GSK3174998 / GSK - LARVOL DELTA

DREAMM 5: Platform Study of Belantamab Mafodotin as Monotherapy and in Combination With Anti-cancer Treatments in Participants With Relapsed/Refractory Multiple Myeloma (RRMM) (clinicaltrials.gov) - P2 | N=208 | Active, not recruiting | Sponsor: GlaxoSmithKline | Trial completion date: Feb 2029 ➔ Mar 2027 | Trial primary completion date: Feb 2029 ➔ Apr 2025

Monotherapy • Trial completion date • Trial primary completion date • Hematological Malignancies • Multiple Myeloma • Oncology

DREAMM 5: Platform Study of Belantamab Mafodotin as Monotherapy and in Combination With Anti-cancer Treatments in Participants With Relapsed/Refractory Multiple Myeloma (RRMM) (clinicaltrials.gov) - P2 | N=209 | Active, not recruiting | Sponsor: GlaxoSmithKline | Recruiting ➔ Active, not recruiting | Phase classification: P1/2 ➔ P2 | N=464 ➔ 209 | Trial primary completion date: Feb 2026 ➔ Feb 2029

Enrollment change • Enrollment closed • Monotherapy • Phase classification • Trial primary completion date • Hematological Malignancies • Multiple Myeloma • Oncology

Impact of isotype on the mechanism of action of agonist anti-OX40 antibodies in cancer: implications for therapeutic combinations. (PubMed, J Immunother Cancer) - "These findings underline the importance of understanding the role of isotype in the mechanism of action of therapeutic mAbs. As an hIgG1, the anti-hOX40 mAb can elicit multiple mechanisms of action that could aid or hinder therapeutic outcomes, dependent on the microenvironment. This should be considered when designing potential combinatorial partners and their FcγR requirements to achieve maximal benefit and improvement of patient outcomes."

Journal • Oncology

Platform Sub-study of Belantamab Mafodotin (GSK2857916) in Combination With aOX40 (GSK3174998) in Participants With RRMM (clinicaltrials.gov) - P1/2 | N=9 | Terminated | Sponsor: GlaxoSmithKline

Combination therapy • Monotherapy • New P1/2 trial • Hematological Malignancies • Multiple Myeloma • Oncology

DREAMM 5: Platform Study of Belantamab Mafodotin as Monotherapy and in Combination With Anti-cancer Treatments in Participants With Relapsed/Refractory Multiple Myeloma (RRMM) (clinicaltrials.gov) - P1/2 | N=464 | Recruiting | Sponsor: GlaxoSmithKline | Trial completion date: Feb 2028 ➔ Feb 2029 | Trial primary completion date: Feb 2025 ➔ Feb 2026

Combination therapy • Monotherapy • Trial completion date • Trial primary completion date • Hematological Malignancies • Multiple Myeloma • Oncology

Dose Escalation and Expansion Study of GSK3359609 in Participants With Selected Advanced Solid Tumors (INDUCE-1) (clinicaltrials.gov) - P1 | N=829 | Completed | Sponsor: GlaxoSmithKline | Active, not recruiting ➔ Completed

Combination therapy • Metastases • Trial completion • Esophageal Cancer • Head and Neck Cancer • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • ICOS • MSI

First-in-human phase I study of the OX40 agonist GSK3174998 with or without pembrolizumab in patients with selected advanced solid tumors (ENGAGE-1). (PubMed, J Immunother Cancer) - P1 | "GSK3174998±pembrolizumab was well tolerated over the dose range tested and demonstrated target engagement. Limited clinical activity does not support further development of GSK3174998±pembrolizumab in advanced cancers."

IO biomarker • Journal • Metastases • P1 data • Cardiovascular • Fatigue • Immune Modulation • Oncology • Respiratory Diseases • Solid Tumor • CD4 • CD8 • FOXP3 • GZMB • NCAM1 • PD-1

First-in-human phase I study of the OX40 agonist GSK3174998 with or without pembrolizumab in patients with selected advanced solid tumors (ENGAGE-1) (J Immunother Cancer) - P1 | N=141 | ENGAGE-1 (NCT02528357) | Sponsor: GlaxoSmithKline | "138 patients were enrolled (45 (P1) and 96 (P2, including 3 crossovers)). Treatment-related adverse events occurred in 51% (P1) and 64% (P2) of patients, fatigue being the most common (11% and 24%, respectively)....GSK3174998 ≥0.3 mg/kg demonstrated pharmacokinetic linearity and >80% receptor occupancy on circulating T cells; 0.3 mg/kg was selected for further evaluation. Limited clinical activity was observed for GSK3174998 (P1: disease control rate (DCR) ≥24 weeks 9%) and was not greater than that expected for pembrolizumab alone (P2: overall response rate 8%, DCR ≥24 weeks 28%)."

P1 data • Oncology • Solid Tumor

A phase I, open-label study of GSK1795091 administered in combination with immunotherapies in participants with advanced solid tumours (NCT03447314) (ESMO 2019) - P1; "The current study will evaluate GSK1795091 with immunotherapies that have highly complementary mechanisms of action and supporting preclinical data (e.g. GSK3174998 [an OX40 agonist], GSK3359609 [an ICOS agonist], or pembrolizumab [a PD-1 inhibitor]) with the aim of generating greater antitumor activity than with monotherapy. Legal entity responsible for the study: GlaxoSmithKline. Funding: GlaxoSmithKline."

Clinical • Combination therapy • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck

DREAMM-5 platform trial: Belantamab Mafodotin (GSK2857916; belamaf; BLENREP) in combination with five different novel agents in patients (Pts) with Relapsed/ Refractory Multiple Myeloma (RRMM) (DGHO 2021) - P1/2 | "Sub-study 1 (combination with GSK3174998, OX40 agonist Ab) is closed to enrolment. Sub-studies 2 (combination with GSK3359609, feladilimab, ICOS agonist), 3 (combination with nirogacestat [PF-03084014; SpringWorks Therapeutics], gamma-secretase inhibitor), and 4 (combination with dostarlimab, PD-1 antagonist) are open to enrolment...Nirogacestat and isatuximab produced by and used in collaboration with SpringWorks Therapeutics and Sanofi, respectively. Encore Statement: Presented at 26th Congress of the European Hematology Association (Richardson et al, 2021); submitted with permission of original authors."

Clinical • Combination therapy • IO biomarker • Hematological Disorders • Hematological Malignancies • Immune Modulation • Inflammation • Multiple Myeloma • Oncology • ICOS • PD-1

[VIRTUAL] Dreamm-5 Platform Trial: Belantamab Mafodotin (Belamaf) in Combination with Four Different Novel Agents in Patients with Relapsed/Refractory Multiple Myeloma (RRMM) (ASH 2020) - P2 | "Substudies 1 (combination with GSK3174998, OX40 agonist antibody), 2 (combination with GSK3359609, ICOS agonist antibody), and 3 (combination with nirogacestat [PF-03084014; SpringWorks Therapeutics], gamma-secretase inhibitor) are currently open to enrollment. Substudy 4 (combination with dostarlimab; PD-1 antagonist antibody) is under review...Funding: GSK (Study 208887); belamaf drug linker technology licensed from Seattle Genetics; belamaf monoclonal antibody produced using POTELLIGENT Technology licensed from BioWa; nirogacestat gamma-secretase inhibitor produced by and used in collaboration with SpringWorks Therapeutics. Figure: DREAMM-5 study design"

Clinical • Combination therapy • Hematological Malignancies • Immune Modulation • Inflammation • Multiple Myeloma • Oncology • CD38 • ICOS

Manufacturing-dependent change in biological activity of the TLR4 agonist GSK1795091 and implications for lipid A analog development. (PubMed, Clin Transl Sci) - P1 | "A phase I trial (NCT03447314; 204686) evaluated the safety and efficacy of GSK1795091, a Toll-like receptor 4 (TLR4) agonist, in combination with immunotherapy (GSK3174998 [anti-OX40 monoclonal antibody], GSK3359609 [anti-ICOS monoclonal antibody], or pembrolizumab) in patients with solid tumors. Structural characterization revealed GSK1795091 aggregate size in the modified formulation to be twice that in the original formulation, suggesting a negative correlation between GSK1795091 aggregate size and PD activity. This may have important clinical implications for future development of structurally similar compounds."

Journal • Fatigue • Oncology • Solid Tumor • IL10 • IL1R1 • TLR4

Platform Study of Belantamab Mafodotin as Monotherapy and in Combination With Anti-cancer Treatments in Participants With Relapsed/Refractory Multiple Myeloma (RRMM) (DREAMM 5) (clinicaltrials.gov) - P1/2; N=464; Recruiting; Sponsor: GlaxoSmithKline; Phase classification: P2 ➔ P1/2

Clinical • Combination therapy • Monotherapy • Phase classification • Hematological Malignancies • Multiple Myeloma • Oncology

Belantamab mafodotin in combination with novel agents in relapsed/refractory multiple myeloma: DREAMM-5 study design. (PubMed, Future Oncol) - P2 | "Belantamab mafodotin (belamaf) is a BCMA-targeted antibody-drug conjugate recently approved as monotherapy for adults with relapsed/refractory multiple myeloma who have received ≥4 prior therapies. Here, we describe the rationale and design of DREAMM-5, an ongoing Phase I/II platform study evaluating the safety and efficacy of belamaf combined with novel agents, including GSK3174998 (OX40 agonist), feladilimab (an ICOS; GSK3359609), nirogacestat (a gamma-secretase inhibitor; PF-03084014) and dostarlimab (a PD-1 blocker) versus belamaf monotherapy for patients with relapsed/refractory multiple myeloma. Clinical trial registration: NCT04126200 (ClinicalTrials.gov)."

Combination therapy • Journal • Hematological Malignancies • Immune Modulation • Inflammation • Multiple Myeloma • Oncology

Study of a Combination of GSK1795091 and Immunotherapies in Subjects With Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=54 | Completed | Sponsor: GlaxoSmithKline | Active, not recruiting ➔ Completed

Trial completion • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • CRP

[VIRTUAL] DREAMM-5 platform trial: Belantamab mafodotin (belamaf; GSK2857916) in combination with five different novel agents in patients with relapsed/refractory multiple myeloma (RRMM) (IMW 2021) - P1/2, P2 | "Sub-study 1 (combination with GSK3174998, OX40 agonist antibody) is no longer open to enrollment. Sub-studies 2 (combination with GSK3359609, feladilimab, anti-ICOS agonist), 3 (combination with nirogacestat [PF-03084014; SpringWorks Therapeutics], gamma-secretase inhibitor), and 4 (combination with dostarlimab, PD-1 antagonist antibody) are currently open to enrollment...Nirogacestat and isatuximab produced by and used in collaboration with SpringWorks Therapeutics and Sanofi, respectively...Reused with permission. This abstract was accepted and previously presented at the 2021 EHA Annual Meeting."

Clinical • Combination therapy • IO biomarker • Hematological Disorders • Hematological Malignancies • Immune Modulation • Inflammation • Multiple Myeloma • Oncology

[VIRTUAL] DREAMM-5 platform trial: Belantamab mafodotin in combination with novel agents in patients with relapsed/refractory multiple myeloma (RRMM). (ASCO 2020) - P2, P3 | "Sub-studies 1 (combination with GSK3174998, OX40 agonist antibody) and 2 (combination with GSK3359609, ICOS agonist antibody) are currently enrolling. Sub-study 3 (combination with nirogacestat [PF-03084014; SpringWorks Therapeutics]) is projected to begin enrollment in the first half of 2020...Drug linker technology licensed from Seattle Genetics; monoclonal antibody produced using POTELLIGENT Technology licensed from BioWa. Research Funding: GlaxoSmithKline"

Clinical • Combination therapy • Hematological Disorders • Hematological Malignancies • Immune Modulation • Inflammation • Multiple Myeloma • Oncology • CD38 • TNFRSF4

[VIRTUAL] A first-in-human phase I study of the OX40 agonist GSK3174998 (GSK998) +/- pembrolizumab in patients (Pts) with selected advanced solid tumors (ENGAGE-1) (AACR-I 2020) - P1 | "GSK998 +/- pembrolizumab was well tolerated, with evidence of target engagement; monotherapy clinical activity was limited. While combination responses may not be significantly greater than expected for pembrolizumab alone, responses were observed in some PD-1/L1 experienced pts and some with low PD-L1 expression. Given the low OX40 expression observed and preclinical evidence that increased expression improves activity of OX40 agonism, ongoing clinical evaluation of GSK998 will assess whether concurrent immune-stimulation or immunogenic cell death impacts OX40 expression and increases the efficacy of this agent."

Clinical • IO Biomarker • P1 data • Bladder Cancer • Breast Cancer • Colorectal Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Head and Neck Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Renal Cell Carcinoma • Sarcoma • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • Thoracic Cancer • Triple Negative Breast Cancer • Urothelial Cancer • PD-L1 • TLR4 • TNFRSF4

[VIRTUAL] DREAMM-5 PLATFORM TRIAL: BELANTAMAB MAFODOTIN (BELAMAF) IN COMBINATION WITH FIVE DIFFERENT NOVEL AGENTS IN PATIENTS WITH RELAPSED/REFRACTORY MULTIPLE MYELOMA (RRMM) (EHA 2021) - P1/2, P2 | "Sub-study 1 (combination with GSK3174998, OX40 agonist antibody) is no longer open to enrollment. Sub-studies 2 (combination with GSK3359609, feladilimab, anti-ICOS agonist), 3 (combination with nirogacestat [PF-03084014; SpringWorks Therapeutics], gamma-secretase inhibitor), and 4 (combination with dostarlimab, PD-1 antagonist antibody) are currently open to enrollment...Conclusion . Funding: GSK (Study 208887, NCT04126200); belamaf drug linker technology licensed from Seagen Inc; belamaf monoclonal antibody produced using POTELLIGENT Technology licensed from BioWa; nirogacestat gamma-secretase inhibitor produced by and used in collaboration with SpringWorks Therapeutics and isatuximab produced by and used in collaboration with Sanofi."

Clinical • Combination therapy • IO biomarker • Hematological Malignancies • Immune Modulation • Inflammation • Multiple Myeloma • Oncology

[VIRTUAL] DREAMM-5 PLATFORM TRIAL: BELANTAMAB MAFODOTIN IN COMBINATION WITH NOVEL AGENTS IN PATIENTS WITH RELAPSED/REFRACTORY MULTIPLE MYELOMA (RRMM) (EHA 2020) - P2 | "Sub-studies 1 (combination with GSK3174998, OX40 agonist antibody) and 2 (combination with GSK3359609, ICOS agonist antibody) are currently enrolling. Sub-study 3 (combination with nirogacestat [PF-03084014; SpringWorks Therapeutics]) is projected to begin enrollment in the first half of 2020...Results - Conclusion - Funding: GlaxoSmithKline (208887). Drug linker technology licensed from Seattle Genetics; monoclonal antibody produced using POTELLIGENT Technology licensed from BioWa."

Clinical • Combination therapy • Hematological Disorders • Hematological Malignancies • Immune Modulation • Inflammation • Multiple Myeloma • Oncology • CD38 • TNFRSF4

Dose Escalation and Expansion Study of GSK3359609 in Participants With Selected Advanced Solid Tumors (INDUCE-1) (clinicaltrials.gov) - P1; N=828; Active, not recruiting; Sponsor: GlaxoSmithKline; Recruiting ➔ Active, not recruiting; Trial completion date: Dec 2024 ➔ Jun 2023; Trial primary completion date: Dec 2024 ➔ Jun 2023

Clinical • Combination therapy • Enrollment closed • Trial completion date • Trial primary completion date • Esophageal Cancer • Head and Neck Cancer • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • ICOS • MSI

Dose Escalation and Expansion Study of GSK3359609 in Participants With Selected Advanced Solid Tumors (INDUCE-1) (clinicaltrials.gov) - P1; N=500; Recruiting; Sponsor: GlaxoSmithKline; Trial completion date: May 2020 ➔ Dec 2022; Trial primary completion date: May 2020 ➔ Dec 2022

Clinical • Combination therapy • Trial completion date • Trial primary completion date • Esophageal Cancer • Head and Neck Cancer • Immune Modulation • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • Thoracic Cancer • ICOS • MSI

Dose Escalation and Expansion Study of GSK3359609 in Participants With Selected Advanced Solid Tumors (INDUCE-1) (clinicaltrials.gov) - P1; N=304; Recruiting; Sponsor: GlaxoSmithKline; Trial primary completion date: Jun 2019 ➔ May 2020; Trial completion date: Jun 2019 ➔ May 2020; Initiation date: Jun 2016 ➔ Jun 2016

Clinical • Combination therapy • Trial completion date • Trial initiation date • Trial primary completion date • Esophageal Cancer • Head and Neck Cancer • Immune Modulation • Melanoma • Non Small Cell Lung Cancer • Squamous Cell Carcinoma of Head and Neck • ICOS • MSI

Dose Escalation and Expansion Study of GSK3359609 in Participants With Selected Advanced Solid Tumors (INDUCE-1) (clinicaltrials.gov) - P1; N=500; Recruiting; Sponsor: GlaxoSmithKline; N=304 ➔ 500

Clinical • Combination therapy • Enrollment change • Esophageal Cancer • Head and Neck Cancer • Immune Modulation • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • ICOS • MSI

Dose Escalation and Expansion Study of GSK3359609 in Participants With Selected Advanced Solid Tumors (INDUCE-1) (clinicaltrials.gov) - P1; N=873; Recruiting; Sponsor: GlaxoSmithKline; Trial completion date: Dec 2022 ➔ Dec 2024; Trial primary completion date: Dec 2022 ➔ Dec 2024

Clinical • Combination therapy • Trial completion date • Trial primary completion date • Esophageal Cancer • Head and Neck Cancer • Immune Modulation • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • ICOS • MSI