Ogsiveo (nirogacestat)

P2, N=40, Recruiting, M.D. Anderson Cancer Center | Active, not recruiting --> Recruiting

P3, N=142, Completed, SpringWorks Therapeutics, Inc. | Active, not recruiting --> Completed

Examples are the tyrosine kinase inhibitors avapritinib and ripretinib in gastrointestinal stromal tumours (GIST), the immune check point inhibitor atezolizumab in alveolar soft part tissue sarcoma, the γ-secretase inhibitor nirogacestat in desmoid tumours, the NTRK inhibitors larotrectinib and entrectinib in tumours with NTRK fusions, the mTOR inhibitor nab-sirolimus in PEComa, and the EZH-2 inhibitor tazemetostat in epithelioid sarcoma...The challenges in drug development in soft tissue sarcoma are due to the rarity and the molecular heterogeneity of the disease and the fact that many subtypes are associated with complex karyotypes or non-targetable molecular alterations. We believe that progress maybe possible with a better understanding of the complex biology, the development of novel compounds for difficult targets such as proteolysis targeting chimeras (Protacs), the utilisation of modern clinical trial designs, and enhanced collaboration of academia with industry to develop treatments with a strong biologic rationale.

P2, N=35, Active, not recruiting, Children's Oncology Group | Trial completion date: Dec 2024 --> Mar 2025 | Trial primary completion date: Dec 2024 --> Mar 2025

P2, N=209, Active, not recruiting, GlaxoSmithKline | Recruiting --> Active, not recruiting | Phase classification: P1/2 --> P2 | N=464 --> 209 | Trial primary completion date: Feb 2026 --> Feb 2029

P2, N=40, Active, not recruiting, M.D. Anderson Cancer Center | Not yet recruiting --> Active, not recruiting

Here we report the cryo-electron microscopy structures of human γ-secretase bound individually to five clinically tested GSIs (RO4929097, crenigacestat, BMS906024, nirogacestat and MK-0752) at overall resolutions of 2.4-3.0 Å. The size and shape of the binding pocket are induced by the bound GSI. Analysis of these structural features suggest strategies for modification of the GSI with improved inhibition potency.

Our findings support the Notch pathway as a druggable target in MPNSTs. Our identification of PRC2-regulated genes and pathways could result in more novel therapeutic approaches.

P1, N=9, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Recruiting --> Active, not recruiting | N=30 --> 9

Furthermore, we showed that pharmacological inhibition of γ-secretase with γ-secretase inhibitors (Nirogacestat and DAPT) can reverse Taxol resistance in vivo and in vitro. Our results for the first time demonstrate that the activation of γ -secretase/NCD-PXR/Notch pathway is one of important mechanisms to cause Taxol resistance in TNBC, and the blockades of this pathway may represent a new therapeutic strategy for overcoming Taxol resistance in TNBC.

P3, N=142, Active, not recruiting, SpringWorks Therapeutics, Inc. | Trial completion date: Dec 2023 --> Dec 2024

P1, N=317, Recruiting, Regeneron Pharmaceuticals | Trial completion date: Aug 2032 --> Jan 2033

P2, N=120, Recruiting, Pfizer | N=92 --> 120

P1, N=270, Recruiting, TeneoOne Inc. | Trial completion date: Nov 2028 --> Jul 2031

P1, N=140, Active, not recruiting, Janssen Research & Development, LLC | Trial primary completion date: Jun 2024 --> Oct 2024

P2, N=17, Completed, National Cancer Institute (NCI) | Active, not recruiting --> Completed

P2, N=92, Recruiting, Pfizer | Phase classification: P1b/2 --> P2 | Trial completion date: Sep 2027 --> Jun 2027 | Trial primary completion date: Mar 2025 --> Jul 2025

P2, N=53, Active, not recruiting, SpringWorks Therapeutics, Inc.

P2, N=40, Not yet recruiting, M.D. Anderson Cancer Center | Initiation date: Oct 2023 --> Oct 2024

P1, N=140, Active, not recruiting, Janssen Research & Development, LLC | Phase classification: P1b --> P1

P1, N=317, Recruiting, Regeneron Pharmaceuticals | Phase classification: P1b --> P1

P1/2, N=464, Recruiting, GlaxoSmithKline | Trial completion date: Feb 2028 --> Feb 2029 | Trial primary completion date: Feb 2025 --> Feb 2026

P1/2, N=36, Recruiting, Hellenic Society of Hematology | Not yet recruiting --> Recruiting

P2, N=17, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Sep 2024 --> Dec 2023

P1b, N=140, Active, not recruiting, Janssen Research & Development, LLC | Trial completion date: Jun 2024 --> Feb 2025

P1b/2, N=105, Recruiting, Pfizer | Trial completion date: Feb 2028 --> Sep 2027 | Trial primary completion date: Aug 2025 --> Mar 2025

P1/2, N=48, Terminated, Precision BioSciences, Inc. | Completed --> Terminated; Study was terminated due to lack of sufficient therapeutic effect

We also demonstrated that the combination of LAQ and a Notch signaling pathway inhibitor significantly inhibited the growth of tumor cells in vivo using an allograft tumor model. This study indicates that inhibition of the Notch signaling pathway provides a valuable strategy for enhancing solid tumor sensitivity to LAQ.

GODDESS was found to be reliable, valid, responsive, and interpretable as a clinical trial endpoint in the pooled sample of DT/AF patients. Estimated MCTs can be used to define responders and assess group-level differences in future, unblinded, efficacy analyses.

P2, N=23, Not yet recruiting, Stanford University

P2, N=53, Active, not recruiting, SpringWorks Therapeutics, Inc. | Recruiting --> Active, not recruiting

P1, N=30, Recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Oct 2023 --> Oct 2026 | Trial primary completion date: Oct 2023 --> Oct 2026

No abstract available

P2, N=40, Not yet recruiting, M.D. Anderson Cancer Center

Up to 40% of DLBCL patients display refractory disease or relapse after standard chemotherapy treatment (R-CHOP; rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), leading to significant morbidity and mortality. Targeting CHOP-resistant DLBCL tumors with the Phase 3 clinical trial molecules nirogacestat, a selective g-secretase inhibitor, and ipatasertib, a pan-AKT inhibitor, synergistically promotes DLBCL death. These findings establish the rationale for therapeutic strategies aimed at targeting the oncogenic pathway activated in KLHL6- or NOTCH2-mutated DLBCL.

P1b, N=317, Recruiting, Regeneron Pharmaceuticals | Trial completion date: May 2032 --> Aug 2032 | Trial primary completion date: Oct 2026 --> Jan 2027

Aims: This open-label, multi-center, Phase 1b, dose-escalation and expansion study (NCT05259839) will evaluate the safety profile, tolerability, preliminary efficacy, pharmacokinetics and recommend Phase 2 dose of ABBV-383 in combination with pomalidomide-dexamethasone (Pd), lenalidomide-dexamethasone (Rd), daratumumab- dexamethasone (Dd) or nirogacestat (Niro) in patients with RRMM. Efficacy endpoints include ORR, PFS, DOR, time to progression and minimal residual disease negativity. Summary/

The combination of tec + niro yielded response rates of 57–92% across 3 dose levels assessed. This initial experience with tec + niro provides insights on the combination of BCMA-directed therapies with a gamma secretase inhibitor. Phase I, Bispecific, Multiple myeloma, B-cell maturation antigen

Despite utilizing a belamaf dose and schedule that are expected to have limited activity as a monotherapy, low- dose belamaf + nirogacestat demonstrated an encouraging ORR with a substantial reduction of high-grade ocular events, indicating an increase in BCMA target density by nirogacestat. Furthermore, the efficacy and safety data from the monotherapy arm were consistent with DREAMM-2, DREAMM-3, and real-world evidence observed to date. These data support ongoing exploration in DREAMM-5 of belamaf + nirogacestat + standard of care agents in patients with RRMM.

P2, N=35, Active, not recruiting, Children's Oncology Group | Trial completion date: Mar 2025 --> Dec 2024 | Trial primary completion date: Mar 2025 --> Dec 2024

P1/2, N=48, Completed, Precision BioSciences, Inc. | Recruiting --> Completed | Trial completion date: Dec 2021 --> Oct 2022 | Trial primary completion date: Dec 2021 --> Oct 2022