A 71 years old woman received the MENi revumenib (REV) for relapsed/refractory NPM1m AML...However, to our knowledge, this is the first report ever of MENi induced PG-like ND and cutaneous involvement of DS. This report highlights the fact that ND such as PG, as a manifestation of DS, are a possibly severe adverse effect of MENi.

P1, N=200, Recruiting, Janssen Research & Development, LLC | N=150 --> 200

P1, N=0, Withdrawn, Janssen Research & Development, LLC | N=80 --> 0 | Not yet recruiting --> Withdrawn

P1, N=150, Recruiting, Janssen Research & Development, LLC | Trial primary completion date: May 2024 --> Mar 2025

P1/2, N=350, Recruiting, Janssen Research & Development, LLC | N=150 --> 350 | Trial completion date: Feb 2026 --> Oct 2027

JNJ-75276617 demonstrated synergistic effects with gilteritinib in vitro in AML cells harboring KMT2A-r. JNJ-75276617 further exhibited synergistic effects with venetoclax and azacitidine in AML cells bearing KMT2A-r in vitro, and significantly increased survival in mice...A co-crystal structure of menin in complex with JNJ-75276617 indicates a unique binding mode distinct from other menin-KMT2A inhibitors, including revumenib. JNJ-75276617 is being clinically investigated for acute leukemias harboring KMT2A or NPM1 alterations, as a monotherapy for relapsed/refractory (R/R) acute leukemia (NCT04811560), or in combination with AML-directed therapies (NCT05453903).

Finally, we demonstrate significant synergy between revumenib and the DOT1L inhibitor pinometostat in KMT2A-rearranged ALL, suggesting that such drug combinations represent a potent therapeutic strategy for these patients. Collectively, our findings underscore the complexity of resistance mechanisms and advocate for precise patient stratification to optimize the use of menin inhibitors in KMT2A-rearranged acute leukemia.

P1/2, N=150, Recruiting, Janssen Research & Development, LLC | Phase classification: P1 --> P1/2

P1, N=150, Recruiting, Janssen Research & Development, LLC | N=110 --> 150

P1, N=150, Recruiting, Janssen Research & Development, LLC | Phase classification: P1b --> P1

P1, N=80, Not yet recruiting, Janssen Research & Development, LLC | Trial completion date: Sep 2026 --> Jan 2030

P1, N=110, Recruiting, Janssen Research & Development, LLC | Trial completion date: Jun 2025 --> Oct 2025

Hypomethylating agents (e.g. azacitidine, decitabine) in combination with venetoclax have significantly improved clinical outcomes for AML patients and have become a preferred frontline treatment for AML patients ≥75 years of age, or who have comorbidities that preclude use of intensive induction chemotherapy. These studies suggest that the doublet combinations of either JNJ-75276617 plus venetoclax or azacitidine, or the triplet combination could potentially provide a beneficial treatment option for KMT2A- or NPM1-altered AML, and support the recently initiated clinical trial investigating JNJ-75276617 in combination with AML-directed therapies, including venetoclax and azacitidine (NCT05453903). JNJ-75276617 is also being clinically investigated as a monotherapy for R/R acute leukemia (NCT04811560).

Dose escalation in 75276617ALE1001 is ongoing with the RP2D(s) yet to be determined. Pts in dose expansion will receive JNJ-75276617 at the identified RP2D(s). Preliminary results of this FIH Phase 1 study demonstrate that JNJ-75276617 monotherapy has an acceptable safety profile, encouraging antileukemic activity, and emerging biologic activity consistent with the proposed mechanism of action in pts with R/R acute leukemia harboring KMT2A or NPM1 alterations.

Our findings demonstrate that MLL1 inhibits the neurogenic potential of SCAPs by interacting with WDR5 and repressing HES1. These results provide a potential therapeutic target for promoting the recovery of motor function in SCI patients.

In summary, our multilayer molecular profiling of AML with poor prognosis and KMT2A-MLLT3 karyotypes identified a phosphoproteomics signature that defines two biologically and phenotypically distinct groups of KMT2A rearranged leukaemia. These data provide a rationale for the potential development of specific therapies for AML patients characterised by the MLLGA phosphoproteomics signature identified in this study.

We have generated a novel, potent, orally available small-molecule inhibitor of the Menin-MLL1 interaction, DS-1594a. Our results suggest that DS-1594a has medicinal properties distinct from those of cytarabine and that DS-1594a has the potential to be a new anticancer therapy and support oral dosing regimen for clinical studies (NCT04752163).

P1, N=110, Recruiting, Janssen Research & Development, LLC | Trial completion date: Jun 2026 --> Jun 2025

P1, N=110, Recruiting, Janssen Research & Development, LLC | Trial completion date: Jun 2025 --> Jun 2026

P1/2, N=199, Recruiting, Kura Oncology, Inc. | N=60 --> 199 | Trial completion date: Dec 2022 --> Sep 2025 | Trial primary completion date: Jun 2022 --> Sep 2024

Of note, all tested combinations (venetoclax + PI3K inhibitors idelalisib or BKM-120, as well as AKT inhibitors MK-2206 or perifosine) achieved comparable anti-leukemic effects. The present study provides rational combination strategies involving selective BCL-2 and PI3K/AKT inhibition in B-ALL cell lines. Furthermore, we identified a potential mechanistic background of the synergistic activity of combined venetoclax and perifosine application.

P1, N=80, Ongoing, Janssen-Cilag International NV

P1, N=80, Not yet recruiting, Janssen Research & Development, LLC | Initiation date: Dec 2022 --> Feb 2024

Conclusion s : We have optimized the method of cell surface protein identification on primary BCP-ALL samples (Fig.1). It allowed us to overcome the technical issues of proteomics analysis of samples from the patients and to identify a subset of surface proteins, which can be promising targets for immunotherapy.

Here we investigated potential application of the Menin-MLL inhibitor SNDX-5613 in MLL/AF4 MPAL infants who presented with the bilineage B/Myeloid phenotype...These myeloid data are consistent with observations of differentiation syndrome as an on-target effect in current clinical trials while the phenotypic changes in the lymphoid cells are new findings. Together, these data strongly suggests that MLL-r MPAL patients could benefit from the inclusion of the Menin-MLL1 inhibitors into their treatment regimens.

As anticipated, pinometostat-resistant cells displayed a slight cross-resistance to most chemotherapeutic agents currently used in ALL treatments but became remarkably more sensitive toward the BCL-2 inhibitor venetoclax. Also, our model demonstrates that under prolonged pressure of DOT1L inhibition, KMT2A-rearranged ALL cells seem to initiate a reprogramming process that involves the acquirement (or selection) of myeloid-like characteristics, an ability that may be connected to leukemic lineage switches which are not uncommon in KMT2A-rearranged acute leukemias. Hence, our model represents an important tool to study the complex biology of KMT2A-rearranged leukemia, and its existence and availability requires to be shared with the community.

These antigens are very specific for KMT2Ar AML and are expressed homogeneously in primary human KMT2Ar AML samples, suggesting that targeting these antigens represents a promising therapeutic strategy for these patients. Several immunotherapeutic approaches to target these antigens are currently being developed and tested by our group, with the hope of identifying novel therapeutic strategies for the treatment of KMT2Ar AML.

Clinical benefit with disease control (eg, decreasing blast counts [BC] or hydroxyurea requirement) occurred across dose levels. P1b results suggest that with appropriate DS management, ziftomenib is well tolerated. Additionally, the 600 mg dose demonstrates meaningful signs of efficacy in heavily pretreated R/R AML pts, warranting further investigation of ziftomenib as a monotherapy and in combination with rational therapeutic partners.

Our study demonstrates that the epigenetic activity of transcription factor oncogenes exhibits a shift during prostate cancer progression with distinctive phenotypic effects on metabolism. These epigenetically driven changes in lipid metabolism may serve as novel targets for the development of novel imaging agents and therapeutics.

Leukemic infiltration of the orbital adnexa in myeloid malignancies is rare and associated with an inordinately high proportion of MECOM rearrangements in addition to adverse outcomes.

P1b, N=150, Recruiting, Janssen Research & Development, LLC | Trial completion date: Dec 2024 --> Jan 2026

P1, N=80, Not yet recruiting, Janssen Research & Development, LLC

Taken together, the present study focused on the mutant genes in ctDNA, ascites and tumor tissues, and suggested that the integrated information of different samples could be examined to comprehensively reflect the mutational landscape in ovarian cancer. However, procedures and protocols to interpret and utilize the integrated information obtained from various forms of liquid biopsies will require optimization prior to their use for future clinical applications.

P1, N=110, Recruiting, Janssen Research & Development, LLC | Trial completion date: Aug 2024 --> Jun 2025

P1b, N=150, Recruiting, Janssen Research & Development, LLC | Not yet recruiting --> Recruiting

P1b, N=150, Not yet recruiting, Janssen Research & Development, LLC

Our results suggest that MLL1-induced epigenetic mark is responsible for the maternal inflammatory and oxidative phenotypes in GD women, and it is transmitted to the offspring. The deciphering of epigenetic-induced chromatin remodeling opens the perspective for pharmacological reprogramming of adverse histone modifications to reduce the burden of early abnormal phenotypes in the offspring potentially leading to ASCVD.

P1, N=110, Recruiting, Janssen Research & Development, LLC | Trial completion date: Apr 2024 --> Aug 2024