Zykadia (ceritinib) / Novartis 
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  • ||||||||||  Journal:  Design and evaluation of anaplastic lymphoma kinase degraders using a covalent fumarate handle. (Pubmed Central) -  Dec 17, 2024   
    However, the enhanced anti-proliferative activity of dALK-3 was found to be independent of RNF126, a presumed potential E3 ligase, suggesting the need for investigation of other components within the ubiquitin-proteasome system. Our findings further support the potential application of the fumarate moiety as a binder for E3 ligases in targeted protein degradation.
  • ||||||||||  Venclexta (venetoclax) / Roche, AbbVie, Xalkori (crizotinib) / Pfizer, Zykadia (ceritinib) / Novartis
    The TFG-ROS1 Fusion Is an Oncogenic Driver of Human Myeloid Leukemia (Room 6A (San Diego Convention Center)) -  Nov 6, 2024 - Abstract #ASH2024ASH_2220;    
    He failed to respond to induction chemotherapy based on Cladribine and Cytarabine and then received salvage hematopoietic stem cell transplantation (HSCT), but relapsed only half a month after a transient remission post-HSCT...Our in vitro drug toxicity assays demonstrated that ALK/ROS1 inhibitors Ceritinib and Crizotinib were the most effective in treating primary samples of the patient comparing to chemotherapy and VA...In summary, to our knowledge, this is the first characterization of TFG-ROS1 fusion as a novel oncogenic driver of myeloid leukemia. Our analysis elucidate that TFG-ROS1 fusion is a rare but recurrent oncogenic driver of human leukemia through the MEK/ERK signaling axis, and this fusion protein can be effectively targeted by ALK/ROS1 inhibitors.
  • ||||||||||  Zykadia (ceritinib) / Novartis
    Ceritinib-induced organising pneumonitis () -  Nov 5, 2024 - Abstract #APSR2024APSR_213;    
    If respiratory symptoms arise after initiating TKI treatment, a thorough clinical and lung function evaluation should be conducted. Ceritinib-associated pneumonitis represents a rare form of pulmonary toxicity, emphasizing the importance of early identification and intervention to mitigate mortality risk.
  • ||||||||||  Zykadia (ceritinib) / Novartis, Promacta (eltrombopag) / Novartis
    Review, Journal:  Overcoming antibiotic resistance: the potential and pitfalls of drug repurposing. (Pubmed Central) -  Nov 1, 2024   
    This article aims to explore the potential of drug repurposing as a strategy to combat antibiotic resistance, examining its benefits, challenges, and future prospects. We address the legal, economic, and practical challenges associated with repurposing existing drugs, highlight successful examples, and propose solutions to enhance the efficacy and viability of this approach in combating MDR bacterial infections.
  • ||||||||||  Zykadia (ceritinib) / Novartis, ALK PROTAC / GNI Group
    Journal:  Discovery of orally bioavailable ALK PROTACs based ceritinib against ALK positive cancers. (Pubmed Central) -  Oct 27, 2024   
    We address the legal, economic, and practical challenges associated with repurposing existing drugs, highlight successful examples, and propose solutions to enhance the efficacy and viability of this approach in combating MDR bacterial infections. A series of rigid ALK PROTACs were developed through conjugation of Ceritinib and thalidomide, orally bioavailable PROTAC 4B (F
  • ||||||||||  Zykadia (ceritinib) / Novartis
    Trial completion date:  Ceritinib Plus Docetaxel in ALK-Negative, EGFR WT Advanced NSCLC (clinicaltrials.gov) -  Sep 19, 2024   
    P1,  N=21, Active, not recruiting, 
    Active, not recruiting --> Completed Trial completion date: Apr 2025 --> Apr 2026
  • ||||||||||  Zykadia (ceritinib) / Novartis
    Journal:  In-cell bioluminescence resonance energy transfer (BRET)-based assay uncovers ceritinib and CA-074 as SARS-CoV-2 papain-like protease inhibitors. (Pubmed Central) -  Aug 20, 2024   
    Using this assay, three protease inhibitors were identified as novel PLpro inhibitors that are structurally disparate from those previously known. Subsequent enzymatic assays and ligand-protein interaction analysis based on molecular docking revealed that ceritinib directly inhibited PLpro, showing high geometric complementarity with the substrate-binding pocket in PLpro, whereas CA-074 methyl ester underwent intracellular hydrolysis, exposing a free carboxyhydroxyl group essential for hydrogen bonding with G266 in the BL2 groove, resulting in PLpro inhibition.
  • ||||||||||  Lorbrena (lorlatinib) / Pfizer
    A Patient-Centric, Phase II Trial of First-Line Lorlatinib&alk TKIs in China Advanced ALK+ Non-Small Cell Lung Cancer (Exhibit Hall) -  Jul 24, 2024 - Abstract #IASLCWCLC2024IASLC_WCLC_2211;    
    The RO cohort is designed to serve as comparison cohort, which will enroll 63 treatment-naive subjects who may receive crizotinib, ceritinib, alectinib, brigatinib, ensartinib, lorlatinib, etc. Real-world efficacy and safety data of ALK TKIs were collected in the same cross-section. The primary endpoint is real-world progression-free survival (rwPFS) of ALK TKIs in the first-line treatment of advanced NSCLC patients with ALK fusion.
  • ||||||||||  OBX02-011 / Oncobix
    OBX02-011, a Novel Oral ALK and EGFR Dual-target Tyrosine Kinase Inhibitor for the Treatment of Advanced NSCLC Patients (Exhibit Hall) -  Jul 24, 2024 - Abstract #IASLCWCLC2024IASLC_WCLC_2194;    
    In addition, OBX02-011 demonstrated superior inhibition compared to lorlatinib in ALK_C1156Y, G1202R, and L1196M mutations associated with clinical resistance to the first generation ALK inhibitor crizotinib and/or the second generation ALK inhibitors alectinib, brigatinib, and ceritinib...OBX02-011 also demonstrated tumor regression in the osimertinib-resistant lung cancer patient-derived xenograft model with EGFR_exon 19 deletion/T790M/C797S...In vitro cell-based assay results showed that OBX02-011 does not inhibit NTRK2 (TRKB), which causes neurological toxicity, and there were also no significant findings for OBX02-011 in the CNS safety pharmacology study. Based on these studies, a first-in-human study will be conducted in 2024 to address the current resistance mechanisms in ALK-positive or EGFR-positive NSCLC patients and prolong progression free survival.
  • ||||||||||  Characterizing the Severity and Timing of Real-World ALK-Inhibitor Associated Weight Gain in Non-Small Cell Lung Cancer (Exhibit Hall) -  Jul 24, 2024 - Abstract #IASLCWCLC2024IASLC_WCLC_2170;    
    Future investigation of optimal prevention and management of weight gain is encouraged. Table 1: Real World Weight Gain Characteristics on ALK-TKIs Crizotinib Brigatinib Alectinib Lorlatinib p-value Mean Max Weight Gain (% baseline) [95% CI] +4.2% [1.9-6.7] +4.5% [2.3-6.6] +6.4% [4.4-8.5] +13.3% [9.3-17.4] <0.001 Mean Time to Max Weight Gain (mo) [95% CI] 20.0mo [12.4-27.6] 24.6mo [14.0-35.2] 16.0mo [11.8-20.1] 22.2mo [13.7-30.8] 0.24 Mean Max Weight Gain by 6 mo (% baseline) [95% CI] -1.4% [-4.0-1.2] +0.9% [-1.2-3.0] +3.2% [1.3-5.1] +5.8% [2.9-8.7] 0.02 % Grade 2-3 Weight Gain [% Grade 3] 11.8% [0%] 13.0% [0%] 30.2% [3.9%] 61.3% [29.0%] <0.001
  • ||||||||||  Lorbrena (lorlatinib) / Pfizer
    Patterns of Progression with Lorlatinib and Insights into Subsequent Anticancer Therapy Efficacy in Advanced ALK+ NSCLC (20D) -  Jul 24, 2024 - Abstract #IASLCWCLC2024IASLC_WCLC_978;    
    P3
    Best Overall Response and Objective Response Rate on First Subsequent Anticancer Therapy Study treatment Lorlatinib Crizotinib First Subsequent Therapy Any ALK TKI (n=23) a Any non-ALK TKI (n=15) b Overall (n=38) Any ALK TKI (n=101) a Any non-ALK TKI (n=8) b Overall (n=109) Objective response rate (95% CI), % c 26.1 (10.2-48.4) 20.0 (4.3-48.1) 23.7 (11.4-40.2) 17.8 (10.9-26.7) 12.5 (0.3-52.7) 17.4 (10.8-25.9) Best overall response, n (%) Complete response 2 (9) 1 (7) 3 (8) 1 (1) 0 1 (1) Partial response 4 (17) 2 (13) 6 (16) 17 (17) 1 (13) 18 (17) Stable disease 1 (4) 3 (20) 4 (11) 23 (23) 0 23 (21) Progressive disease 6 (26) 3 (20) 9 (24) 10 (10) 2 (25) 12 (11) Unknown 3 (13) 5 (33) 8 (21) 9 (9) 4 (50) 13 (12) Not reported, therapy ongoing 7 (30) 1 (7) 8 (21) 41 (41) 1 (13) 42 (39) a Includes alectinib, brigatinib, ceritinib, crizotinib, and lorlatinib. b Includes chemotherapy
  • ||||||||||  Zykadia (ceritinib) / Novartis
    Trial completion date, Trial primary completion date:  Study of Safety and Efficacy of Ceritinib in Combination With Nivolumab in Patients With ALK-positive Non-small Cell Lung Cancer (clinicaltrials.gov) -  Jun 19, 2024   
    P1,  N=57, Active, not recruiting, 
    Patient-sourced drug sensitivity testing of lung cancer-like organs selects drug-sensitive medications based on NGS results and provides a reference for subsequent drug therapy for patients after drug resistance, particularly those who remain ALK rearrangement-positive at baseline. Trial completion date: Sep 2024 --> Apr 2025 | Trial primary completion date: Sep 2024 --> Apr 2025
  • ||||||||||  Phase classification, Enrollment change, Trial completion date, Trial primary completion date:  PIKACHU: Treatment Strategies and Survival Outcome for Non-small Cell Lung Cancer With Oncogenic Mutation (clinicaltrials.gov) -  Jun 3, 2024   
    P2,  N=6000, Recruiting, 
    This information serves as a valuable reference for guiding the treatment of this molecular subset of NSCLC. Phase classification: P --> P2 | N=100 --> 6000 | Trial completion date: Dec 2025 --> Dec 2027 | Trial primary completion date: Dec 2024 --> Dec 2026
  • ||||||||||  Zykadia (ceritinib) / Novartis
    Journal:  The synthesis and evaluation of novel ALK inhibitors containing the sulfoxide structure. (Pubmed Central) -  Jun 3, 2024   
    With ceritinib as the lead, a series of novel compounds containing the sulfoxide structure were synthesized and evaluated as anaplastic lymphoma kinase inhibitors...Using 18d as a representative, which exhibited the best in vivo results, we carried out mechanistic studies such as anti-colony formation, induced tumor cell apoptosis, ALK kinase protein phosphorylation in H2228 tumor cells, and molecular docking. All these results indicate that compound 18d is a good anti-tumor lead compound and worthy of further study.
  • ||||||||||  Review, Journal:  Comprehensive review of ROS1 tyrosine kinase inhibitors (TKIs)-classified by structural designs and mutation spectrum [solvent front mutation (G2032R) and central ?-sheet 6 (C?6) mutation (L2086F)]. (Pubmed Central) -  May 8, 2024   
    Despite ROS1 fusion-positive NSCLC accounting for approximately 1% to 2% of NSCLC, there is a long list of ROS1 tyrosine kinase inhibitors (TKIs) being developed in addition to three approved ROS1 TKIs, crizotinib, entrectinib and repotrectinib...Additionally, the less known central ?-sheet 6 (C?6) mutation ROS1 L2086F confer resistances to next-generation ROS1 TKIs (taletrectinib, lorlatinib, potentially NVL-520) that can be overcome by cabozantinib as documented in published patient reports and may potentially by certain L-shaped Type I ROS1 TKIs including gilteritinib which is approved as a FLT3 inhibitor for AML. Future clinical trials should investigate cabozantinib and gilteritinib to repurpose them as ROS1 TKIs that can target C?6 mutation.
  • ||||||||||  Zykadia (ceritinib) / Novartis, Mekinist (trametinib) / Novartis, BeiGene
    Trial completion date:  Study of Trametinib + Ceritinib in Patients With Unresectable Melanoma (clinicaltrials.gov) -  Apr 30, 2024   
    P1,  N=27, Active, not recruiting, 
    Future clinical trials should investigate cabozantinib and gilteritinib to repurpose them as ROS1 TKIs that can target C?6 mutation. Trial completion date: Mar 2024 --> Aug 2024
  • ||||||||||  Xalkori (crizotinib) / Pfizer, Zykadia (ceritinib) / Novartis
    Targeted treatment in inflammatory myofibroblastic tumors in children. (Hall A; Poster Bd #: 413) -  Apr 24, 2024 - Abstract #ASCO2024ASCO_3416;    
    Surgery is the mainstay of treatment. The effectiveness of chemotherapy is yet unclear despite its use in inoperable cases.
  • ||||||||||  Qi Xinke (iruplinalkib) / Qilu Pharma
    Journal, Metastases:  Chinese expert consensus on iruplinalkib for the treatment of locally advanced or metastatic ALK-positive non-small cell lung cancer (2024 edition) (Pubmed Central) -  Mar 22, 2024   
    On January 16, 2024, the NMPA approved iruplinalkib for the first-line treatment of locally advanced or metastatic ALK-positive NSCLC patients. In order to better understand the efficacy and safety of iruplinalkib, and facilitate more rationally clinical application of iruplinalkib, the Medical Oncology Branch of China International Exchange and Promotive Association for Medical and Health Care and the Chinese Association for Clinical Oncologists co-organized experts to compile the "Chinese expert consensus on iruplinalkib for the treatment of locally advanced or metastatic ALK-positive non-small cell lung cancer (2024 edition)".
  • ||||||||||  Enrollment closed, Enrollment change, IO biomarker:  MULTISARC: Molecular Profiling of Advanced Soft-tissue Sarcomas (clinicaltrials.gov) -  Mar 5, 2024   
    P3,  N=603, Active, not recruiting, 
    Overall, this study presents the added value of using spheroids and positions lorlatinib and repotrectinib as the most effective TKIs against the studied ROS1 resistance point mutations. Recruiting --> Active, not recruiting | N=960 --> 603
  • ||||||||||  Interrogation of autophagy inhibition in anaplastic large cell lymphoma (ALCL) (Section 14) -  Mar 5, 2024 - Abstract #AACR2024AACR_7051;    
    With the addition of crizotinib or brentuximab vedotin to the ALCL99 chemotherapy backbone, the recently reported Children's Oncology Group ANHL12P1 study demonstrated a 2-year event-free survival for ALCL patients of 79%...Target engagement of autophagy inhibition (ULK-101 directed against ULK1/2 and hydroxychloroquine (HCQ) targeting the lysosome) was assessed by western blot using phospho-ATG14S29 and LC3B-II intensity in 6-point dose response curves...Decreased viability in Karpas 299 cells was observed after crizotinib, ceritinib and lorlatinib treatments with nanomolar potency...ALK inhibition activates autophagy in ALCL cells and autophagy activation is effectively mitigated through concurrent autophagy inhibition. ALK inhibitor resistance in Karpas 299 cells will be further evaluated to determine whether autophagy contributes to the resistant phenotype.
  • ||||||||||  Xalkori (crizotinib) / Pfizer, Zykadia (ceritinib) / Novartis, Rozlytrek (entrectinib) / Roche
    Real-world clinical outcomes in patients with advanced ROS1+non-small cell lung cancer in the US (Section 46) -  Mar 5, 2024 - Abstract #AACR2024AACR_5146;    
    Only 59% of pts initiated 1L ROS1-sensitive TKI monotherapy. These results highlight potential disparities in the diagnosis and treatment of ROS1+ NSCLC and opportunities for improving clinical outcomes.
  • ||||||||||  Zykadia (ceritinib) / Novartis, Mekinist (trametinib) / Novartis, BeiGene
    Phase 1/2 trial of trametinib + ceritinib in patients with unresectable melanoma (Section 48) -  Mar 5, 2024 - Abstract #AACR2024AACR_3857;    
    These results highlight potential disparities in the diagnosis and treatment of ROS1+ NSCLC and opportunities for improving clinical outcomes. Abstract is embargoed at this time.