Ninlaro (ixazomib)

P2, N=46, Active, not recruiting, University of California, San Diego | Trial completion date: Oct 2024 --> Oct 2025 | Trial primary completion date: Mar 2024 --> Mar 2025

P=N/A, N=420, Recruiting, RenJi Hospital | Not yet recruiting --> Recruiting

P3, N=1, Active, not recruiting, National Cancer Institute (NCI) | N=510 --> 1 | Trial completion date: Mar 2024 --> Apr 2025 | Trial primary completion date: Mar 2024 --> Aug 2023

P2, N=18, Recruiting, Larysa Sanchez | N=38 --> 18 | Trial completion date: Jun 2024 --> Jun 2025 | Trial primary completion date: Feb 2024 --> Dec 2024

P2, N=40, Active, not recruiting, M.D. Anderson Cancer Center | Recruiting --> Active, not recruiting | N=60 --> 40

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

P1/2, N=32, Completed, City of Hope Medical Center | Active, not recruiting --> Completed

P1/2, N=61, Recruiting, Omar Nadeem, MD | Trial completion date: Mar 2024 --> Dec 2024 | Trial primary completion date: Mar 2024 --> Dec 2024

P1, N=7, Completed, Mayo Clinic | Active, not recruiting --> Completed

P1, N=14, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Feb 2024 --> Feb 2025 | Trial primary completion date: Feb 2024 --> Feb 2025

Serial analysis of ctDNA mutations in 94 cases revealed that TP53 and KRAS mutations frequently emerge after therapy. Thus, we clarify the genetic characteristics and clonal architecture of ctDNA mutations and demonstrate their superiority over BMPC mutations for prognostic prediction in RRMM.

P1/2, N=31, Active, not recruiting, Therapeutic Advances in Childhood Leukemia Consortium | Recruiting --> Active, not recruiting | Trial completion date: Jun 2024 --> Jun 2025 | Trial primary completion date: Dec 2023 --> Dec 2024

P2, N=15, Active, not recruiting, Roswell Park Cancer Institute | Trial completion date: Jan 2024 --> Jan 2025

P1/2, N=57, Active, not recruiting, M.D. Anderson Cancer Center | Phase classification: P2 --> P1/2

P2, N=79, Active, not recruiting, Alliance Foundation Trials, LLC. | Recruiting --> Active, not recruiting

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.

In aggressive MYC-aberrant NHL, DA-EPOCH-R induction with ixazomib followed by maintenance ixazomib is feasible and appears effective in DEL patients. (NCT02481310, ClinicalTrials.gov).

P1/2, N=43, Completed, PrECOG, LLC. | Active, not recruiting --> Completed | Trial completion date: Jul 2024 --> Sep 2023

P2, N=30, Active, not recruiting, M.D. Anderson Cancer Center | Recruiting --> Active, not recruiting | Trial completion date: Jan 2024 --> Jan 2025 | Trial primary completion date: Jan 2024 --> Jan 2025

P2, N=46, Active, not recruiting, University of California, San Diego | Trial primary completion date: Oct 2023 --> Mar 2024

P1, N=34, Recruiting, University of Pennsylvania

P3, N=31, Completed, Millennium Pharmaceuticals, Inc. | Active, not recruiting --> Completed

Combining lenalidomide with other medications such dexamethasone, bortezomib, ixazomib, carfilzomib and daratumumab can markedly alleviate MM. Carfilzomib produces a rapid and profound response in patients with NDMM eligible for transplantation, but its cardiovascular side effects need to be closely monitored. The primary aim of the present review was to examine the pharmacological properties and pharmacokinetics of lenalidomide, as well as the efficacy and safety of lenalidomide-based treatments with reference to data from clinical trials and real-world studies.

P3, N=510, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2023 --> Mar 2024 | Trial primary completion date: Dec 2023 --> Mar 2024

This study included patients aged ≥18 identified in the IQVIA PharMetrics database (>72 million lives 2021-2022 total) who were newly initiating pharmacological treatment with bendamustine, bortezomib, carfilzomib, cyclophosphamide, daratumumab, ixazomib, lenalidomide, melphalan, pomalidomide, or venetoclax 01Jan2021-30Jun2022 (date of first therapy classified as “index date”). A total of 194 patients met all eligibility criteria, out of which the majority were male (N=119; 61%), with the largest insurance coverage being self-insured (N=80; 41%), and a mean age of 62 years (SD=9. 8). The most common index treatment regimen was CyBorD+daratumumab (N=53; 27%) followed by dexamethasone+daratumumab (N=24; 12%) and daratumumab monotherapy (N=16; 8%) ( Table).

MethodsTransplant-ineligible/delayed-transplant (≥24 months) NDMM pts with ≥stable disease after 3 cycles of parenteral V-based induction were enrolled at US community sites to receive all-oral ixazomib-lenalidomide-dexamethasone (IRd) for up to 39 cycles or until progression or toxicity (Manda CLML 2020). Although 41% of US MM-6 pts would have been ineligible for RCTs, there were no notable differences in PFS, ORR, OS, and safety data between the two groups. These data show that iCT from V-based induction to IRd permits long-term, tolerable PI-based therapy translating into improved efficacy in community-treated pts with NDMM who are more representative of the wider MM population.

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.

This study indicates that the risk of vCJD was no longer a concerning factor for physicians and would no longer influence their willingness to prescribe ixazomib.

In this study, we designed and synthesized the first dual PARP-1 and proteasome inhibitor based on Olaparib and Ixazomib. Additionally, 42i induced more significant apoptosis and showed better inhibitory effect on cell proliferation in clonal formation experiments in breast cancer cells than 42d. In summary, our study presented a new class of dual PARP-1/proteasome inhibitors with significant synergistic effects for the treatment of breast cancer.

P2, N=17, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Recruiting --> Active, not recruiting | N=47 --> 17

P=N/A, N=3000, Recruiting, Takeda | Trial completion date: Oct 2024 --> Sep 2025 | Trial primary completion date: Oct 2024 --> Sep 2025

P1, N=21, Active, not recruiting, Mayo Clinic | Trial completion date: Dec 2023 --> Oct 2024

P2, N=60, Recruiting, M.D. Anderson Cancer Center | Trial completion date: Dec 2023 --> Dec 2024 | Trial primary completion date: Dec 2023 --> Dec 2024

P1/2, N=34, Recruiting, Kathleen Dorritie | Not yet recruiting --> Recruiting

Key exclusion criteria included prior ixazomib exposure, refractoriness to anti-CD38 therapy, and refractoriness to bortezomib or carfilzomib therapy at last exposure. Treatment with DVd followed by DId with a PI iCT from bortezomib to ixazomib is a feasible approach for continuous PI and anti-CD38 therapy, leading to durable responses in RRMM pts, among whom nearly all (97%) were lenalidomide refractory. Immune correlates revealed distinct patterns of T-cell and NK-cell phenotypes when profiled serially in responding and non-responding pts. Additional correlative analyses are ongoing.

Briefly, the MM19 trial evaluated the addition of ixazomib to thalidomide and dexamethasone consolidation therapy for 12 months in transplant eligible newly diagnosed MM (TE NDMM) patients undergoing front-line autologous stem cell transplantation (ASCT), whilst the MM21 trial evaluated an intensive salvage approach using daratumumab-lenalidomide-dexamethasone (DRd) as re-induction (DRd x 4 cycles) and post-ASCT consolidation (DRd x 12 cycles followed by R maintenance until disease progression) in TE NDMM patients failing (<partial response as best response) front-line bortezomib-based induction therapy. This preliminary data highlights the potential of EasyM for sequential PB-based clonotypic MS MRD monitoring in MM. Concordance with standard BM NGF was poor, with 63% of samples with confirmed CR showing detectable M-protein by EasyM but NGF MRD negativity, consistent with the higher sensitivity of EasyM. Comparison of larger sample sets and validation through prospective clinical trials is warranted to better assess the clinical utility of EasyM and rationalise BM-based assessment for MM patients.

Treatment outcome of NTE-NDMM patients treated with daratumumab-ixazomib-dexamethasone was positively associated with higher absolute numbers of total NK-cells and higher percentages of CD57+ and CD16+ NK-cells at baseline, corresponding to a mature and cytotoxic phenotype capable of mediating potent antibody-dependent cellular cytotoxicity. This study highlights the importance of NK-cell phenotype for the effectivity of daratumumab-based combination therapies in NTE-NDMM.

The knockout cells, in which an CRISPR library lentivirus was introduced into a Cas9-expressing AMO1 MM cell line, were treated with ixazomib (IXA), carfilzomib (CFZ), and DMSO for two weeks... We identified 35 genes for PI resistance including the genes encoding subunits of the proteasome 19S complex, consistent with previous reports that shows reducing 19S subunits protects MM cells from bortezomib... Our CRISPR screen revealed that CNOT4 inactivation induced PI resistance in human MM cells. CNOT4 inactivation suppresses the function of 19S proteasome, which is reported the influence of PI resistance, and downregulates the ER stress signal leading to avoid PI induced cell death. Our findings demonstrate that CNOT4 plays an important role in PI sensitivity.

As such, we performed a comprehensive study of qMYD88 L265P response assessment utilizing BM and PB CD19-selected tissue across 5 prospective clinical studies in WM: Ixazomib, Dexamethasone and Rituximab (IDR; NCT02400437) Ibrutinib monotherapy (IBR; NCT02604511); Venetoclax monotherapy (VEN; NCT02677324); Ibrutinib plus Ulocuplomab (IBR/ULO; NCT03225716); and Ibrutinib plus Venetoclax (IBR/VEN; NCT04273139). In contrast, minimal changes in BM and PB MYD88 L265P ΔCt from baseline were observed at best response for most major responders on IBR or IBR/ULO, including individuals who achieved very good partial responses denoted by >90% decrease in IgM by IWWM-11 criteria. In this first prospective evaluation of BM and PB qMYD88 L265P response assessment, we show that both BM and PB L265P qMYD88 analysis can provide more accurate assessment of treatment related changes in disease burden over the current standard of IgM response assessment alone, and can be used to more robustly evaluate clinical trial performance by identifying treatments or regimens that produce more meaningful tumor reductions in WM patients.

P2, N=30, Active, not recruiting, Fred Hutchinson Cancer Center | Trial completion date: Jul 2023 --> Oct 2024

P1/2, N=45, Completed, Oncotherapeutics | Unknown status --> Completed