BMS-986178 / BMS - LARVOL DELTA

A Phase I Clinical Trial Adding OX40 Agonism to In Situ Therapeutic Cancer Vaccination in Patients with Low-Grade B-cell Lymphoma Highlights Challenges in Translation from Mouse to Human Studies. (PubMed, Clin Cancer Res) - "Clinical results of T cell costimulatory receptor agonism have now repeatedly been inferior to the motivating preclinical results. Our study highlights potential barriers to clinical translation, particularly differences in preclinical and clinical reagents and the complex biology of these coreceptors in heterogenous T cell subpopulations, some of which may antagonize immunotherapy."

IO biomarker • Journal • P1 data • Preclinical • B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

A Phase I Clinical Trial Adding OX40 Agonism to In Situ Therapeutic Cancer Vaccination in Patients with Low-Grade B-cell Lymphoma Highlights Challenges in Translation from Mouse to Human Studies (Clin Cancer Res) - P1 | N=14 | NCT03410901 | "We treated 14 patients with low-dose radiation, intratumoral SD101, and intratumoral and intravenous BMS986178, an agonistic anti-OX40 antibody....Adverse events were consistent with prior experience with low-dose radiation and SD101. No synergistic or dose-limiting toxicities were observed. One patient had a partial response, and nine patients had stable disease, a result inferior to our experience with TLR9 agonism and low-dose radiation alone. Flow cytometry and single-cell RNA sequencing of serial tumor biopsies revealed that T and NK cells were activated after treatment."

P1 data • B Cell Lymphoma • Non-Hodgkin’s Lymphoma

TLR9 Agonist SD-101, Anti-OX40 Antibody BMS 986178, and Radiation Therapy in Treating Patients With Low-Grade B-Cell Non-Hodgkin Lymphomas (clinicaltrials.gov) - P1 | N=14 | Completed | Sponsor: Ronald Levy | Active, not recruiting ➔ Completed

Combination therapy • Trial completion • B Cell Lymphoma • B Cell Non-Hodgkin Lymphoma • Follicular Lymphoma • Hematological Malignancies • Lymphoplasmacytic Lymphoma • Mantle Cell Lymphoma • Marginal Zone Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Small Lymphocytic Lymphoma • Waldenstrom Macroglobulinemia

Challenges in translating preclinical mouse results to human patients: insights from a clinical trial combining OX40 agonism with in situ vaccination (SITC 2024) - P1 | "Fourteen patients were enrolled and treated with low-dose radiation (2 x 2Gy), intratumoral SD101, and intratumoral and intravenous BMS986178,2 a fully human agonistic anti-OX40 antibody (figure 1). TREG, FoxP3+ regulatory T. TFH, T follicular helper. TR1, T regulatory type 1 cellsDownload figure Open in new tab Download powerpoint Abstract 990 Figure 3 On-treatment (Day 8 and Week 6) soluble OX40 plasma levels between patients with progression free survival (PFS) 6 months (6M)"

IO biomarker • Preclinical • B Cell Non-Hodgkin Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CD4 • FOXP3 • TNFRSF9

Loss of the OX40 Target in Lymphoma Patients after Combining an Anti-OX40 Agonist Antibody with in Situ Vaccination (ASH 2023) - P1 | "STUDY: Fourteen patients with low-grade lymphoma received low-dose (2Gy x 2) radiotherapy to a single tumor site followed by 5 weekly intratumoral injections of 2 mg CpG-ODN (SD-101, TriSalus Life Sciences) and 3.75 mg anti-OX40 antibody into the same site...This loss was reproduced by in vitro assays where activated blood CD4 T cells exhibited a loss of cell surface OX40 when cultured with BMS-986178... Our observations suggest that treatment with an agonistic anti-OX40 antibody induced a loss of OX40 on the cell surface of effector CD4 T cells in the tumor microenvironment. Fewer molecules of OX40 receptor may have constrained the efficacy of subsequent anti-OX40 infusions and may explain why the clinical responses observed in this study were lower than observed in our past clinical trials of in situ vaccination."

Clinical • Hematological Malignancies • Indolent Lymphoma • Lymphoma • Oncology • Solid Tumor • CD4

TLR9 Agonist SD-101, Anti-OX40 Antibody BMS 986178, and Radiation Therapy in Treating Patients With Low-Grade B-Cell Non-Hodgkin Lymphomas (clinicaltrials.gov) - P1 | N=15 | Active, not recruiting | Sponsor: Ronald Levy | Trial completion date: Oct 2023 ➔ Oct 2024 | Trial primary completion date: Oct 2023 ➔ Oct 2024

Trial completion date • Trial primary completion date • Follicular Lymphoma • Hematological Malignancies • Lymphoplasmacytic Lymphoma • Mantle Cell Lymphoma • Marginal Zone Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Small Lymphocytic Lymphoma • Waldenstrom Macroglobulinemia

SD-101 and BMS-986178 in Treating Patients With Advanced or Metastatic Solid Malignancies (clinicaltrials.gov) - P1 | N=12 | Completed | Sponsor: Ronald Levy | Active, not recruiting ➔ Completed

Combination therapy • Metastases • Trial completion • Neutropenia • Oncology • Solid Tumor

Discovery of HX011, a novel OX40 mAb, for potential cancer immunotherapy (AACR 2023) - "In another word, HX011 is similar to BMS-986178 for the first two assays, but contrastingly different for the third assay. In vivo pharmacology modeling of HX011 in the humanized syngeneic CRC model, MC38, where syngeneic C57BL/6 mouse mice were knocked in with huOX40 (“HuGEMM-OX40”), demonstrated strong anti-tumor activity (TGI ~100% at 1 mg/kg, twice weekly). HX011 is being further investigated as a potential new immunotherapy for the treatment of cancers."

Oncology • BCL2L1 • BIRC5 • CTLA4 • FOXP3

TLR9 Agonist SD-101, Anti-OX40 Antibody BMS 986178, and Radiation Therapy in Treating Patients With Low-Grade B-Cell Non-Hodgkin Lymphomas (clinicaltrials.gov) - P1 | N=15 | Active, not recruiting | Sponsor: Ronald Levy | Recruiting ➔ Active, not recruiting | Trial completion date: Oct 2021 ➔ Oct 2023 | Trial primary completion date: Oct 2021 ➔ Oct 2023

Combination therapy • Enrollment closed • Trial completion date • Trial primary completion date • Follicular Lymphoma • Hematological Malignancies • Lymphoplasmacytic Lymphoma • Mantle Cell Lymphoma • Marginal Zone Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Small Lymphocytic Lymphoma • Waldenstrom Macroglobulinemia

From bench to bedside: Exploring OX40 receptor modulation in a phase 1/2a study of the OX40 costimulatory agonist BMS-986178nivolumab (NIVO) or ipilimumab (IPI) in patients with advanced solid tumors (AACR 2018) - P1/2; "Clinical PK/PD findings showed efficient BMS-986178 target engagement and confirmed preclinical observations that BMS-986178 can modulate RO and OX40/sOX40 expression. Furthermore, peripheral T-cell activation was observed in patients treated with BMS-986178 NIVO or IPI. Coupled with our preclinical observations, these findings highlight a complex dose-response relationship between BMS-986178 receptor saturation, receptor modulation, and induction of soluble receptor."

Clinical • IO biomarker • P1/2 data • PD(L)-1 Biomarker • Solid Tumor

TLR9 Agonist SD-101, Anti-OX40 Antibody BMS 986178, and Radiation Therapy in Treating Patients With Low-Grade B-Cell Non-Hodgkin Lymphomas (clinicaltrials.gov) - P1; N=15; Recruiting; Sponsor: Ronald Levy; Trial completion date: Oct 2020 ➔ Oct 2021; Trial primary completion date: Oct 2020 ➔ Oct 2021

Clinical • Combination therapy • Trial completion date • Trial primary completion date • Follicular Lymphoma • Hematological Malignancies • Lymphoplasmacytic Lymphoma • Mantle Cell Lymphoma • Marginal Zone Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Small Lymphocytic Lymphoma • Waldenstrom Macroglobulinemia

An Investigational Immuno-Therapy Study of Experimental Medication BMS-986178 by Itself or in Combination With Nivolumab and/or Ipilimumab in Participants With Solid Cancers That Are Advanced or Have Spread (clinicaltrials.gov) - P1/2; N=171; Completed; Sponsor: Bristol-Myers Squibb; Recruiting ➔ Completed

Trial completion • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer

SD-101 and BMS-986178 in Treating Patients With Advanced or Metastatic Solid Malignancies (clinicaltrials.gov) - P1; N=12; Active, not recruiting; Sponsor: Ronald Levy; Recruiting ➔ Active, not recruiting; N=27 ➔ 12; Trial completion date: Jun 2022 ➔ Jun 2023; Trial primary completion date: Jun 2022 ➔ Mar 2023

Clinical • Combination therapy • Enrollment change • Enrollment closed • Trial completion date • Trial primary completion date • Immunology • Neutropenia • Oncology • Solid Tumor

Cancer specialist demonstrates safety of novel agent (Medical Xpress) - "'We were pleasantly surprised to find that T-cell stimulation with an OX40 agonist did not exacerbate the inflammatory response and other off-target effects of checkpoint inhibitors,' said Dr. Gutierrez...'Indeed, the adverse events we observed in the monotherapy and combination cohorts were manageable, suggesting that BMS-986178 is safe to use in combination with checkpoint inhibitor therapy, and possibly also with a cancer vaccine.'...'Dr. Gutierrez, leading our Experimental Drugs program through phase I, has been at the forefront of immunotherapy, particularly in the use of checkpoint inhibitors that unleash the immune system and are now approved across many cancer subtypes,' said Andre Goy, M.D., M.S..."

Media quote

Generation and characterization of a high-affinity chimeric anti-OX40 antibody with potent anti-tumor activity. (PubMed, FEBS Lett) - "Using a hybridoma platform and three different types of immunization strategies, namely recombinant protein, DNA, and overexpressing cells, we identified a chimeric anti-OX40 antibody (mAb035-hIgG1 from DNA immunization) that shows excellent binding specificity, and slightly stronger activation of human memory CD4 T cells and similar potent anti-tumor activity compared to BMS 986178, an anti-OX40 antibody currently being evaluated for the treatment of solid tumors. This paper further systematically investigates the antigen-specific immune response, the number of binders, epitope bins, and functional activities of antibodies among different immunization strategies. Interestingly, we found that different immunization strategies affect the biological activity of monoclonal antibodies."

Journal • Immune Modulation • Inflammation • Solid Tumor • CD4 • TNFA

SD-101 and BMS-986178 in Treating Patients With Advanced or Metastatic Solid Malignancies (clinicaltrials.gov) - P1; N=27; Recruiting; Sponsor: Ronald Levy; Suspended ➔ Recruiting

Clinical • Combination therapy • Enrollment open • Immunology • Neutropenia • Oncology • Solid Tumor

An Investigational Immuno-Therapy Study of Experimental Medication BMS-986178 by Itself or in Combination With Nivolumab and/or Ipilimumab in Participants With Solid Cancers That Are Advanced or Have Spread (clinicaltrials.gov) - P1/2; N=207; Recruiting; Sponsor: Bristol-Myers Squibb; Active, not recruiting ➔ Recruiting; Trial completion date: Aug 2022 ➔ Oct 2024; Trial primary completion date: May 2021 ➔ Jul 2023

Clinical • Combination therapy • Enrollment open • Trial completion date • Trial primary completion date • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer

OX40 Agonist BMS-986178 Alone or in Combination With Nivolumab and/or Ipilimumab in Patients With Advanced Solid Tumors. (PubMed, Clin Cancer Res) - P1/2 | "In this study, BMS-986178 ± nivolumab and/or ipilimumab appeared to have a manageable safety profile, but no clear efficacy signal was observed above that expected for nivolumab and/or ipilimumab."

Clinical • Combination therapy • Journal • Bladder Cancer • Dermatology • Fatigue • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pruritus • Renal Cell Carcinoma • Solid Tumor

Examining the dynamic regulation of OX40 following receptor agonism and T-cell activation: Implications for antibody-mediated enhancement of T-cell function (AACR 2018) - "These results demonstrate a clear relationship between RO and the ability of BMS-986178, an agonist OX40 antibody, to enhance T-cell responses. Furthermore, these findings provide insight into antibody-mediated receptor modulation in vitro, with potential implications for defining the optimal dose and schedule of agonist OX40 antibodies and, perhaps more broadly, for agonists targeting other costimulatory molecules."

IO Biomarker • PD(L)-1 Biomarker • Oncology

Decreased immune response in monkeys administered a human T-effector cell agonist (OX40) antibody. (PubMed, Toxicol Appl Pharmacol) - "However, despite target engagement, PD assays and other immune endpoints demonstrated immune suppression, not stimulation. Due to the inverted immune response at higher doses and the onset of ADAs, additional repeat-dose toxicity studies of BMS-986178 in monkeys (that would typically be required to support Phase 3 clinical trials and registration) would not add value for human safety assessment."

Journal • Immune Modulation • Immunology • Inflammation • Oncology

OX40 agonists for cancer treatment: a patent review. (PubMed, Expert Opin Ther Pat) - "United States was the leader in generating patents, followed by China and England. Major pharmaceutical companies have at least one anti-OX40 agonist, MEDI6469 and MEDI-0562 (AstraZeneca), PF-04518600 (Pfizer), GSK3174998 (GlaxoSmithKline), BMS-986178 (Bristol-Myers Squibb) and MOXR0916 (Roche), which represent 68% of clinical trials conducted with OX40 agonists."

Journal • Immune Modulation • Inflammation • Oncology

An Integrative Approach to Inform Optimal Administration of OX40 Agonist Antibodies in Patients with Advanced Solid Tumors. (PubMed, Clin Cancer Res) - "Our results highlight the value of an integrated translational approach applied during early clinical development to aggregate preclinical and clinical data in an effort to define the optimal dose and schedule for T-cell agonists in the clinic."

Biomarker • Clinical • IO Biomarker • Journal • Immune Modulation • Inflammation • Oncology • Solid Tumor

SD-101 and BMS-986178 in Treating Patients With Advanced or Metastatic Solid Malignancies (clinicaltrials.gov) - P1; N=27; Suspended; Sponsor: Ronald Levy; Recruiting ➔ Suspended

Clinical • Combination therapy • Trial suspension • Neutropenia • Oncology • Psychiatry • Solid Tumor

An Investigational Immuno-therapy Study of Experimental Medication BMS-986178 by Itself or in Combination With Nivolumab and/or Ipilimumab in Patients With Solid Cancers That Are Advanced or Have Spread (clinicaltrials.gov) - P1/2; N=170; Active, not recruiting; Sponsor: Bristol-Myers Squibb; Recruiting ➔ Active, not recruiting

Clinical • Combination therapy • Enrollment closed • Oncology • Solid Tumor

UbiVac announces clinical trial collaboration with Bristol Myers Squibb on combination immunotherapy for advanced triple negative breast cancer (Businesswire) - "UbiVac, Inc…announced it has entered into a clinical trial collaboration with Bristol Myers Squibb (NYSE:BMY) to evaluate the safety, tolerability, and preliminary efficacy of UbiVac’s investigational product, DPV-001™, a first-in-class cancer vaccine that exploits autophagy, in combination with Bristol Myers Squibb’s anti-OX40 (BMS-986178) combined with sequenced administration of the programmed death-1 (PD-1) immune checkpoint inhibitor, Opdivo (nivolumab). The Phase 1b multicenter trial will test the hypothesis that combination immunotherapy with the DPV-001 cancer vaccine and anti-OX40 will augment anticancer immunity in patients with advanced triple negative breast cancer."

Licensing / partnership • Breast Cancer • Oncology • Triple Negative Breast Cancer