thalidomide

P=N/A, N=120, Recruiting, University of Nottingham

Curcumin combined with thalidomide can synergistically down-regulate the expression of STAT3 and Bcl-xL, inhibit the proliferation of KG-1 cells, and induce apoptosis.

P=N/A, N=40, Not yet recruiting, Children's Hospital of Fudan University

P3, N=177, Active, not recruiting, University of Arkansas | Trial completion date: Aug 2024 --> Aug 2025 | Trial primary completion date: Aug 2024 --> Aug 2025

The patient with skin nodules and the pathology diagnosed BPDCN, the next generation sequencing of skin nodules showed mutations of IDH2 and ASXL1. DVT (decitabine combined with Venetoclax and thalidomide) has significant efficacy with rapid and deep remission for BPDCN, and the adverse effects is less, especially suitable for elderly patients who cannot tolerate intense chemotherapy.

The vast majority of current cereblon (CRBN) ligands is based on the thalidomide scaffold, relying on glutarimide as the core binding moiety...In this new orientation it forms additional hydrophobic interactions and is not available for direct interactions with the canonical neo-substrates. We therefore propose this chemotype as an attractive building block for the design of PROTACs.

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

P2, N=132, Recruiting, Henan Cancer Hospital | Not yet recruiting --> Recruiting

Multi-agent regimens incorporating immunomodulatory (IMiD®) agents such as thalidomide, lenalidomide, and pomalidomide have become the preferred standard of care for the treatment of patients with multiple myeloma (MM), resulting in improved survival outcomes. Here, we discuss AEs associated with pomalidomide and present five clinically relevant hypothetical case studies in patients with RRMM to provide scenario-driven guidance regarding treatment selection and AE prevention and management in the clinical setting. Lastly, as new treatment approaches continue to be explored in MM, we also discuss novel cereblon E3 ligase modulator (CELMoD™) agents including iberdomide (CC-220) and mezigdomide (CC-92480).

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

P3, N=306, Active, not recruiting, National Cancer Institute (NCI)

P2, N=30, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Feb 2024 --> Feb 2025 | Trial primary completion date: Feb 2024 --> Feb 2025

P2, N=96, Not yet recruiting, Xinqiao Hospital of Chongqing

Thalidomide regimen or bortezomib regimen combined with rhEPO has similar clinical efficacy on MM, but bortezomib regimen combined with rhEPO is more prominent and safer on improving tumor-related biochemical indicators, bone marrow-related indicators and coagulation status in patients with MM.

P4, N=104, Not yet recruiting, Tongji University

To overcome these challenges, we conjugated a STAT3-specific decoy to thalidomide, a ligand to cereblon in E3 ubiquitin ligase complex, to generate a proteolysis-targeting chimera (STAT3DPROTAC)...Finally, local C-STAT3DPROTAC administration to human Ly3 lymphoma-bearing mice triggered tumor regression, while control C-STAT3D and C-SCR treatments had limited effects. Our results underscore the feasibility of using a PROTAC strategy for cell-selective, decoy oligonucleotide-based STAT3 targeting of and potentially other tumorigenic transcription factors for cancer therapy.

P2, N=30, Recruiting, Xuanwu Hospital, Beijing

P=N/A, N=130, Recruiting, Henan Cancer Hospital

P2, N=132, Not yet recruiting, Henan Cancer Hospital

Cereblon-targeting degraders, including immunomodulatory imide drugs lenalidomide and pomalidomide alongside cereblon E3 ligase modulators like iberdomide and mezigdomide, have demonstrated significant anti-myeloma effects...Despite their evident efficacy, approximately 5% to 10% of MM patients exhibit primary resistance to lenalidomide, and resistance commonly develops over time. Understanding the intricate mechanisms of action and resistance to this drug class becomes imperative for refining and advancing novel therapeutic combinations.

Dual luciferase verification revealed that there was a targeting relationship between miR-524-5p and FSTL1. In conclusion, that can up-regulate the expression of miR-524-5p to reduce the expression of FSTL1 protein, inhibit the invasion of gastric cancer cells, and achieve alleviation of the disease.

P1, N=14, Completed, Washington University School of Medicine | Active, not recruiting --> Completed

FPFT-2216 exhibited stronger inhibitory effects on human lymphoma cell proliferation than known thalidomide derivatives and induced upregulation of p53 and its transcriptional targets, namely, p21 and MDM2...FPFT-2216 also enhanced the anti-tumor activity of rituximab and showed anti-tumor activity in a patient-derived diffuse large B-cell lymphoma xenograft model...In conclusion, FPFT-2216 inhibits tumor growth by activating the p53 signaling pathway and inhibiting the CBM complex/NF-κB pathway via CK1α degradation. Therefore, FPFT-2216 may represent an effective therapeutic agent for hematopoietic malignancies, such as lymphoma.

The concept of induced protein degradation by small molecules has emerged as a promising therapeutic strategy that is particularly effective in targeting proteins previously considered "undruggable." Thalidomide analogs, employed in the treatment of multiple myeloma, stand as prime examples...These include heterobifunctional degraders, polymerization-induced degradation, ligand-dependent degradation of nuclear hormone receptors, disruption of protein interactions, and various other strategies. In this Review, we will provide a concise overview of various degradation modalities, their clinical applications, and potential future directions in the field of protein degradation.

P2, N=50, Active, not recruiting, University of Arkansas

P2, N=26, Active, not recruiting, AIDS Malignancy Consortium | Recruiting --> Active, not recruiting

Thalidomide and its analogs are molecular glues (MGs) that lead to targeted ubiquitination and degradation of key cancer proteins via the cereblon (CRBN) E3 ligase...In this platform, automated, high throughput, and nano scale synthesis of hundreds of pomalidomide-based MGs was combined with rapid phenotypic screening, enabling an unprecedented fast identification of potent CRBN-acting MGs...This revealed E14 as a potent MG degrader targeting IKZF1/3, GSPT1 and 2 with profound effects on a panel of cancer cells. In a more generalized view, integration of automated, nanoscale synthesis with phenotypic assays has the potential to accelerate MGs discovery.

Thalidomide, lenalidomide, and pomalidomide, these three CRBN-binding MGDs, were clinically approved to treat several intractable diseases (including multiple myeloma). Several other MGDs and CRBN-based PROTACs (ARV-110 and AVR-471) are undergoing clinical trials. In addition, several new related technologies regarding PROTACs and MGDs have also been developed, and achievements of protein degraders impact not only therapeutic fields but also basic biological science. In this article, I introduce the history of protein degraders, from the development of thalidomide to the latest PROTACs and related technologies.

Herein we first disclosed the design, synthesis, and evaluation of a series of thalidomide-based PROTAC molecules and identified B1 as a highly efficient HPK1 degrader with DC value of 1.8 nM. Further mechanism investigation demonstrated that compound B1 inhibits phosphorylation of the SLP76 protein with IC value of 496.1 nM, and confirmed that B1 is a bona fide HPK1-PROTAC degrader. Thus, this study provides a basis for HPK1 degraders development and the candidate could be used as a potential chemical tool for further investigation of the kinase-independent signaling of HPK1 in TCR.

SC is associated with exposure to immunosuppressive medications, especially in SOTR patients. A significant portion of cases with SC had an associated haematology malignancy, in particular multiple myeloma with exposure to lenalidomide.

P1, N=242, Active, not recruiting, Janssen Research & Development, LLC | Phase classification: P1b --> P1

Overall survival of our patients was 4.1 months and overall survival of patients treated with VTD (bortezomib, thalidomide, dexamethasone) and VCD (bortezomib, cyclophosphamide, dexamethasone) regimen was 3.4 and 4.1 months, respectively, which was not statically significant ( p -value 0.816). Conclusion  Because of rarity of the disease, prospective studies are very limited and hence management and outcome of the disease are difficult to analyze. The current treatment protocols have no survival advantage and hence newer therapeutic approach is mandatory to attain better outcome.

Patient 1, a lenalidomide-bortezomib-daratumumab and alkylator treatment refractory patient, achieved sustained stringent complete remission (sCR) after combining carfilzomib-dexamethasone with venetoclax, which was his best response ever. Similarly, Patient 2, refractory to frontline bortezomib-thalidomide-dexamethasone therapy, attained CR following a transition to bortezomib-dexamethason-venetoclax treatment...The outcomes observed in our patients suggest that venetoclax-based therapy holds substantial promise as an effective treatment option for this specific genetic subgroup. Furthermore, the similarities in treatment response between t(11;14) and t(6;14) translocation subgroups highlight the importance of personalized approaches targeting specific genetic abnormalities to optimize therapeutic outcomes.

Post transplant treatment included lenalidomide maintenance, followed by a variety of salvage regimens over the next 7 years including thalidomide, carfilzomib, daratumumab and pomalidomide...He received a second ASCT after melphalan 140 mg/m2 in Oct 2017 followed by recovery of normal blood counts...Case 3 = 65-year-old man with MM treated with bortezomib + dexamethasone followed by ASCT in Aug 2012...Six months of decitabine did not improve his blood counts...This approach was well tolerated and provided durable hematopoietic recovery. Second ASCT using banked autologous stem cells should be considered in such patients who are not otherwise candidates for allogeneic transplantation.

Bone marrow (BM) aspirates were collected from newly diagnosed MM patients treated with 4 cycles of Dara-VTD (Daratumumab, bortezomib, thalidomide, dexamethasone) induction followed by autologous stem cell transplantation (ASCT) in complete-response/very-good-partial-response at day 100 (+/- 15 days) after ASCT. our preliminary results demonstrate the importance of a harmonized NGF-MRD assessment to improve the accuracy and comparability of MM-MRD testing among different laboratories. Major discrepancies have been found in fresh samples vs the retrospective dataset suggesting an impact of the transportation time and sample processing on the concordance of our results.

In SCT patients, after the novel agent Introduction , the most common regimens changed to VT (bortezomib/thalidomide) from T in 1L, KR (carfilzomib/lenalidomide) from V in 2L, P (pomalidomide) from R in 3L, and D (daratumumab) from R in 4L. The HCRU and costs increased with the advancement of LOT. These findings suggest that a comprehensive understanding of economic burden and treatment outcomes would be required for evaluating the value of novel agent and selecting the optimal treatment options.

Six patients were treated with RVD induction (Lenalidomide, Bortizomib, Dexamethasone), two patients treated by CTD (Cyclophosphamide, Thalidomide, Dexamethasone), one pt treated by VCD (Bortizomib,Cyclophosphamide,Dexamethasone), one patient treated by Daratumumab RVD, and one patient treated by VTD. ConclusionMM is an uncommon disease among AYA in Kuwait (3. 2%) of all myeloma patients, with favorable durable responses in this group of patients.

Here we present the results of a multicenter, retroprospective and prospective, observational study, aiming to compare the impact of daratumumab on HSC mobilization with G-CSF + on-demand PLX in patients with NDMM treated with bortezomib-thalidomide-dexamethasone (VTd) or VTd plus daratumumab (D-VTd). Despite a higher rate of patients requiring PLX for HSC collection and lower CD34 + yields, the incorporation of daratumumab as part of the induction treatment did not negatively impact the possibility to achieve an optimal HSC collection. Our results, along with the lack of chemotherapy-associated toxicity, support the use of a chemotherapy-free HSC mobilization with G-CSF and on-demand plerixafor also in patients receiving daratumumab upfront.

Patients (aged ≥18 years) with a confirmed MM diagnosis receiving all ixazomib-based regimen as 2nd-line and above therapy (RR-MM), or as a 1st-line therapy (ND-MM) will form group one and TCR-MM patients' refractory to at least one IMiD (lenalidomide, pomalidomide or thalidomide), one PI (bortezomib, ixazomib, or carfilzomib) and one anti-CD-38 monoclonal antibody (daratumumab and isatuximab) will form group two. Descriptive statistics will be used for the analyses. Our findings will also help clinicians in making strategic decision about more apt positioning of ixazomib in the treatment algorithm of MM.

After induction therapy, a combination of cyclophosphamide (CTX) with granulocyte colony stimulating factor (G-CSF) at standard dose of 10 mg/sqm/day was used as the first mobilizing regimen attempt in both groups. ConclusionsIn conclusion, frontline induction daratumumab-based therapy is likely to affect PBSC collection after first mobilization attempt, even if not clinically relevant, and potentially mitigated with higher use of plerixafor. Furthermore, the inclusion of daratumumab in pretransplant therapy regimens did not impair ASCT.

Unlike previously reported cases, these two patients required additional drugs like Thalidomide along with steroids, and their response to treatment was not as rapid...Clinicians should maintain a high index of suspicion for GHDD in cases of refractory anemia or myelofibrosis-like features, especially in adults with an earlier history of anemia. Early recognition and appropriate management are crucial to mitigate morbidity and improve patients' quality of life