utomilumab (PF-05082566) / Pfizer, Novartis - LARVOL DELTA

InCITe: Avelumab With Binimetinib, Sacituzumab Govitecan, or Liposomal Doxorubicin in Treating Stage IV or Unresectable, Recurrent Triple Negative Breast Cancer (clinicaltrials.gov) - P2 | N=150 | Recruiting | Sponsor: Laura Huppert, MD, BA | Trial completion date: Jun 2025 ➔ Jun 2026 | Trial primary completion date: Jun 2025 ➔ Jun 2026

Trial completion date • Trial primary completion date • Tumor mutational burden • Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • ER • HER-2 • PD-L1 • PGR

Multabodies: A next-generation approach for cancer immunotherapy and 4-1BB agonist therapy (AACR 2025) - "However clinical development has been hindered by severe liver toxicity (i.e., urelumab), or insufficient single agent activity, as seen with utomilumab. Furthermore, RBT101 also provided long-term protection in a tumor rechallenge study, suggesting generation of a durable immunological memory response driven by RBT101. These data suggest the Multabody™ platform provides a novel approach to delivering a 4-1BB therapeutic with a differentiated profile to address an unmet clinical need in cancer immunotherapy for patients with solid malignancies."

Oncology • Solid Tumor • TNFRSF9

Avelumab, Utomilumab, Rituximab, Ibrutinib, and Combination Chemotherapy in Treating Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma or Mantle Cell Lymphoma (clinicaltrials.gov) - P1 | N=16 | Completed | Sponsor: City of Hope Medical Center | Active, not recruiting ➔ Completed | Trial completion date: Dec 2024 ➔ Jun 2024 | Trial primary completion date: Dec 2024 ➔ Jun 2024

Trial completion • Trial completion date • Trial primary completion date • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CCND1 • CD20

A phase I/II trial of avelumab combinations with ivuxolimab, utomilumab, and radiation therapy in patients with advanced gastrointestinal malignancies. (PubMed, Oncologist) - P1/2 | "Combining avelumab with co-stimulatory checkpoint agonists produces modest activity without added safety concerns in patients with advanced GI malignancies (ClinicalTrials.gov Identifier: NCT03217747)."

Journal • P1/2 data • Colon Cancer • Fatigue • Gastric Cancer • Gastroenterology • Gastrointestinal Cancer • Gastrointestinal Disorder • Hepatology • Immunology • Oncology • Pancreatic Cancer • Solid Tumor

Rituximab + Immunotherapy in Follicular Lymphoma (clinicaltrials.gov) - P1 | N=24 | Terminated | Sponsor: Dana-Farber Cancer Institute | Phase classification: P1b ➔ P1 | Active, not recruiting ➔ Terminated; Stopped was stopped prematurely due to drug manufacturer withdrawing supply/funding. Patients already enrolled on study were allowed to continue treatment.

Phase classification • Trial termination • Follicular Lymphoma • Hematological Malignancies • Lymphoma • Oncology

Cardiac Glycosides Induce Immunogenic Changes in Myeloma Cells and Enhance the Efficacy of Monoclonal and Bispecific Antibody Therapy (ASH 2024) - "Therefore, the 4-1BB agonist Utomilumab is being tested in combination with CAR-T therapy (NCT 03704298).Here, to develop improved immune cell therapies for MM, we evaluated whether CGs enhances the anti-myeloma activity of monoclonal and bispecific antibodies by augmenting immune responses.Methods : Alterations of ICAM1 and 4-1BBL or SLAMF7 at the protein level were evaluated on two MM cell lines, AMO1 and KMS12PE, by flow cytometry after exposure to the CGs, i.e., digoxin, periplocin, ouabain, or hellebrin at minimally toxic concentrations.Treated MM cells were then co-cultured with immune effector cells from healthy donors together with elotuzumab (anti-SLAMF7 antibody) or teclistamab (BCMA bispecific antibody) in the presence or absence of low doses of CGs for 48 h. Thereafter, cytotoxic effects and effector cell activity were evaluated. Digoxin, a drug that can be used in clinical practice, also caused immunogenic changes in MM cells and enhanced the efficacy of..."

Clinical • IO biomarker • Cardiovascular • Congestive Heart Failure • Heart Failure • Hematological Malignancies • Multiple Myeloma • Oncology • ICAM1 • IL2RA • SLAMF7

NCI-2018-01118: Avelumab, Utomilumab, Anti-OX40 Antibody PF-04518600, and Radiation Therapy in Treating Patients with Advanced Malignancies (clinicaltrials.gov) - P1/2 | N=173 | Active, not recruiting | Sponsor: M.D. Anderson Cancer Center | Trial completion date: Sep 2024 ➔ Sep 2025 | Trial primary completion date: Sep 2024 ➔ Sep 2025

Combination therapy • Metastases • Trial completion date • Trial primary completion date • Castration-Resistant Prostate Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Hepatocellular Cancer • Oncology • Prostate Cancer • Solid Tumor • CD8

A Study Of Avelumab In Combination With Other Cancer Immunotherapies In Advanced Malignancies (JAVELIN Medley) (clinicaltrials.gov) - P1/2 | N=409 | Terminated | Sponsor: Pfizer | Phase classification: P1b/2 ➔ P1/2

Combination therapy • Metastases • Phase classification • Bladder Cancer • Breast Cancer • Gastric Cancer • Gastrointestinal Cancer • Head and Neck Cancer • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Small Cell Lung Cancer • Squamous Cell Carcinoma of Head and Neck • Triple Negative Breast Cancer • ALK • EGFR • ROS1

ZUMA-11: Safety and Efficacy of Axicabtagene Ciloleucel in Combination With Utomilumab in Adults With Refractory Large B-cell Lymphoma (clinicaltrials.gov) - P1 | N=15 | Terminated | Sponsor: Kite, A Gilead Company | Phase classification: P1/2 ➔ P1

Combination therapy • Phase classification • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • BCL2 • BCL6

Utomilumab, Cetuximab, and Irinotecan Hydrochloride in Treating Patients With Metastatic Colorectal Cancer (clinicaltrials.gov) - P1 | N=42 | Active, not recruiting | Sponsor: M.D. Anderson Cancer Center | Trial completion date: Dec 2023 ➔ Dec 2026 | Trial primary completion date: Dec 2023 ➔ Dec 2026

Metastases • Trial completion date • Trial primary completion date • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • MSI

A novel anti-4-1BB antibody with no liver toxicity and its application in a bi-specific antibody (AACR 2024) - "However, the development of 4-1BB agonist antibodies has encountered challenges, with limited clinical efficacy (e.g., utomilumab) or dose-dependent liver toxicity (e.g., urelumab)...Furthermore, we've developed HLX34, a Her2x4-1BB bispecific antibody, derived from Trastuzumab and HLX25...These results provide evidence that our novel anti-4-1BB antibody activates proper 4-1BB signaling through tumor-enriched FcgRIIB or tumor-associated antigen-mediated clustering, inhibiting tumor growth with good safety in both in vitro and in vivo settings. This underscores HLX34 as a promising alternative therapeutic strategy for next-generation cancer immunotherapy."

Oncology • CD8 • HER-2 • TNFA • TNFRSF9

Continued Access Study for Participants Deriving Benefit in Pfizer-Sponsored Avelumab Parent Studies That Are Closing (clinicaltrials.gov) - P3 | N=61 | Active, not recruiting | Sponsor: Pfizer | Recruiting ➔ Active, not recruiting | N=262 ➔ 61 | Trial completion date: May 2025 ➔ Sep 2026 | Trial primary completion date: May 2025 ➔ Sep 2026

Enrollment change • Enrollment closed • Trial completion date • Trial primary completion date • Genito-urinary Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Solid Tumor • Urothelial Cancer

Avelumab, Utomilumab, Rituximab, Ibrutinib, and Combination Chemotherapy in Treating Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma or Mantle Cell Lymphoma (clinicaltrials.gov) - P1 | N=16 | Active, not recruiting | Sponsor: City of Hope Medical Center | Trial completion date: Dec 2023 ➔ Dec 2024 | Trial primary completion date: Dec 2023 ➔ Dec 2024

Combination therapy • Trial completion date • Trial primary completion date • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CCND1 • CD20

Development of a c-MET x CD137 bispecific antibody for targeted immune agonism in cancer immunotherapy. (PubMed, Cancer Treat Res Commun) - "Overall, the c-MET x CD137 BsAb exhibits a promising developability profile as a tumor-targeted immune agonist by minimizing off-target effects while effectively delivering immune agonism. It has the potential to overcome resistance to anti-PD-(L)1 therapies."

Journal • Hepatology • Oncology • MET • TNFRSF9

Continued Access Study for Participants Deriving Benefit in Pfizer-Sponsored Avelumab Parent Studies That Are Closing (clinicaltrials.gov) - P3 | N=262 | Recruiting | Sponsor: Pfizer | Trial completion date: Dec 2025 ➔ May 2025 | Trial primary completion date: Dec 2025 ➔ May 2025

Trial completion date • Trial primary completion date • Genito-urinary Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Solid Tumor • Urothelial Cancer

T-Cell Infusion, Aldesleukin, and Utomilumab in Treating Patients With Recurrent Ovarian Cancer (clinicaltrials.gov) - P1/2 | N=8 | Completed | Sponsor: M.D. Anderson Cancer Center | Suspended ➔ Completed

Combination therapy • Trial completion • Oncology • Ovarian Cancer • Solid Tumor • COL6A3 • HLA-A • PRAME

M9657 is a bispecific tumor-targeted anti-CD137 agonist that induces MSLN-dependent antitumor immunity without liver inflammation. (PubMed, Cancer Immunol Res) - "Development of the first-generation CD137-agonist monotherapies utomilumab and urelumab was unsuccessful due to low antitumor efficacy mediated by the epitope recognized on CD137 or hepatotoxicity mediated by FcγR ligand-dependent CD137 activation, respectively. Compared with 3H3, a murine surrogate of urelumab, FS122m and chimeric M9657 displayed significantly lower on-target/off-tumor toxicity. Taken together, M9657 exhibits a promising profile for development as a tumor-targeting immune agonist with potent anticancer activity without systemic immune activation and associated hepatotoxicity."

IO biomarker • Journal • Hepatology • Oncology • CD8 • MSLN

AVIATOR/TBCRC045: A randomized phase II study of vinorelbine (N) + trastuzumab (H) alone or combined with avelumab (A) +/- utomilumab (U) in patients (pts) with HER2+ metastatic breast cancer (MBC) (NCT03414658) (SABCS 2023) - P2 | " Eligible pts had HER2+ MBC previously treated with H, pertuzumab (P), and T-DM1...All pts were previously treated with H, P, and T-DM1, and 17% had prior trastuzumab deruxtecan... This trial demonstrated significant improvement in PFS with addition of avelumab to NH among pts with heavily pre-treated HER2+ MBC. 4-1BB agonist did not improve PFS. To our knowledge, this is the first randomized trial to report results of chemo/H +/- ICI in HER2+ MBC."

Clinical • IO biomarker • Metastases • P2 data • Breast Cancer • HER2 Breast Cancer • Oncology • Solid Tumor • HER-2 • PD-L1

InCITe: Avelumab With Binimetinib, Sacituzumab Govitecan, or Liposomal Doxorubicin in Treating Stage IV or Unresectable, Recurrent Triple Negative Breast Cancer (clinicaltrials.gov) - P2 | N=150 | Recruiting | Sponsor: Hope Rugo, MD | Trial completion date: Jun 2024 ➔ Jun 2025 | Trial primary completion date: Jun 2024 ➔ Jun 2025

Metastases • Trial completion date • Trial primary completion date • Tumor mutational burden • Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • ER • HER-2 • PD-L1 • PGR

Phase I/II study to evaluate the safety and tolerability of avelumab in combination with other anti-cancer therapies in patients with advanced malignancies (SITC 2023) - P1/2 | "1 Preclinical studies suggest that combining utomilumab (4–1BB agonist) and ivuxolimab (OX40 agonist) with avelumab (an anti-PD-L1 monoclonal antibody) can potentially synergize to enhance T cell function and simultaneously overcome the effects of upregulation of PD-L1 resulting in clinical benefit. Conclusions Combining immune checkpoint inhibitors with checkpoint agonists produces modest activity without added safety concerns in patients with advanced GI malignancies. The findings from this study can provide insights for future investigations in this field of research."

Clinical • Combination therapy • Metastases • P1/2 data • Colon Cancer • Gastric Cancer • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Solid Tumor

PBMC humanized mouse model with clinical relevance in assessing the safety profile of 4–1BB agonist, urelumab, in 5 donors (SITC 2023) - "Two 4–1BB agonists, urelumab and utomilumab, investigated in clinical trials showed different safety profiles. Furthermore, the differing toxicity profiles from the five PBMC donors illustrate the value of using PBMC humanized mouse models for preclinical safety assessments. Data from multiple PBMC donors can be used as a tool to evaluate how therapeutics will be tolerated in the greater population as well as used as a tool to assess individual patient responses."

Preclinical • Oncology • CCL4 • CXCL8 • IFNG • TNFA

Phase 1/2 trial of avelumab combined with utomilumab (4-1BB agonist), PF-04518600 (OX40 agonist), or radiotherapy in patients with advanced gynecologic malignancies. (PubMed, Cancer) - "The findings from this trial highlight that, in heavily pretreated patients with gynecologic cancer, even multidrug regimens targeting multiple immunologic pathways, although safe, did not produce significant responses. A DCR of 78% in patients with cervical cancer who received avelumab and utomilumab indicates that further research on this combination in select patients may be warranted."

Journal • Metastases • P1/2 data • Cervical Cancer • Endometrial Cancer • Gynecologic Cancers • Oncology • Ovarian Cancer • Solid Tumor

A multi-cohort phase 1b trial of rituximab in combination with immunotherapy doublets in relapsed/refractory follicular lymphoma. (PubMed, Ann Hematol) - P1b | "We therefore conducted a phase 1b trial testing time-limited therapy with different immunotherapy doublets targeting 4-1BB (utomilumab), OX-40 (ivuxolimab), and PD-L1 (avelumab) in combination with rituximab among patients with relapsed/refractory grade 1-3A FL. Abundance of Akkermansia in stool samples was also associated with response. Our results support a possible role for 4-1BB agonist therapy in FL and suggest that features of the tumor microenvironment and stool microbiome may be associated with clinical outcomes (NCT03636503)."

Combination therapy • Journal • P1 data • Follicular Lymphoma • Hematological Malignancies • Lymphoma • Oncology • TIGIT

Costimulatory capacity of CD137 mAbs on T cells depends on elaborate CRD structures but not on blocking ligand-receptor binding. (PubMed, Eur J Immunol) - "Two representative CD137 antibodies, utomilumab and urelumab, show different costimulatory capacities in clinical trials. However, the costimulatory capacity of mAbs on T cells was not closely related to their ability to block CD137L-CD137 binding and may be controlled by more elaborate CRD conformational structures. This study provides additional information for the development of next-generation CD137 mAbs to meet clinical needs."

Journal • Oncology • CD8 • TNFRSF9

Axicabtagene Ciloleucel in Combination with the 4–1BB Agonist Utomilumab in Patients with Relapsed/Refractory Large B-Cell Lymphoma: Phase 1 Results from ZUMA-11 (Clin Cancer Res) - P1 | N=15 | ZUMA-11 (NCT03704298) | Sponsor: Kite, A Gilead Company | "No DLTs were observed among patients treated with axi-cel and utomilumab (n = 12). Grade ≥3 adverse events occurred in 10 patients (83%); none were Grade ≥3 cytokine release syndrome or neurologic events. The objective response rate was 75% and seven patients (58%) had a complete response. Peak CAR T-cell levels increased in a utomilumab dose-dependent manner up to 100 mg. Patients who received utomilumab 100 mg had persistently increased CAR T cells on days 57 to 168 compared with other dose levels. Utomilumab was associated with dose-dependent increases in IL2, IFNγ, and IL10."

P1 data • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology