P1/2, N=222, Terminated, Kymab Limited | Active, not recruiting --> Terminated; Early discontinuation based on strategic sponsor decision not driven by any safety concerns.

P3, N=117, Terminated, GlaxoSmithKline | Phase classification: P2/3 --> P3

P3, N=315, Terminated, GlaxoSmithKline | Phase classification: P2/3 --> P3

P1/2, N=4, Terminated, Jounce Therapeutics, Inc. | Completed --> Terminated; Sponsor decision to discontinue providing study drug to patients who have been on study treatment for more than two years

P2, N=69, Terminated, Jounce Therapeutics, Inc. | Active, not recruiting --> Terminated; The Sponsor decided to discontinue development of pimivalimab prior to the planned study completion. At the time of the decision to discontinue development, enrollment in the study had been completed.

P1/2, N=280, Active, not recruiting, Kymab Limited | Trial completion date: Apr 2024 --> Aug 2024 | Trial primary completion date: Apr 2024 --> Aug 2024

P2, N=69, Active, not recruiting, Jounce Therapeutics, Inc. | Trial primary completion date: Sep 2022 --> May 2024

P2/3, N=118, Terminated, GlaxoSmithKline | Active, not recruiting --> Terminated; The trial was stopped by the sponsor based on assessment of the clinical data

P1/2, N=280, Active, not recruiting, Kymab Limited | Trial completion date: Nov 2024 --> Apr 2024 | Trial primary completion date: Nov 2024 --> Apr 2024

P2/3, N=315, Terminated, GlaxoSmithKline | Active, not recruiting --> Terminated; The trial was stopped by the sponsor based on assessment of the clinical data

In addition to nonclinical evaluation, we present three patient case studies from a first-time-in-human, phase I, open-label, dose-escalation and dose-expansion clinical trial (INDUCE-1; ClinicalTrials.gov: NCT02723955), evaluating feladilimab alone and in combination with pembrolizumab in patients with advanced solid tumors. Additional work is needed to further validate the translation to the clinic, which includes identifying select patient populations that will benefit from this therapeutic approach, and randomized data with survival endpoints to illustrate its potential, similar to that shown with CTLA-4 and PD-1 blocking antibodies. Stimulation of the T-cell activation marker ICOS with the anti-ICOS agonist mAb feladilimab, alone and in combination with PD-1 inhibition, induces antitumor activity across nonclinical models as well as select patients with advanced solid tumors.

P1/2, N=280, Active, not recruiting, Kymab Limited | Recruiting --> Active, not recruiting

P1; Active, not recruiting --> Completed

P2, N=69, Active, not recruiting, Jounce Therapeutics, Inc. | Trial completion date: Mar 2023 --> May 2024

However, with larger numbers of DEL cases available in mRNA-based measurement cohorts, there was a statistically significant stratification for PFS (GSE117556: OS, p = 0.084, PFS, p = 0.031; GOYA: OS, p = 0.065, PFS, p = 0.047), suggesting that the following formula refines the current DEL definition and improves its prognostic value: Using a pan-immune protein-marker DSP panel, we identified that the T-cell immune regulators ICOS and 4-1BB were negatively correlated with M+2+6- percentage extent (r = −0.27, p = 0.0046; r = −0.22, p = 0.019, respectively), suggesting a potential role for ICOS or 4-1BB stimulatory therapeutics (e.g. feladilimab, utomilumab) in combination with chemotherapy for high M+2+6- cases. A simple mathematical formula for estimation of MYC+BCL2+BCL6- cells in DLBCL refines the DEL diagnosis, and could be of value in selecting high risk DLBCL for trials of novel agents. High M+2+6- DLBCL display unique T-cell infiltrates, and immunomodulation by ICOS and 4-1BB agonists could represent a therapeutic vulnerability for this high-risk subgroup.

P1/2, N=80, Terminated, Bristol-Myers Squibb | Completed --> Terminated; Study CA021-002 was terminated because the Sponsor discontinued further development of BMS-986226 due to a change in business objectives. The decision for the study closure was not related to any safety concerns associated with BMS-986226.

Our findings support a model wherein ICOSaa administration induces IL-10 expression to facilitate neuropathic pain relief in female mice. ICOSaa treatment is in clinical development for solid tumors and given our observation of T cells in the human DRG, ICOSaa therapy could be developed for combination chemotherapy-CIPN clinical trials.

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.

To our knowledge, this is the first detailed description of the use of a novel immune-PET imaging technique to assess the kinetics of CD8 T-cell infiltration into tumor and lymphoid tissues following ICOS agonist and PD-1 blocking antibody therapy. By demonstrating the capacity for increased spatial and temporal resolution of CD8 T-cell infiltration across tumors and lymphoid tissues, these observations underscore the widespread potential clinical utility of non-invasive PET imaging for T-cell-based immunotherapy in cancer.

P2, N=105, Completed, GlaxoSmithKline

P1/2, N=280, Recruiting, Kymab Limited | N=412 --> 280 | Trial completion date: May 2023 --> Nov 2024 | Trial primary completion date: May 2023 --> Nov 2024

Finally, we demonstrate in a poorly immunogenic pancreatic tumor model which is resistant to combined radiation and anti-PD1 checkpoint blockade that the addition of this novel ICOS agonist antibody to the treatment regimen results in tumor control. These findings identify ICOS as part of a T cell pathway that is modulated by radiation and targeting this pathway with a novel ICOS antibody results in durable tumor control in preclinical models.

Vopratelimab demonstrated a favorable safety profile alone and in combination with nivolumab. Efficacy was observed only in a subset of patients with a vopratelimab-specific pharmacodynamic biomarker. A potential predictive biomarker of response was identified, which is being prospectively evaluated in a randomized Phase 2 non-small cell lung cancer trial.

P1, N=54, Completed, GlaxoSmithKline | Active, not recruiting --> Completed

P2, N=185, Recruiting, GlaxoSmithKline | N=140 --> 185 | Trial completion date: Jun 2024 --> Jul 2025 | Trial primary completion date: Jun 2024 --> Jul 2025

P2, N=140, Recruiting, GlaxoSmithKline | N=341 --> 140 | Trial completion date: Mar 2025 --> Jun 2024 | Trial primary completion date: Mar 2025 --> Jun 2024

In this substudy, belamaf is combined with feladilimab (GSK3359609), an inducible co-stimulatory T-cell molecule (ICOS, CD278) agonist (aICOS). A total of 23 patients treated with belamaf + aICOS were included in this preliminary analysis. The median (range) of prior lines of therapy was 5 (3–10). The majority of patients (21 [91%]) had an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0–1 and the remainder (2 [9%]) had an ECOG PS of 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.

P1, N=828, Active, not recruiting, GlaxoSmithKline | Recruiting --> Active, not recruiting | Trial completion date: Dec 2024 --> Jun 2023 | Trial primary completion date: Dec 2024 --> Jun 2023

P2/3, N=314, Active, not recruiting, GlaxoSmithKline | Recruiting --> Active, not recruiting | Phase classification: P3 --> P2/3 | N=600 --> 314 | Trial completion date: Jul 2023 --> Apr 2023 | Trial primary completion date: Jul 2023 --> Apr 2021

P2/3, N=118, Active, not recruiting, GlaxoSmithKline | Recruiting --> Active, not recruiting | Phase classification: P3 --> P2/3 | N=640 --> 118 | Trial completion date: Mar 2024 --> May 2023 | Trial primary completion date: Mar 2024 --> Apr 2021

Fela is the first ICOS agonist with reported single-agent activity in anti-PD-1/L1–exp relapsed/refractory UC . Fela + P in combo shows promising clinical activity and manageable safety in PD-1/L1–naïve R/M UC . Further study is warranted .

The preliminary efficacy of vopratelimab +/- nivolumab was assessed in the phase 1/2 ICONIC study in which durable responses were observed in a subset of patients who demonstrated on treatment emergence of peripheral ICOS hi CD4 T effector cells . Secondary endpoints include ORR and PFS according to RECIST v1.1, OS, safety, and association of baseline TIS score with clinical outcomes . The study has a target enrollment goal of approximately 75 patients; the first patient was dosed October 2020.

To support ongoing and future clinical studies for feladilimab (GSK3359609), a non-depleting IgG4 ICOS agonist antibody currently being evaluated in pivotal clinical trials, we conducted a series of in vivo studies using a rodent surrogate (7E.17G9 mouse [m]IgG1; analogous non-depleting Fc) in ICOS-sensitive (EMT6 breast carcinoma) and ICOS-insensitive (CT26 colon carcinoma) tumor models...Collectively, these data support the combination of ICOS co-stimulation with different checkpoint immunotherapies (doublets and triplets), several of which are currently being evaluated in clinical studies. Moreover, these data demonstrate potential of ICOS co-stimulation with cytotoxic strategies, such as FRT - providing various dosing considerations and a framework future therapeutic intervention strategies.

FE is the first ICOS agonist with reported single-agent activity in ICB exp R/R melanoma, supporting ICOS as a target. FE + PE in combo shows promising clinical activity and manageable safety in R/R melanoma. Continued survival follow-up of ECs is warranted.

Overall, these data support the ongoing pivotal investigation of feladilimab. Moreover, this translational imaging method may be a useful tool to non-invasively monitor CD8+ T cell in response to immunotherapies and understand the temporal relationship between CD8+ T cell flux in tumor and in TDLN.

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).

No abstract available

No abstract available

P2, N=341, Recruiting, GlaxoSmithKline | Trial completion date: Jun 2024 --> Dec 2024 | Trial primary completion date: Jun 2024 --> Dec 2024

P2, N=341, Recruiting, GlaxoSmithKline | N=105 --> 341

A 69-year-old male with a history of successful chemoradiation for stage 4 HPV+ squamous cell carcinoma of the tongue developed secondary myelodysplastic syndrome that failed azacitidine. He received an 11/12 HLA-matched, unrelated peripheral blood stem cell graft after conditioning with fludarabine and melphalan, with neutrophil engraftment by day +28...The post-transplant course was complicated by severe mucositis, difficult oral intake and aspiration leading to PEG tube placement, and biopsy-confirmed lower intestinal tract GVHD diagnosed on day +54 that was refractory to 5 lines of therapy, including high dose methylprednisolone, budesonide and ruxolitinib...The course suggests that GVHD responded briskly to a single dose of ALPN-101 following failure of 5 lines of therapy, despite withdrawal of tacrolimus and an abrupt steroid taper, and prior to the potentially confounding addition of eculizumab. Dual inhibition of CD28 and ICOS, such as by ALPN-101, warrants further clinical study for the treatment and/or prevention of GVHD.