selicrelumab (RG7876) / Roche - LARVOL DELTA

MORPHEUS-PDAC: A Study of Multiple Immunotherapy-Based Treatment Combinations in Participants With Metastatic Pancreatic Ductal Adenocarcinoma (Morpheus-Pancreatic Cancer) (clinicaltrials.gov) - P1/2 | N=341 | Completed | Sponsor: Hoffmann-La Roche | Active, not recruiting ➔ Completed

Trial completion • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • PD-L1

MORPHEUS-PDAC: A Study of Multiple Immunotherapy-Based Treatment Combinations in Participants With Metastatic Pancreatic Ductal Adenocarcinoma (Morpheus-Pancreatic Cancer) (clinicaltrials.gov) - P1/2 | N=340 | Active, not recruiting | Sponsor: Hoffmann-La Roche | Trial completion date: Oct 2026 ➔ Jan 2025 | Trial primary completion date: Oct 2025 ➔ Jan 2025

Metastases • Trial completion date • Trial primary completion date • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • PD-L1

Comparison of receptor occupancy and optimal doses of PD1xCD40 and PDL1xCD40 bispecific antibodies using physiologically based pharmacokinetic modeling (SITC 2024) - "For PD1xCD40 BsAb kinetic parameters, YH008 antibody was used; 1 for PDL1xCD40 BsAb, HBM9027 antibody.2 Results The model was validated using PK data for monospecific antibodies against PD1 (pembrolizumab, nivolumab), PDL1 (avelumab, durvalumab, atezolizumab), and CD40 (selicrelumab, Chi Lob 7/4, BI 655064), and showed good agreement with clinical data. Conclusions The developed PBPK model integrating data on immune cell levels, target expression, and binding parameters of PD1xCD40 and PDL1xCD40 BsAbs predicts PK and receptor occupancy of the antibodies in tumor and plasma. The model shows that higher doses of PDL1xCD40 BsAb are required for maximal engagement of target molecules compared to PD1xCD40 BsAb."

IO biomarker • PK/PD data • Hematological Malignancies • Oncology

Morpheus-TNBC: A Study Evaluating the Efficacy and Safety of Multiple Treatment Combinations in Patients With Metastatic or Locally Advanced Breast Cancer (clinicaltrials.gov) - P1/2 | N=580 | Recruiting | Sponsor: Hoffmann-La Roche | N=242 ➔ 580 | Trial completion date: May 2026 ➔ May 2028 | Trial primary completion date: May 2026 ➔ May 2028

Enrollment change • Metastases • Trial completion date • Trial primary completion date • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • HER-2 • PD-L1 • PIK3CA

Systemic Immune Response to a CD40-Agonist Antibody in Nonhuman Primates. (PubMed, J Leukoc Biol) - "Two independent studies in cynomolgus macaque (Macaca fascicularis) studies were performed to further evaluate, potentially immunotoxicological effects associated with drug-induced adverse events seen in human subjects. Studies conducted in monkeys showed that when selicrelumab is administered at doses currently used in clinical trial patients, via subcutaneous injection, it is safe and effective at stimulating a systemic immune response."

Journal • Hematological Disorders • Hematological Malignancies • Oncology • Solid Tumor • ACACA • CD40 • TNFA

Harnessing the potential of CD40 agonism in cancer therapy. (PubMed, Cytokine Growth Factor Rev) - "In this review, we present the current understanding of the mechanism of action for CD40, along with results from the clinical development of agonistic human CD40 antibodies in cancer treatment (selicrelumab, CDX-1140, APX005M, mitazalimab, 2141-V11, SEA-CD40, LVGN7409, and bispecific antibodies). This review also examines the safety profile of CD40 agonists in both preclinical and clinical settings, highlighting optimized dosage levels, potential adverse effects, and strategies to mitigate them."

IO biomarker • Journal • Review • Oncology • CD40 • CD40LG • CD8 • TNFA

MORPHEUS-PDAC: A Study of Multiple Immunotherapy-Based Treatment Combinations in Participants With Metastatic Pancreatic Ductal Adenocarcinoma (Morpheus-Pancreatic Cancer) (clinicaltrials.gov) - P1/2 | N=340 | Active, not recruiting | Sponsor: Hoffmann-La Roche | Recruiting ➔ Active, not recruiting

Enrollment closed • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • PD-L1

Evaluation of efficacy and toxicity of human CD40 agonistic antibodies in C57BL/6-hCD40/hFcγRIIB HuGEMMTM (SITC 2023) - "In addition, Selicrelumab showed a highly efficient anti-tumor effect with increased T cell infiltration in tumors compared with APX005M-hIgG1(S267E). However, FcγRIIB engagement exacerbated the irAE response with enhanced liver damage, pro-inflammatory cytokine secretion, and immune cell infiltration into livers. Conclusions This study revealed that human CD40 agonistic antibodies evaluated in C57BL/6-CD40/FcγRIIB HuGEMMTM mice reproduce the efficacy and toxicity phenotypes observed in clinic, demonstrating the improved clinical relevance of this HuGEMMTM model to evaluate future biologic molecules targeting CD40."

Clinical • IO biomarker • Oncology • CD40 • CD8 • IFNG • IL6 • TNFA

Morpheus-TNBC: A Study Evaluating the Efficacy and Safety of Multiple Treatment Combinations in Patients With Metastatic or Locally Advanced Breast Cancer (clinicaltrials.gov) - P1/2 | N=242 | Recruiting | Sponsor: Hoffmann-La Roche | Active, not recruiting ➔ Recruiting

Enrollment open • Metastases • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • HER-2 • PD-L1 • PIK3CA

MORPHEUS-PDAC: A Study of Multiple Immunotherapy-Based Treatment Combinations in Participants With Metastatic Pancreatic Ductal Adenocarcinoma (Morpheus-Pancreatic Cancer) (clinicaltrials.gov) - P1/2 | N=340 | Recruiting | Sponsor: Hoffmann-La Roche | Trial completion date: Jun 2024 ➔ Oct 2026 | Trial primary completion date: Jun 2024 ➔ Oct 2025

Metastases • Trial completion date • Trial primary completion date • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • PD-L1

Morpheus-TNBC: A Study Evaluating the Efficacy and Safety of Multiple Treatment Combinations in Patients With Metastatic or Locally Advanced Breast Cancer (clinicaltrials.gov) - P1/2 | N=242 | Active, not recruiting | Sponsor: Hoffmann-La Roche | N=133 ➔ 242 | Trial completion date: May 2024 ➔ May 2026 | Trial primary completion date: May 2024 ➔ May 2026

Enrollment change • Metastases • Trial completion date • Trial primary completion date • Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • HER-2 • PD-L1 • PIK3CA

[VIRTUAL] Phase Ib/II open-label, randomized evaluation of atezolizumab (atezo) + selicrelumab (seli) + gemcitabine+nab-paclitaxel (gem+nabP) or bevacizumab (bev) vs control in MORPHEUS-PDAC, -TNBC and -CRC (SITC 2020) - P1/2 | "Control treatments were gem+nabP in PDAC, capecitabine in TNBC, and regorafenib in CRC. Preliminary efficacy was observed for atezo+seli+gem+nabP in PDAC. Together with preliminary evidence of on-treatment pharmacodynamic effects in CRC and TNBC tumor samples, CD40 agonist strategies warrant further investigation."

Clinical • IO biomarker • P1/2 data • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Triple Negative Breast Cancer • CD8

[VIRTUAL] Phase Ib Study of Selicrelumab (CD40 agonist) in Combination with Atezolizumab (anti-PD-L1) in Patients with Advanced Solid Tumors (SITC 2020) - P1 | "Signals of clinical and PD activity were observed. However, efficacy of the combination in this unselected population was limited, when compared to monotherapy efficacy of atezolizumab."

Clinical • Combination therapy • P1 data • Colorectal Cancer • Gastrointestinal Cancer • Head and Neck Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • CD8

Morpheus-TNBC: A Study Evaluating the Efficacy and Safety of Multiple Immunotherapy-Based Treatment Combinations in Patients With Metastatic or Inoperable Locally Advanced Triple-Negative Breast Cancer (clinicaltrials.gov) - P1/2 | N=133 | Active, not recruiting | Sponsor: Hoffmann-La Roche | N=280 ➔ 133

Enrollment change • Metastases • Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • HER-2 • PD-L1

A Study Evaluating the Efficacy and Safety of Multiple Immunotherapy-Based Treatment Combinations in Patients With Metastatic Colorectal Cancer (Morpheus-CRC) (clinicaltrials.gov) - P1/2 | N=94 | Terminated | Sponsor: Hoffmann-La Roche | Trial completion date: Dec 2022 ➔ Sep 2022 | Active, not recruiting ➔ Terminated | Trial primary completion date: Dec 2022 ➔ Sep 2022; The Sponsor made the decision to terminate the study due to start up and recruitment issues caused by limited resource availability at the treating centers.

Trial completion date • Trial primary completion date • Trial termination • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

Morpheus-TNBC: A Study Evaluating the Efficacy and Safety of Multiple Immunotherapy-Based Treatment Combinations in Patients With Metastatic or Inoperable Locally Advanced Triple-Negative Breast Cancer (clinicaltrials.gov) - P1/2 | N=280 | Active, not recruiting | Sponsor: Hoffmann-La Roche | Recruiting ➔ Active, not recruiting | Trial completion date: Sep 2023 ➔ May 2024 | Trial primary completion date: Sep 2023 ➔ May 2024

Enrollment closed • Trial completion date • Trial primary completion date • Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • HER-2 • PD-L1

A Study Evaluating the Efficacy and Safety of Multiple Immunotherapy-Based Treatment Combinations in Patients With Metastatic Colorectal Cancer (Morpheus-CRC) (clinicaltrials.gov) - P1/2 | N=94 | Active, not recruiting | Sponsor: Hoffmann-La Roche | Recruiting ➔ Active, not recruiting | N=382 ➔ 94 | Trial completion date: Nov 2023 ➔ Dec 2022 | Trial primary completion date: May 2023 ➔ Dec 2022

Enrollment change • Enrollment closed • Trial completion date • Trial primary completion date • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

Study of Neo-adjuvant RO7009789 Alone or Neo-adjuvant RO7009789 Plus Nab-Paclitaxel and Gemcitabine Followed by Adjuvant RO7009789 Plus Nab-Paclitaxel and Gemcitabine for Patients With Newly Diagnosed Resectable Pancreatic Carcinoma (clinicaltrials.gov) - P1 | N=19 | Completed | Sponsor: Abramson Cancer Center of the University of Pennsylvania | N=10 ➔ 19

Enrollment change • Gastrointestinal Cancer • Hepatology • Immune Modulation • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor

Morpheus-TNBC: A Study Evaluating the Efficacy and Safety of Multiple Immunotherapy-Based Treatment Combinations in Patients With Metastatic or Inoperable Locally Advanced Triple-Negative Breast Cancer (clinicaltrials.gov) - P1/2 | N=280 | Recruiting | Sponsor: Hoffmann-La Roche | Trial completion date: Mar 2023 ➔ Sep 2023 | Trial primary completion date: Mar 2023 ➔ Sep 2023

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

MORPHEUS-PDAC: A Study of Multiple Immunotherapy-Based Treatment Combinations in Participants With Metastatic Pancreatic Ductal Adenocarcinoma (Morpheus-Pancreatic Cancer) (clinicaltrials.gov) - P1/2 | N=290 | Recruiting | Sponsor: Hoffmann-La Roche | Active, not recruiting ➔ Recruiting

Enrollment open • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • PD-L1

Neoadjuvant selicrelumab, an agonist CD40 antibody, induces changes in the tumor microenvironment in patients with resectable pancreatic cancer. (PubMed, Clin Cancer Res) - "This unparalleled examination of CD40 therapeutic mechanisms in patients provides insights for design of subsequent clinical trials targeting this pathway."

Biomarker • Clinical • Journal • Tumor microenvironment • Fibrosis • Gastrointestinal Cancer • Hepatology • Immune Modulation • Immunology • Inflammation • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CCL2 • CCL22 • CD40 • CXCL10

YH008, a PD-1-CD40 bispecific antibody, inhibits tumor growth in vivo through PD-1-dependent activation of CD40 signaling (AACR 2022) - "Furthermore, YH008 showed a superior liver toxicity profile compared to a selicrelumab analog...Similarly, no significant adverse events were observed in a cynomolgus dose-escalation study. YH008 is currently in pre-clinical development with anticipated IND application in 2022."

IO biomarker • Preclinical • Oncology • CD40 • CD8

Prediction of pharmacokinetics and receptor occupancy of a bispecific antibody against CD40 and PD-L1 (AACR 2022) - "Optimal dose of YH008 was selected on the basis of maximal exposure/area under curve (AUC) of the trimers in ISs between APCs and CD8+ T cells in the tumor. Model simulations show good agreement with the experimental PK and RO data for monospecific mAbs against PD1 (Pembrolizumab) and CD40 (Selicrelumab, BI 655064). The PBPK/RO model for a bispecific mAb based on physiological levels of immune cells, target molecule expression, and binding parameters for YH008 antibody against CD40 and PD1 predicts PK and RO in peripheral blood and tumor. The model shows that competition for CD40 binding site between the mAb and CD40L does not significantly affect PK and RO. The optimal dose for maximal effect of YH008 was estimated."

IO biomarker • PK/PD data • Oncology • CD40 • CD40LG • CD8 • PD-L1

The development of an Adaptable Drug Affinity Conjugate (ADAC) targeting CD40 for a flexible therapeutic peptide cargo delivery to dendritic cells (AACR 2022) - "Similar to selicrelumab, STRIKE-1001 does not block CD40L binding to Fc-CD40. STRIKE-1001 shows a dose-dependent agonistic activity (EC50 of ~28 nM based on measured induction of HLA-DR expression) on human DCs and can be designed into a bispecific antibody without loss of agonistic activity. STRIKE-1001 is currently incorporated into the ADAC platform to be used as the first-in-class candidate for flexible peptide cargo delivery ensuring T cell priming and expansion in vivo as a means to transform CD40 agonistic antibody to clinically relevant drug candidates."

IO biomarker • Oncology • CD40 • CD40LG

MORPHEUS-PDAC: A Study of Multiple Immunotherapy-Based Treatment Combinations in Participants With Metastatic Pancreatic Ductal Adenocarcinoma (Morpheus-Pancreatic Cancer) (clinicaltrials.gov) - P1/2 | N=290 | Active, not recruiting | Sponsor: Hoffmann-La Roche | Trial completion date: Nov 2022 ➔ Jun 2024 | Trial primary completion date: Nov 2022 ➔ Jun 2024

Trial completion date • Trial primary completion date • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • PD-L1