CB-103

P2, N=2, Terminated, M.D. Anderson Cancer Center | N=30 --> 2 | Trial completion date: Jul 2026 --> Aug 2024 | Recruiting --> Terminated | Trial primary completion date: Jul 2026 --> Aug 2024; The sponsor requested termination due to internal reprioritization of resources.

P1/2, N=34, Recruiting, Glenn J. Hanna | Trial primary completion date: Jun 2024 --> Jun 2025

P2, N=2, Terminated, MedSIR | N=80 --> 2 | Active, not recruiting --> Terminated; Sponsor decision

Peripheral downregulation of select Notch target gene levels was observed with escalating doses. Future studies exploring CB-103 should enrich for patients with NOTCH-mutant ACC and investigate rational combinatorial approaches in tumors where there is limited success with investigational or approved drugs.

Here, we present the growth- and differentiation-modulating effects of various "next generation" small molecule Notch modulators represented by RIN-1, and CB-103, on HNSCC, compared to gamma secretase inhibitors as "conventional" NOTCH interfering compounds, like DAPT...In contrast, RIN-1 treatment resulted in inhibition of Notch signalling and the growth of HNSCC spheroids under non-adherent cell culture conditions. Our results suggest that modulation of Notch signalling could be used as a chemotherapeutic agent in selected patients with intact NOTCH signaling.

our data indicate that CB-103 is an attractive candidate for clinical investigation in endocrine-resistant, recurrent breast cancers with biomarker-confirmed Notch activity in combination with SERDs and/or CDKis and in TNBCs with biomarker-confirmed Notch activity in combination with taxane-containing chemotherapy regimens.

P1/2, N=34, Recruiting, Glenn J. Hanna | Not yet recruiting --> Recruiting

We identified a frequent, unexpected pL1575P_c4724T_C NOTCH1 mutation as a new biomarker for ccRCC metastases, predictive of response to the CB103 NOTCH1-intracellular domain inhibitor.

P2, N=30, Recruiting, M.D. Anderson Cancer Center | Not yet recruiting --> Recruiting | Initiation date: Dec 2023 --> Apr 2023

P1/2, N=34, Not yet recruiting, Glenn J. Hanna

P2, N=30, Not yet recruiting, M.D. Anderson Cancer Center | Initiation date: Dec 2022 --> Dec 2023

P1/2, N=79, Terminated, Cellestia Biotech AG | N=200 --> 79 | Recruiting --> Terminated; business reason

P2, N=30, Not yet recruiting, M.D. Anderson Cancer Center

P1/2, N=200, Recruiting, Cellestia Biotech AG | Trial completion date: Dec 2021 --> Dec 2022 | Trial primary completion date: Dec 2021 --> Oct 2022

P2, N=80, Active, not recruiting, MedSIR | Recruiting --> Active, not recruiting

Various dysregulated pathways converge to produce an overarching stimulation of nuclear factor κB (NF-κB) and the MYD88-IRAK4 axis, which can be thus leveraged or targeting B-cell receptor signaling through BTK inhibitors (such as ibrutinib, zanubrutinib, acalabrutinib) and PI3K inhibitors (such as idelalisib, copanlisib, duvelisib umbralisib) or via more novel agents in development such as MALT1 inhibitors, SMAC mimetics, NIK inhibitors, IRAK4 or MYD88 inhibitors. NOTCH signaling is also crucial for marginal zone cells, but no clinical data are available with NOTCH inhibitors such as the γ-secretase inhibitor PF-03084014 or the NICD inhibitor CB-103. The hypermethylation phenotype, the overexpression of the PRC2-complex or the presence of TET2 mutations reported in MZL subsets make epigenetic agents (demethylating agents, EZH2 inhibitors, HDAC inhibitors) also potential therapeutic tools for MZL patients.

P2, N=80, Recruiting, MedSIR | Not yet recruiting --> Recruiting | Initiation date: Jan 2021 --> Apr 2021

P2, N=80, Not yet recruiting, MedSIR

P1/2, N=165, Recruiting, Cellestia Biotech AG | Trial completion date: Jun 2021 --> Dec 2021 | Trial primary completion date: Jun 2021 --> Dec 2021

Funding: Cellestia Biotech AG. Clinical trial identification: NCT03422679.