinical and Preclinical Data from its Immuno-Oncology Portfolio

At the 2023 American Association for Cancer Research Annual Meeting BI 765063, first-in-class SIRPα inhibitor on the SIRPα/CD47 myeloid pathway in advanced solid tumors. OSE-127, monoclonal immunomodulatory antibody targeting the CD127 receptor, the alpha chain of the interleukin-7 receptor (IL-7R) in Acute Lymphoblastic Leukemia. BiCKI®-IL-7, bifunctional therapy targeting PD1 and IL-7 to sustain exhausted T cell function and to disarm Treg suppressive activity. NANTES, France--(BUSINESS WIRE)-- Regulatory News: OSE Immunotherapeutics SA (ISIN: FR0012127173; Mnemo: OSE) announces three presentations at the American Association for Cancer Research (AACR) Annual Meeting in Orlando (Florida), April 14-19, 2023. The presentations include the first data on biomarker analyses from the Phase 1 study of BI 765063 (anti-SIRPα monoclonal antibody on the CD47/SIRPα pathway) in advanced solid tumors. Two other presentations report the latest preclinical updates on OSE-127 (anti-IL-7 receptor antagonist) in hematology and on BiCKI®-IL-7 (new bifunctional therapy targeting PD1 and IL-7). In addition, preclinical characterization data on CLEC-1 (new myeloid immune checkpoint) binding mechanism will also be presented on April 19. Nicolas Poirier, Chief Executive Officer of OSE Immunotherapeutics, comments: “We are very pleased to share our latest scientific advances with the leading international cancer scientific community. The solid clinical and preclinical data derived from our innovative research programs in immuno-oncology demonstrate our continued commitment and progress to delivering first-in-class immunotherapies for cancer patients in high need for new therapeutic options.” BI 765063, a first-in-class selective SIRPα inhibitor on the SIRPα/CD47 myeloid pathway targeting myeloid cells in immuno-oncology, with a strong biological rationale for clinical response. The escalation Phase 1 clinical trial data on selective SIRPα antagonist BI 765063 showed preliminary clinical efficacy results in monotherapy and in combination with PD1 inhibitor ezabenlimab in patients with advanced solid tumors. A biomarker analysis from this escalation Phase 1 study was performed to characterize the impact of BI 765063 on the tumor environment. The AACR presentation featured analysis results showing a predictive response of identified biomarkers: High levels of myeloid cells expressing SIRPα (CD11b+, SIRPα+ myeloid cells) in tumor microenvironment at baseline (but not CD47 tumor cell expression) correlate with longer survival. MDSC (Myeloid-Derived Suppressor Cells) signature in tumor microenvironment at baseline correlates also with clinical response. Three clinical studies of BI 765063 in combination are currently being conducted: - NCT05249426: in patients with 1st or 2nd line hepatocellular carcinoma in combination with anti-PD1 ezabenlimab +/- VEGF/Ang2 inhibitor and 2nd line head and neck squamous cell carcinoma in combination with cetuximab or chemotherapy and who received no prior anti-PD-L1 inhibitors (in the United States, Europe and Japan). - NCT03990233: in patients with microsatellite stable (MSS) advanced colorectal cancer and MSS advanced endometrium cancer whose disease relapsed after standard of care and who received no prior anti-PD-L1 inhibitors (in Europe) (1). |- NCT04653142: in patients with solid tumors (in Japan). OSE-127, a monoclonal immunomodulatory antibody antagonist of IL-7 receptor, represents a novel promising immunotherapy option in Acute Lymphoblastic Leukemia. (2) The CD127 receptor is over-expressed by acute lymphoblastic leukemia and is efficiently targeted by the IL-7R-antagonist OSE-127 through macrophage-mediated antibody dependent phagocytosis. Targeting IL-7R CD127 is a promising novel strategy in B-Cell Precursor ALL (BCP-ALL) and T-ALL (T-Cell ALL) since CD127 signalling is important for B- and T-cell development, survival and proliferation. Despite the favourable prognosis of BCP-ALL, relapse remains a clinical challenge and novel targeted immunotherapy options are urgently needed. T-ALL is an aggressive haematological cancer for which treatment options are limited at relapse. The poster presentation concluded on the strong rationale that OSE-127 may represent a powerful novel immunotherapy option for ALL patients based on a unique dual mechanism of action. This antibody both blocks oncogenic interleukin-7 fuel pathway and simultaneously triggers macrophage-driven phagocytosis of leukemic cells. This research program, conducted on patient-derived xenograft experiments, is led by OSE Immunotherapeutics in collaboration with Pr. Denis Schewe (Head of the Pediatrics Department, Otto-von-Guericke-University, Magdeburg and formerly from the University Medical Center Schleswig-Holstein of Kiel) and Dr. Lennart Lenk (Department of Pediatrics I, Christian-Albrechts University Kiel and University Medical Center Schleswig-Holstein, Kiel). BiCKI®IL-7, a bifunctional immunotherapy targeting PD1 and IL-7, represents a high potential asset for cancer patients suffering from immune escape following checkpoint inhibitor treatments. BiCKI®IL-7, the most advanced candidate from OSE Immunotherapeutics’ BiCKI® platform, is a novel bifunctional therapy which targets PD1 and at the same time selectively deliver IL-7 pro-survival cytokine to tumor-specific T-cells expressing PD1. BiCKI®IL-7 restores exhausted T-cell function, disarms Treg suppressive activity and extends stem-like memory T-cells, the key T-cell subpopulation associated with anti-PD-(L)1 clinical responses. The presentation reports that anti-PD1/IL-7v BiCKI®-IL-7 showed significant monotherapy anti-tumor efficacy in different in vivo models. In addition, BiCKI®-IL-7 showed significant anti-tumor efficacy post-anti-PD-(L)1 failure in a preclinical model, highlighting the clinical potential of BiCKI®-IL-7v in immune checkpoint inhibitor resistant patients. These results validate the rationale of selective delivery of IL-7 to PD1 tumor-specific T-cells to limit risk of I-O/I-O immunotoxicity and sustain long-lasting proliferation and survival of stem-like CD8 T-cells to strengthen anti-PD-(L)1 therapy. This Phase 1 clinical trial with BI 765063 is being conducted by OSE Immunotherapeutics as part of a collaboration and license agreement under which Boehringer Ingelheim obtained exclusive rights to BI 765063. In parallel, OSE-127 is currently being developed in clinical stage in partnership with Servier. Two clinical studies are ongoing in inflammatory diseases: a phase 2a study conducted in primary Sjögren’s syndrome by Servier and a Phase 2 study conducted in ulcerative colitis by OSE Immunotherapeutics. Poster presentation details: Poster BI 765063 Title: “Predictive response biomarkers from Phase I clinical trial of a SIRPalpha inhibitor BI765063, stand-alone and in combination with ezabenlimab, a PD1 inhibitor, in patients with advanced solid tumors” Session Category: Clinical Research Excluding Trials Session Title: Biomarkers of Therapeutic Benefit 2 Date & Time: April 17, 2023 - 9:00 AM - 12:30 PM Location: Poster Section 39, Poster Board 3 Poster Number: 2129 Poster OSE-127 Title: “CD127 is expressed by acute lymphoblastic leukemias and is efficiently targeted by the IL7R-antagonist OSE-127 through macrophage-mediated antibody dependent phagocytosis” Session Category: Immunology Session Title: Therapeutic Antibodies 3 Session Date and Time: April 17, 2023 - 1:30 PM - 5:00 PM Location: Poster Section 24 Poster Board Number: 4 Poster BiCKI®-IL-7 Title: “Anti-PD-1/IL-7v bispecific antibody promotes TCF1+ stem like CD8 T cells expansion and long-lasting in vivo efficacy” Session Category: Immunology Session Title: Therapeutic Antibodies 3 Session Date and Time: April 17, 2023 - 1:30 PM - 5:00 PM Location: Poster Section 24 Poster Board Number: 2 Poster CLEC#1* Title: “CLEC-1 inhibitory myeloid checkpoint blockade enhances antitumor responses and tumor phagocytosis by macrophages”” Session Category: Immunology Session Title: Immune Checkpoints Session Date and Time: April 19, 2023 - 9:00 AM – 12:30 PM Location: Section 23 Poster Board Number: 2 Poster CLEC#2* Title: “TRIM21 is a novel endogenous partner of the inhibitory myeloid checkpoint CLEC-1 involved in tumor antigen cross-presentation” Session Category: Immunology Session Title: Immune Checkpoints Session Date and Time: April 19, 2023 - 9:00 AM - 12:30 PM Location: Poster Section 23 Poster Board Number: 9 * Collaborative academic program between OSE Immunotherapeutics and Dr Elise Chiffoleau’s research teams (Center for Research in Transplantation and Translational Immunology (CR2TI), UMR1064, INSERM, Nantes University at Nantes University Hospital, ). ABOUT OSE Immunotherapeutics OSE Immunotherapeutics is a biotech company dedicated to developing first-in-class assets in immuno-oncology and immuno-inflammation. The Company’s current well-balanced first-in-class clinical pipeline includes: Tedopi® (immunotherapy activating tumor specific T-cells, off-the-shelf, neoepitope-based): this cancer vaccine is the Company’s most advanced product; positive results from the Phase 3 trial (Atalante 1) in Non-Small Cell Lung Cancer patients in secondary resistance after checkpoint inhibitor failure. Other Phase 2 trials, sponsored by clinical oncology groups, of Tedopi® in combination are ongoing in solid tumors. OSE-279 (anti-PD1): ongoing Phase 1/2 in solid tumors or lymphomas (first patient included). OSE-279 is the backbone therapy of the BiCKI® platform. OSE-127/S95011 - lusvertikimab (humanized monoclonal antibody antagonist of IL-7 receptor) developed in partnership with Servier; ongoing Phase 2 in ulcerative colitis (sponsor OSE Immunotherapeutics) and ongoing Phase 2a in Sjögren’s syndrome (sponsor Servier); ongoing pre-clinical research in leukemia (OSE Immunotherapeutics). FR-104/VEL-101 (anti-CD28 monoclonal antibody): developed in partnership with Veloxis Pharmaceuticals, Inc. in transplantation; ongoing Phase 1/2 in renal transplant (sponsor Nantes University Hospital); Phase 1 ongoing in the US (sponsor Veloxis Pharmaceuticals, Inc.). OSE-172/BI 765063 (anti-SIRPα monoclonal antibody on CD47/SIRPα pathway) developed in partnership with Boehringer Ingelheim in advanced solid tumors; positive Phase 1 dose escalation results in monotherapy and in combination, in particular with anti-PD-1 antibody ezabenlimab; international Phase 1b ongoing clinical trial in combination with ezabenlimab alone or with other drugs in patients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) and hepatocellular carcinoma (HCC). OSE Immunotherapeutics expects to generate further significant value from its two proprietary drug discovery platforms, which are central to its ambitious goal to deliver next-generation first-in-class immunotherapeutics: BiCKI® platform focused on immuno-oncology (IO) is a bispecific fusion protein platform built on the key backbone component of anti-PD1 combined with a new immunotherapy target to increase anti-tumor efficacy. BiCKI-IL-7 is the most advanced BiCKI® candidate targeting anti-PD1xIL-7. Myeloid platform focused on optimizing the therapeutic potential of myeloid cells in IO and immuno-inflammation (I&I). OSE-230 (ChemR23 agonist mAb) is the most advanced candidate generated by the platform, with the potential to resolve chronic inflammation by driving affected tissues to tissue integrity. Additional information about OSE Immunotherapeutics assets is available on the Company’s website: Click and follow us on Twitter and LinkedIn Forward-looking statements This press release contains express or implied information and statements that might be deemed forward-looking information and statements in respect of OSE Immunotherapeutics. They do not constitute historical facts. These information and statements include financial projections that are based upon certain assumptions and assessments made by OSE Immunotherapeutics’ management in light of its experience and its perception of historical trends, current economic and industry conditions, expected future developments and other factors they believe to be appropriate. These forward-looking statements include statements typically using conditional and containing verbs such as “expect”, “anticipate”, “believe”, “target”, “plan”, or “estimate”, their declensions and conjugations and words of similar import. Although the OSE Immunotherapeutics management believes that the forward-looking statements and information are reasonable, the OSE Immunotherapeutics’ shareholders and other investors are cautioned that the completion of such expectations is by nature subject to various risks, known or not, and uncertainties which are difficult to predict and generally beyond the control of OSE Immunotherapeutics. These risks could cause actual results and developments to differ materially from those expressed in or implied or projected by the forward-looking statements. These risks include those discussed or identified in the public filings made by OSE Immunotherapeutics with the AMF. Such forward-looking statements are not guarantees of future performance. This press release includes only summary information and should be read with the OSE Immunotherapeutics Universal Registration Document filed with the AMF on 15 April 2022, including the annual financial report for the fiscal year 2021, available on the OSE Immunotherapeutics’ website. Other than as required by applicable law, OSE Immunotherapeutics issues this press release at the date hereof and does not undertake any obligation to update or revise the forward-looking information or statements. View source version on businesswire.com: Contacts OSE Immunotherapeutics Sylvie Détry sylvie.detry@ose-immuno.com +33 1 53 198 757 Investor Relations Thomas Guillot thomas.guillot@ose-immuno.com +33 6 07 380 431 French Media: FP2COM Florence Portejoie fportejoie@fp2com.fr +33 6 07 768 283 Source: OSE Immunotherapeutics SA View this news release online at:

Phase 1Clinical ResultPhase 2ImmunotherapyLicense out/in

02 Feb 2023

·www.fiercebiotech.com

BMS knocks down a handful of early cancer candidates amid pipeline cleanout

Bristol Myers Squibbs' pipeline cuts come as the company expects to keep R&D spending at 2022 levels. Bristol Myers Squibb is taking a broom to the bottom of its pipeline, axing at least nine assets including one phase 2 med being studied in a variety of solid tumors. The cleanout was disclosed in the company’s fourth-quarter earnings release Thursday morning, providing an updated glimpse of the company’s early-stage plans. All told the company cut six cancer prospects, including a phase 2 anti-CTLA4 candidate, one fibrosis candidate and two immunology assets. Most of the cancer prospects were phase 1-level solid tumor prospects, including a STING agonist, IL-12 F, SIRPα antagonist and the anti-CTLA4 med. But BMS also whittled down its blood cancer prospects as well, ending development of a ROR CAR-T therapy that was in phase 1. Following behind the line of axed cancer meds is branebrutinib, an immunology asset that finished up a phase 2 trial in patients with lupus, primary Sjögren's syndrome and rheumatoid arthritis. Patients with RA also received BMS’s approved med Orencia in an open-label follow-up portion. An update to the clinical trial record in December showed that the study jumped from recruiting to completed. Another mid-stage immunology option, an MK2 inhibitor to treat ankylosing spondylitis, was culled as well. The move to wipe away nearly 10 assets comes as the company has projected that R&D spending in the new year will be in line with 2022, which was roughly $9.5 billion. BMS also expanded on a recent decision to terminate a phase 2 trial of the company’s anti-TIGIT med, BMS-986207, as part of a triple combination therapy with Yervoy and Opdivo due to safety reasons. Chief Medical Officer Samit Hirawat, M.D., said that toxicity was observed when tacked onto the immuno-oncology combo. Hirawat promised more data and specifics on what happened with the triple-combo, "but because of those safety reasons, we have decided to terminate this particular trial at this time.” The decision pours additional cold water onto the anti-TIGIT class of immunotherapies, once-thought to be a rising star to replace the current generation of checkpoint inhibitors. But disappointing readouts from Roche last year made others reconsider their bets. Still, companies like Gilead, Novartis and GSK are pressing ahead as Roche waits for critical overall survival data.

Phase 2ImmunotherapyDrug ApprovalClinical Trial FailurePhase 1

02 Nov 2022

·endpts.com

Exelixis shells out $100M cash in a pair of deals, shooting for different takes on CD47, ADCs

Now that its cabozantinib franchise — branded Cabometyx in the US and Cometriq in the EU — has nestled its way into blockbuster status, Exelixis is replenishing the pipeline with some early-stage bets. The biotech revealed a pair of deals right as it reported Q3 results, shelling out a total of $100 million in cash to grab a preclinical antibody targeting SIRPα and a Phase I peptide-drug conjugate. There are also plenty of biobucks attached should the compounds make it down the treacherous development journey. Exelixis’ deals shed light on two private startups that have kept a relatively low profile. Sairopa, which is supplying the anti-SIRPα drug, is the reincarnation of troubled Aduro Biotech after kidney-focused Chinook Therapeutics reverse merged with Aduro and spun out the remaining oncology assets. Cybrexa, on the other hand, is partnered with the National Cancer Institute on its tech for selectively delivering a toxic payload to tumor cells. First, the Sairopa deal: Exelixis has its eyes on ADU-1805, which blocks SIRPα . Expressed on macrophages and other myeloid cells, the protein is thought to play a key role in the CD47 “don’t eat me” signal put out by cancer cells to evade an immune attack — making it a promising checkpoint target. Peter Lamb, EVP, scientific strategy and CSO at Exelixis, noted that the drug has been “carefully optimized” to maximize benefit and minimize potential toxicities. In addition to monotherapy, his team is looking at combining the drug with an in-house tyrosine kinase inhibitor and other approved checkpoint inhibitors. Sairopa has also lined up a suite of follow-on antibodies hitting the same target. An IND is expected in early 2023. After Sairopa completes certain Phase I studies, Exelixis will have an option to license the program. On top of $40 million in upfront and $70 million in milestones to grab the option, it promises Sairopa an option exercise fee of $225 million. As for Cybrexa, its CBX-12 is a peptide-drug conjugate composed of what it calls a pH-low insertion peptide, a linker and the cancer-killing agent exatecan. The peptide is designed to insert itself into tumor cells when and only when it encounters an acidic tumor microenvironment. While the concept is similar to antibody-drug conjugates in that it aims to hit cancer cells while sparing healthy cells, it’s a target-independent approach, according to the company. The upfront of $60 million gives Exelixis the right to acquire CBX-12 pending results from an ongoing Phase I. The bigger biotech will also take up some development and manufacturing expenses. All told, the acquisition fee and milestones add up to $642.5 million. “Today’s announcement further highlights our ongoing strategy to leverage our balance sheet to gain access to new assets with compelling potential upside in a risk-sharing model, where we can work with partners to further establish proof of concept before investing more heavily,” CEO Michael Morrissey said in a statement.

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Indication	Highest Phase	Country/Location	Organization	Date
Acute Myeloid Leukemia	Phase 1	US	Bristol Myers Squibb Co.	19 Jan 2022
Acute Myeloid Leukemia	Phase 1	AU	Bristol Myers Squibb Co.	19 Jan 2022
Acute Myeloid Leukemia	Phase 1	CA	Bristol Myers Squibb Co.	19 Jan 2022
Acute Myeloid Leukemia	Phase 1	FR	Bristol Myers Squibb Co.	19 Jan 2022
Acute Myeloid Leukemia	Phase 1	IT	Bristol Myers Squibb Co.	19 Jan 2022
Acute Myeloid Leukemia	Phase 1	NO	Bristol Myers Squibb Co.	19 Jan 2022
Acute Myeloid Leukemia	Phase 1	ES	Bristol Myers Squibb Co.	19 Jan 2022
Acute Myeloid Leukemia	Phase 1	SE	Bristol Myers Squibb Co.	19 Jan 2022
Acute Myeloid Leukemia	Phase 1	GB	Bristol Myers Squibb Co.	19 Jan 2022
Myelodysplastic Syndromes	Phase 1	US	Bristol Myers Squibb Co.	19 Jan 2022

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT03783403 (EHA2022) Manual	Phase 1	Non-Hodgkin Lymphoma CD20 Positive	17	Rituximab+CC 95251	naetvawnlv(ocvmbixxyq) = jkptffqeph bgdbupwpqj (zhbdlrzewr ) View more	Positive	12 May 2022
NCT03783403 (ASH2021) Manual	Phase 1	Non-Hodgkin's lymphoma refractory CD20 Positive	18	Rituximab+CC-95251	tdwoylgpsj(paglqshfui) = NR erzgjpnimv (woawxtqqit ) View more	Positive	05 Nov 2021

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