ceritinib and Neoplasms

Anaplastic lymphoma kinase (ALK) gene activation is involved in the carcinogenesis process of several human cancers such as anaplastic large cell lymphoma, lung cancer, inflammatory myofibroblastic tumors and neuroblastoma, as a consequence of fusion with other oncogenes (NPM, EML4, TIM, etc) or gene amplification, mutation or protein overexpression. ALK is a transmembrane tyrosine kinase receptor that, upon ligand binding to its extracellular domain, undergoes dimerization and subsequent autophosphorylation of the intracellular kinase domain. When activated in cancer it represents a target for specific inhibitors, such as crizotinib, ceritinib, alectinib etc. which use has demonstrated significant effectiveness in ALK-positive patients, in particular ALK-positive non- small cell lung cancer. Several mechanisms of resistance to these inhibitors have been described and new strategies are underway to overcome the limitations of current ALK inhibitors.

Topics: Anaplastic Lymphoma Kinase; Animals; Carbazoles; Carcinoma, Non-Small-Cell Lung; Crizotinib; Humans; Neoplasms; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Sulfones

Currently available oral oncology therapies are reviewed, and specialty pharmacy services for patients receiving these drugs are described.. Market introductions of new oral oncology drugs have increased substantially over the past decade, and 25-30% of all oncology agents in development are oral medications. Oral agents for treatment of breast cancer include capecitabine, lafatinib, and palbociclib. Several oral agents are used in treating patients with lung cancer driven by mutations of genes coding for anaplastic lymphoma kinase (ALK) and epidermal growth factor receptor (EGFR); currently available agents include the ALK inhibitors certinib and crizotinib and the EGFR inhibitors afatinib, erlotinib, and gefitinib. Four oral targeted therapies are used in the treatment of melanoma associated with the B-Raf proto-oncogene, BRAF: cobimetinib, dabrafenib, trametinib, and vemurafenib. Oral agents for treatment of prostate cancer include abiraterone acetate and enzalutamide. Oral agents for treatment of renal cell carcinoma include axitinib, everolimus, pazopanib, sorafenib, and sunitinib. Specialty pharmacy services for patients receiving oral oncology agents can include (1) providing patient counseling and education on adverse effects and self-management strategies, (2) processing prior-authorization requests and helping patients navigate copayment assistance programs, and (3) monitoring for medication toxicities and recommending dose adjustments as appropriate.. Many oral oncology medications have been introduced over the past 10-15 years, with many others in clinical development. Due to the complexity of initiating and monitoring patients receiving these oral therapies, specialty pharmacy services are an essential component of many patients' cancer care.

Topics: Administration, Oral; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; ErbB Receptors; Humans; Molecular Targeted Therapy; Neoplasms; Pharmaceutical Services; Pharmacists; Proto-Oncogene Mas; Proto-Oncogene Proteins B-raf; Pyrimidines; Sulfones

In this phase I, dose-escalation study, we sought to determine the maximum tolerated dose (MTD) of the anaplastic lymphoma kinase/c-ROS oncogene 1 receptor (ALK/ROS1) inhibitor ceritinib in combination with gemcitabine-based chemotherapy in patients with advanced solid tumors. Secondary objectives were characterization of the safety profile, pharmacokinetics and preliminary efficacy of these combinations, and identification of potential biomarkers of efficacy. Ceritinib was combined with gemcitabine (Arm 1), gemcitabine/nab-paclitaxel (Arm 2) or gemcitabine/cisplatin (Arm 3). Drug concentrations in plasma were measured by tandem mass spectrometric detection (LC-MS/MS). We analyzed archival tumor tissue for ALK, ROS1, hepatocyte growth factor receptor (c-MET) and c-Jun N-terminal kinase (JNK) expression by immunohistochemistry. Arm 2 closed early secondary to toxicity. Twenty-one patients were evaluable for dose-limiting toxicity (DLT). There was one DLT in Arm 1 (grade 3 ALT increase) and three DLTs in Arm 3 (grade 3 acute renal failure, grade 3 thrombocytopenia, grade 3 dyspnea). The MTD of ceritinib was determined to be 600 mg (Arm 1) and 450 mg orally daily (Arm 3). Main toxicities were hematologic, constitutional and gastrointestinal as expected by the chemotherapy backbone. The apparent clearance for ceritinib decreased substantially after repeated dosing; cisplatin did not significantly affect the pharmacokinetics of ceritinib. The overall response rate was 20%; the median progression-free survival was 4.8 months. Three out of five response-evaluable cholangiocarcinoma patients had clinical benefit. Increased expression of c-MET was associated with a lack of clinical benefit. Ceritinib in combination with gemcitabine and gemcitabine/cisplatin has a manageable toxicity profile. Further development of this strategy in tumors with ALK or ROS1 fusions is warranted.

Topics: Adult; Aged; Anaplastic Lymphoma Kinase; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Female; Gemcitabine; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Progression-Free Survival; Protein Kinase Inhibitors; Pyrimidines; Sulfones

Topics: Anaplastic Lymphoma Kinase; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Drug Resistance, Neoplasm; Humans; Mutation; Neoplasms; Pharmaceutical Preparations; Protein Kinase Inhibitors

T-cell immunotherapies are often thwarted by the limited presentation of tumor-specific antigens abetted by the downregulation of human leukocyte antigen (HLA). We showed that drugs inhibiting ALK and RET produced dose-related increases in cell-surface HLA in tumor cells bearing these mutated kinases

Topics: Anaplastic Lymphoma Kinase; Animals; Antigen Presentation; Antigens, Neoplasm; Cell Line, Tumor; Crizotinib; Female; Histocompatibility Antigens Class I; Humans; Mice, Transgenic; Neoplasms; Peptides; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-ret; Pyrimidines; Sulfones

Ceritinib, an advanced anaplastic lymphoma kinase (ALK) next-generation inhibitor, has been proved excellent antitumor activity in the treatment of ALK-associated cancers. However, the accumulation of acquired resistance mutations compromise the therapeutic efficacy of ceritinib. Despite abundant mutagenesis data, the structural determinants for reduced ceritinib binding in mutants remains elusive. Focusing on the G1123S and F1174C mutations, we applied molecular dynamics (MD) simulations to study possible reasons for drug resistance caused by these mutations. The MD simulations predict that the studied mutations allosterically impact the configurations of the ATP-binding pocket. An important hydrophobic cluster is identified that connects P-loop and the αC-helix, which has effects on stabilizing the conformation of ATP-binding pocket. It is suggested, in this study, that the G1123S and F1174C mutations can induce the conformational change of P-loop thereby causing the reduced ceritinib affinity and causing drug resistance.

Topics: Adenosine Triphosphate; Anaplastic Lymphoma Kinase; Binding Sites; Drug Resistance, Neoplasm; Humans; Molecular Dynamics Simulation; Mutagenesis, Site-Directed; Neoplasms; Principal Component Analysis; Protein Kinase Inhibitors; Protein Structure, Tertiary; Pyrimidines; Sulfones

Recently, proteolysis targeting chimera (PROTAC) technology is highlighted in drug discovery area as a new therapeutic approach. PROTAC as a heterobifunctional molecule is comprised of two ligands, which recruit target protein and E3 ligase, respectively. To degrade the anaplastic lymphoma kinase (ALK) fusion protein, such as NPM-ALK or EML4-ALK, we generated several ALK-PROTAC molecules consisted of ceritinib, one of the ALK inhibitors, and ligand of von Hippel-Lindau (VHL) E3 ligase. Among these molecules, TD-004 effectively induced ALK degradation and inhibited the growth of ALK fusion positive cell lines, SU-DHL-1 and H3122. We also confirmed that TD-004 significantly reduced the tumor growth in H3122 xenograft model.

Topics: Anaplastic Lymphoma Kinase; Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Female; Humans; Ligands; Mice, Inbred BALB C; Mice, Nude; Neoplasms; Oncogene Proteins, Fusion; Proteasome Endopeptidase Complex; Protein Kinase Inhibitors; Proteolysis; Pyrimidines; Sulfones; Von Hippel-Lindau Tumor Suppressor Protein

Topics: Humans; Neoplasms; Polypharmacology; Proteomics; Pyrimidines; Sulfones; Systems Biology

Ceritinib, an ALK inhibitor, was hurriedly approved by the US FDA last year, and demonstrates impressive results in EML4-ALK positive patients. To get a superior ALK inhibitor, we synthesized several ceritinib derivatives with minor modifications to the phenylpiperidine moiety. Biochemical and cellular assays demonstrated the improved activity of KRCA-386 over that of ceritinib. KRCA-386 has superior inhibitory activity against ALK mutants commonly found in crizotinib-resistant patients. Particularly, KRCA-386 has considerably greater activity than ceritinib against the G1202R mutant, one of the most challenging mutations to overcome. The cell cycle analysis indicates that ALK inhibitors induce G1/S arrest, resulting in apoptosis. The in vivo xenograft data also demonstrate that KRCA-386 is significantly better than ceritinib. KRCA-386 dosed at 25 mpk caused 105% tumor growth inhibition (TGI) compared to 72% TGI with ceritinib dosed at 25 mpk. (n = 8, P = 0.010) The kinase profiling assay revealed that several kinases, which are known to be critical for tumor growth, are inhibited by KRCA-386, but not by ceritinib. We anticipate that this characteristic of KRCA-386 enhances its in vivo efficacy. In addition, KRCA-386 shows excellent blood brain barrier penetration compared to ceritinib. These results suggest that KRCA-386 could be useful for crizotinib-resistant patients with brain metastases.

Topics: Anaplastic Lymphoma Kinase; Animals; Antineoplastic Agents; Blood-Brain Barrier; Cell Line, Tumor; Female; Humans; Male; Mice; Mice, Inbred BALB C; Mice, Inbred ICR; Mice, Nude; Neoplasms; Oncogene Proteins, Fusion; Protein Kinase Inhibitors; Pyrimidines; Receptor Protein-Tyrosine Kinases; Structure-Activity Relationship; Sulfones; Xenograft Model Antitumor Assays

Multidrug resistance (MDR) is the leading cause of treatment failure in cancer chemotherapy. The overexpression of ATP-binding cassette (ABC) transporters, particularly ABCB1, ABCC1 and ABCG2, play a key role in mediating MDR by pumping anticancer drugs out from cancer cells. Ceritinib (LDK378) is a second-generation tyrosine kinase inhibitor of anaplastic lymphoma kinase (ALK) currently in phase III clinical trial for the treatment of non-small cell lung cancer. Here, we found that ceritinib remarkably enhanced the efficacy of chemotherapeutic drugs in ABCB1 or ABCG2 over-expressing cancer cells in vitro and in vivo. Ceritinib significantly increased the intracellular accumulation of chemotherapeutic agents such as doxorubicin (DOX) by inhibiting ABCB1 or ABCG2-mediated drug efflux in the transporters-overexpressing cells. Mechanistically, ceritinib is likely a competitive inhibitor of ABCB1 and ABCG2 because it competed with [(125)I]-iodoarylazidoprazosin for photo affinity labeling of the transporters. On the other hand, at the transporters-inhibiting concentrations, ceritinib did not alter the expression level of ABCB1 and ABCG2, and phosphorylation status of AKT and ERK1/2. Thus the findings advocate further clinical investigation of combination chemotherapy of ceritinib and other conventional chemotherapeutic drugs in chemo-refractory cancer patients.

Topics: Anaplastic Lymphoma Kinase; Animals; Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily G, Member 2; ATP-Binding Cassette Transporters; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Doxorubicin; Drug Resistance, Neoplasm; Extracellular Signal-Regulated MAP Kinases; Gene Expression Regulation, Neoplastic; HEK293 Cells; Humans; Inhibitory Concentration 50; MCF-7 Cells; Mice, Nude; Neoplasm Proteins; Neoplasms; Paclitaxel; Phosphorylation; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones; Time Factors; Transfection; Tumor Burden; Up-Regulation; Xenograft Model Antitumor Assays

Topics: Clinical Trials, Phase I as Topic; Drug Approval; Humans; Neoplasms; Pyrimidines; Sulfones; United States; United States Food and Drug Administration

Ceritinib is a highly selective inhibitor of an important cancer target, anaplastic lymphoma kinase (ALK). Because it is an investigational compound, there is a need to develop a robust and reliable analytical method for its quantitative determination in human plasma. Here, we report the validation of a liquid chromatography tandem mass spectrometry (LC-MS/MS) method for the rapid quantification of ceritinib in human plasma. The method consists of protein precipitation with acetonitrile, and salting-out assisted liquid-liquid extraction (SALLE) using a saturated solution of sodium chloride prior to analysis by LC-MS/MS with electrospray ionization (ESI) technique in positive mode. Samples were eluted at 0.800 mL min(-1) on Ascentis Express® C18 column (50 mm × 2.1 mm, 2.7 μm) with a mobile phase made of 0.1 % formic acid in water (A) and 0.1 % formic acid in acetonitrile (B). The method run time was 3.6 min and the low limit of quantification (LLOQ) was estimated at 1.00 ng mL(-1) when using 0.100 mL of human plasma. The assay was fully validated and the method exhibited sufficient specificity, accuracy, precision, and sensitivity. In addition, recovery data and matrix factor (MF) in normal and in hemolyzed plasmas were assessed, while incurred samples stability (ISS) for ceritinib was demonstrated for at least 21 months at a storage temperature of -65 °C or below. The method was successfully applied to the measurement of ceritinib in clinical samples and the data obtained on incurred samples reanalysis (ISR) showed that our method was reliable and suitable to support the analysis of samples from the clinical studies.

Topics: Antineoplastic Agents; Chromatography, Liquid; Clinical Trials, Phase I as Topic; Humans; Liquid-Liquid Extraction; Neoplasms; Pyrimidines; Sulfones; Tandem Mass Spectrometry; Tissue Distribution

The synthesis, preclinical profile, and in vivo efficacy in rat xenograft models of the novel and selective anaplastic lymphoma kinase inhibitor 15b (LDK378) are described. In this initial report, preliminary structure-activity relationships (SARs) are described as well as the rational design strategy employed to overcome the development deficiencies of the first generation ALK inhibitor 4 (TAE684). Compound 15b is currently in phase 1 and phase 2 clinical trials with substantial antitumor activity being observed in ALK-positive cancer patients.

Topics: Anaplastic Lymphoma Kinase; Animals; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Dogs; Humans; Macaca fascicularis; Male; Neoplasms; Protein Kinase Inhibitors; Pyrimidines; Rats; Receptor Protein-Tyrosine Kinases; Structure-Activity Relationship; Sulfones; Xenograft Model Antitumor Assays

Topics: Anaplastic Lymphoma Kinase; Animals; Humans; Male; Neoplasms; Protein Kinase Inhibitors; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones