pomalidomide

The molecules are based on connecting a known MYC binder to a VHL ligand or pomalidomide to induce MYC degradation in various cancer cells known to express MYC...Encouraging results presented herein suggest that the presented analogs may serve as prototype structures of future therapeutic agents for the treatment of MYC-dependent tumors. MYC protein degraders can well complement the more established inhibition approaches that have been presented in the past (e.g., disruption of the MYC-MAX complex formation by small-molecule inhibitors).

P3, N=284, Not yet recruiting, Qilu Pharmaceutical Co., Ltd.

P1, N=125, Recruiting, K36 Therapeutics, Inc. | N=60 --> 125 | Trial completion date: Oct 2025 --> Jun 2026 | Trial primary completion date: Dec 2024 --> Dec 2025

P1, N=126, Active, not recruiting, Genentech, Inc. | Recruiting --> Active, not recruiting | N=184 --> 126

Median number of prior lines was 4 (range 1-13), 19.4% had received CAR-T previously, and 12.9% had been previously exposed to another TCE.Twenty-three pts (74.2%) were enrolled in clinical trials (7 with teclistamab, Tec, 6 with talquetamab, Tal, and 10 with investigational agents). Twelve of these pts received TCE in combination with daratumumab and/or pomalidomide...MRD- seems to translate into long PFS, regardless of HR disease. Prospective studies on fixed duration treatment with TCE based on baseline risk and treatment response are needed.

P2, N=124, Active, not recruiting, University of Leeds | Trial completion date: Jun 2023 --> Jun 2025

Elotuzumab is an approved monoclonal antibody targeting SLAMF7 on plasma and NK cells that enhances the activity of lenalidomide, pomalidomide, and bortezomib in multiple myeloma (MM)...Prior therapies included: pomalidomide (33%), daratumumab (25%), and isatuximab (4%)...Common grade ≥3 adverse events were neutropenia (33%); infections, any (33%); lung infection (27%); hypophosphatemia (19%); and thrombocytopenia (15%). Elo-PVd is one of the first trials of a quadruplet regimen in relapsed/refractory MM incorporating a monoclonal antibody to show efficacy across diverse prior treatments, including triple class exposed with prior anti-CD38 monoclonal antibody.

The instantaneous change in serum M-protein level was found to be associated with PFS in the final joint model. Using model simulations, we retrospectively supported the Isa 10 mg/kg weekly for 4 weeks, then biweekly (QW/Q2W) dosing regimen of the ICARIA-MM phase III pivotal study, and validated it using the same phase III pivotal study data.

P2, N=38, Completed, Mayo Clinic | Active, not recruiting --> Completed

P1/2, N=101, Active, not recruiting, University of Chicago | Trial completion date: Nov 2024 --> Nov 2025 | Trial primary completion date: Nov 2024 --> Nov 2025

P2, N=54, Completed, Amgen | Active, not recruiting --> Completed

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

Background : Ciltacabtagene autoleucel (cilta-cel) demonstrated superior progression-free survival (PFS) and overall survival compared to standard of care (SOC; pomalidomide, bortezomib, and dexamethasone or daratumumab, pomalidomide, and dexamethasone) in patients with lenalidomide-refractory multiple myeloma (MM) after 1-3 prior lines of therapy (LOTs) in the phase 3 CARTITUDE-4 trial. Importantly, with ~3 years of follow-up, a single infusion of cilta-cel provided patients with a longer delay in worsening of MM related symptoms, functional impacts, and GHS/QoL. The totality of clinical and patient-reported evidence demonstrates the significant benefit of cilta-cel.

Conclusions : Tal-DP exhibits a deep, long-term impact on efficacy through complementary mechanisms of action and may be especially beneficial in pts with prior BsAb exposure, who typically have unfavorable BL immune profiles. Ongoing analyses of tec-DP from MajesTEC-2 (NCT04722146) will be presented.

Pts were assigned 1 : 1 to cilta-cel or SoC (pomalidomide, bortezomib, and dexamethasone [PVd]/daratumumab, pomalidomide, and dexamethasone [DPd]). These data further underscore the benefit of cilta-cel, which led to significant >3-fold increases vs SoC in rates of MRD-negative ≥CR at any time and at mo 12, and sustained MRD negativity. Our MRD data demonstrate higher rates of deep and sustained MRD negativity achieved with cilta-cel vs SoC in tx of len-refractory MM as early as first relapse.

P1, N=290, Active, not recruiting, Janssen Research & Development, LLC | Trial primary completion date: Sep 2024 --> Aug 2025

P3, N=650, Recruiting, Janssen Research & Development, LLC | Trial primary completion date: Oct 2025 --> Feb 2026

P1/2, N=32, Not yet recruiting, University of Aarhus

P3, N=222, Recruiting, Stichting European Myeloma Network | Active, not recruiting --> Recruiting | N=109 --> 222

P2, N=76, Recruiting, Ruijin Hospital | Trial primary completion date: Jun 2024 --> Jun 2025

P1, N=174, Terminated, Amgen | Phase classification: P1/2 --> P1

P1, N=184, Recruiting, Genentech, Inc. | Trial completion date: Jul 2025 --> Jan 2026 | Trial primary completion date: Sep 2024 --> Jan 2026

The original molecular glue degraders (thalidomide, lenalidomide, and pomalidomide) are known to bind to cereblon (CRBN) and alter its surface to induce recruitment, ubiquitination, and degradation of therapeutically valuable neosubstrates (IKZF1, IKZF3, and CK1α). Herein, we describe the medicinal chemistry efforts that resulted in the discovery of SJ3149 as well as other potent and selective CK1α degraders. We report kinetic profiling and parameters of CK1α degradation, ternary complex, antiproliferative effects, in vitro ADME data, and in vivo pharmacokinetic studies with demonstrated oral bioavailability.

P3, N=109, Active, not recruiting, Stichting European Myeloma Network | Recruiting --> Active, not recruiting | N=222 --> 109

P3, N=761, Recruiting, Pfizer | Active, not recruiting --> Recruiting

Using miRNA-21 as a model, we engineered DNA hairpins labeled with JQ-1 and pomalidomide and facilitated the modular assembly of DNA-encoded pre-PROTACs through a hybridization chain reaction. The integration of near-infrared light-mediated photodynamic therapy through an upconversion nanosystem further enhanced the efficacy of the platform with potent in vivo anticancer activity. We anticipate that miRiaTAC represents a significant intersection between dynamic DNA nanotechnology and PROTAC, potentially expanding the versatility of PROTAC toolkit for cancer therapy.

P=N/A, N=586, Active, not recruiting, Sanofi | Recruiting --> Active, not recruiting | N=1200 --> 586

P1/2, N=258, Recruiting, Sanofi | N=197 --> 258

P2, N=38, Active, not recruiting, Mayo Clinic | Trial completion date: Oct 2025 --> Oct 2024 | Trial primary completion date: Oct 2024 --> Feb 2024

P1, N=61, Completed, Amgen | Phase classification: P1b --> P1

P3, N=440, Not yet recruiting, Juno Therapeutics, Inc., a Bristol-Myers Squibb Company

These observations imply that Pomalidomide treatment influences the T-cell repertoire, particularly in the CD4 + subpopulation during the later stages of treatment, raising speculation about the potential involvement of these lymphocyte expansions in mechanisms related to antitumor immunity.

P4, N=70, Recruiting, Beijing Chaoyang Hospital, Capital Medical University; Beijing Chaoyang Hospital, Capital Medical University

P1/2, N=300, Recruiting, Karyopharm Therapeutics Inc | Active, not recruiting --> Recruiting

P3, N=761, Active, not recruiting, Pfizer | Recruiting --> Active, not recruiting

P1, N=114, Completed, Celgene | Active, not recruiting --> Completed

P1/2, N=30, Active, not recruiting, Joseph Tuscano | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Aug 2024 --> Aug 2025

P1/2, N=316, Completed, Bristol-Myers Squibb | Active, not recruiting --> Completed | Trial completion date: Dec 2023 --> Jul 2024

P2, N=120, Active, not recruiting, Zhejiang DTRM Biopharma | Recruiting --> Active, not recruiting

Vactosertib is a safe therapeutic that demonstrates tumor-intrinsic activity and can overcome immunosuppressive challenges within the tumor microenvironment to reinvigorate T-cell fitness. Vactosertib offers promise to improve immunotherapeutic responses in heavily-pretreated MM patients refractory to conventional agents.

Persons with myeloma were randomized to receive an anti-TIGIT (T cell immunoreceptor) or anti-LAG3 (lymphocyte activation gene) antibody followed by combination with pomalidomide and dexamethasone ( NCT04150965 ). Anti-TIGIT responders had higher CD226 expression, natural killer cell activation and lower CD112 expression. These data demonstrate the clinical activity of TIGIT-LAG3 blockade and identify pathway-specific response correlates in myeloma.

P3, N=450, Recruiting, Kite, A Gilead Company | Not yet recruiting --> Recruiting