carfilzomib

P1, N=90, Recruiting, Pfizer | Trial primary completion date: Aug 2025 --> Feb 2026

CMS and HFrEF seem to exacerbate Cfz-induced CAEs, by presenting metabolism-related hidden toxicity and PP2A-related cardiac inflammation, respectively. Metformin retains its prophylactic potential in the presence of CMS, while mitigating inflammation and Ca2+ signalling dysregulation in the HFrEF myocardium.

P1/2, N=68, Active, not recruiting, Australasian Myeloma Research Consortium | Recruiting --> Active, not recruiting

P2, N=55, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Jun 2025 --> Jun 2028

Pro-survival proteins: MCL-1, BCL-2 and BCL-XL were inhibited using S63845, ABT-199 and A-1331852 respectively. Furthermore, MCL-1 inhibition led to enhanced binding between BCL-XL and BIM, while blocking BCL-XL increased MCL-1/BIM complex formation, indicating the cooperative role of these proteins. Stromal interactions alter the dependence on BCL-2 family members, providing a rationale for dual inhibition to abrogate the protective effect of stroma and restore sensitivity to CFZ.

P1, N=130, Active, not recruiting, Amgen | Recruiting --> Active, not recruiting | Phase classification: P1b/2 --> P1

P1/2, N=316, Recruiting, Hoffmann-La Roche | Phase classification: P1 --> P1/2

P2, N=120, Active, not recruiting, AbbVie | Recruiting --> Active, not recruiting | Trial completion date: Dec 2027 --> Jun 2027 | Trial primary completion date: Dec 2027 --> Jun 2027

P2, N=43, Recruiting, Andrew Yee, MD | Trial completion date: May 2025 --> May 2026 | Trial primary completion date: May 2024 --> May 2025

This data demonstrates that CFZ is unable to induce ER stress in confluent resting endothelial cells and can conversely attenuate the pro-thrombotic effects of TNFα on the endothelium. This study suggests that CFZ does not negatively alter HUVECs, and proteasome inhibition of the endothelium may offer a potential way to prevent thrombosis.

P2, N=64, Not yet recruiting, Sanofi

P1/2, N=12, Completed, Wake Forest University Health Sciences | Active, not recruiting --> Completed | Trial completion date: Sep 2025 --> Feb 2024

P1, N=83, Active, not recruiting, Thomas Martin, MD | Recruiting --> Active, not recruiting

P2, N=124, Completed, Arbeitsgemeinschaft medikamentoese Tumortherapie | Active, not recruiting --> Completed

The most frequently used regimens were Seli-Pomalidomide-dexamethasone(dex) or Seli-Carfilzomib-dex (Seli-Kd) in the del17p group and Seli-Kd in the OHRC and standard-risk groups. Interestingly, our data suggest that Seli is a particularly effective bridging modality for patients preparing for CAR-T cell therapies in our population. Further investigation into this population is warranted, including in earlier lines of therapy, in hopes of seeing a more durable response.

P1, N=90, Recruiting, Pfizer | N=14 --> 90

P2, N=74, Active, not recruiting, Weill Medical College of Cornell University | Trial completion date: Mar 2024 --> Mar 2025

P1/2, N=300, Active, not recruiting, Karyopharm Therapeutics Inc | Phase classification: P1b/2 --> P1/2 | N=518 --> 300 | Trial completion date: Jan 2025 --> Apr 2027 | Trial primary completion date: Jan 2025 --> Apr 2027

P1, N=15, Recruiting, City of Hope Medical Center | Not yet recruiting --> Recruiting | Trial completion date: Apr 2025 --> Mar 2026 | Trial primary completion date: Apr 2025 --> Mar 2026

P2, N=41, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Jul 2024 --> Jul 2025 | Trial primary completion date: Jul 2024 --> Jul 2025

Paradoxically, carfilzomib has little effect on global average protein half-life, but may instead selectively disrupt sarcomere protein homeostasis. This study provides a view into the interactions of protein spatial and temporal dynamics and demonstrates a method to examine protein homeostasis regulations in stress and drug response.

P1/2, N=66, Suspended, Hackensack Meridian Health | Recruiting --> Suspended

P1, N=242, Completed, Janssen Research & Development, LLC | Active, not recruiting --> Completed

P2, N=29, Active, not recruiting, Emory University | Trial completion date: Aug 2024 --> Mar 2026 | Trial primary completion date: Jul 2024 --> Mar 2025

To improve the outcome of patients with relapsed/refractory multiple myeloma, it is critical to develop new therapies, assess potential therapeutic synergies, and overcome drug resistance by determining the efficacy of multiple myeloma therapies across multiple disease subgroups.

P1, N=182, Recruiting, Janssen Research & Development, LLC | Trial primary completion date: Dec 2024 --> Jul 2025

P1/2, N=532, Active, not recruiting, Celgene | Phase classification: P1b/2a --> P1/2 | Trial completion date: Oct 2029 --> Feb 2028 | Trial primary completion date: Oct 2029 --> Mar 2024

P2, N=265, Active, not recruiting, Janssen Research & Development, LLC | Trial completion date: Nov 2023 --> Feb 2024

P2, N=54, Active, not recruiting, Amgen | Trial completion date: Dec 2025 --> Oct 2024

P1, N=36, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Jan 2024 --> Jan 2025 | Trial primary completion date: Jan 2024 --> Jan 2025

P3, N=466, Not yet recruiting, Celgene

P3, N=492, Recruiting, Pfizer | Not yet recruiting --> Recruiting

We have previously reported that BRAF-mutant human cells display a high rate of protein production, causing proteotoxic stress, and are selectively sensitive to the proteasome inhibitors bortezomib and carfilzomib. Analyses of drug-treated samples revealed increased intratumor recruitment of activated cytotoxic T cells and natural killers, concomitant with the downregulation of forkhead box protein P3 (Foxp3)+ T-cell surface glycoprotein CD4 (CD4)+ T cells, indicating that carfilzomib promotes reshaping of the immune microenvironment of BRAF-mutant murine colorectal tumors. These results will inform the design of clinical trials in BRAF-mutant colorectal cancer patients.

P1, N=15, Not yet recruiting, City of Hope Medical Center

In conclusion, the activation of HTRA1-CDK1 pathway promotes the malignant phenotype of tumor cells by blocking the cell cycle at the G2/M phase, thereby accelerating pancreatitis-initiated PDAC. Carfilzomib is an innovative candidate drug that can inhibit pancreatitis-initiated PDAC through targeted inhibition of HTRA1.

Monotherapy identified nine effective drugs (bortezomib, carfilzomib, cisplatin, delanzomib, docetaxel, epoxomicin, MLN-2238, MLN-9708, and nedaplatin) across all cell lines. PIs (e.g., bortezomib, delanzomib, and epoxomicin) were highly potent drugs in TNBC cells, of which bortezomib and delanzomib inhibited the chymotrypsin-like activity of the 20 S proteasome by 100% at 10 µM. Moreover, several potent 2-drug combinations (e.g., bortezomib+nedaplatin and epoxomicin+epirubicin) that killed virtually 100% of cells were also identified. Although HCC1806- and MCF-7-derived xenografts treated with bortezomib+nedaplatin and carboplatin+paclitaxel were smaller, HCC1806 cells frequently metastasized to the trunk region. Taken together, we show that PIs used in combination with platinum agents or topoisomerase inhibitors exhibit increased efficiency with almost 100% inhibition in TNBC cell lines, indicating that PIs are therefore promising compounds to use as combination therapy for TNBC.

P1/2, N=15, Recruiting, National Institute of Allergy and Infectious Diseases (NIAID) | Trial completion date: Apr 2026 --> Feb 2028 | Trial primary completion date: Apr 2024 --> Feb 2027

P2, N=39, Not yet recruiting, Oncotherapeutics | Initiation date: Dec 2023 --> Mar 2024

To mimic their pharmacokinetic/pharmacodynamic (PK/PD) profiles, MM cells were treated with bortezomib and carfilzomib for 1 h at concentrations up to 400 and 1,000 nM, respectively. PIM and Akt inhibition restored the anti-MM effects of PIs, even against PI-resistant KMS-11 cells. Collectively, these results suggest that increased synthesis of β5 proteasome subunit and acute accumulation of PIM2 and NRF2 reduce the anti-MM effects of PIs.

The serum analysis revealed that CFZ administration significantly elevated the levels of LDH, CK and CKMB in CFZ exposed animals when compared to normal animals while administration of oxyphenbutazone significantly reduced these biochemical changes, Intracellular antioxidant enzymes and NF-kB in treatment groups as compared to disease control animals. Findings of the research protocol suggests significant injuries to cardiac tissues when animals exposed to CFZ and Oxyphenbutazone protected the cardiac tissues.

The suppression of MHC genes and cell adhesion molecules may impair the interaction between immune cells and cancer cells to impair antitumor immunity. Future studies are warranted to further investigate the signaling pathway underlying the regulatory role of TNFRSF1A in MM cells.

P=N/A, N=30, Recruiting, Peking University First Hospital