Vinorelbine Research Articles

Probing the Mechanisms Underlying the Transport of the Vinca Alkaloids by P-glycoprotein

The efficacy of many cancer drugs is hindered by P-glycoprotein (Pgp), a cellular pump that removes drugs from cells. To improve chemotherapy, drugs capable of evading Pgp must be developed. Despite similarities in structure, vinca alkaloids (VAs) show disparate Pgp-mediated efflux ratios. ATPase activity and binding affinity studies show at least two binding sites for the VAs: high- and low-affinity sites that stimulate and inhibit the ATPase activity rate, respectively. The affinity for ATP from the ATPase kinetics curve for vinblastine (VBL) at the high-affinity site was 2- and 9-fold higher than vinorelbine (VRL) and vincristine (VCR), respectively. Conversely, VBL had the highest Km (ATP) for the low-affinity site. The dissociation constants (KDs) determined by protein fluorescence quenching were in the order VBL < VRL< VCR. The order of the KDs was reversed at higher substrate concentrations. Acrylamide quenching of protein fluorescence indicate that the VAs, either at 10 µM or 150 µM, predominantly maintain Pgp in an open-outward conformation. When 3.2 mM AMPPNP was present, 10 µM of either VBL, VRL, or VCR cause Pgp to shift to an open-outward conformation, while 150 µM of the VAs shifted the conformation of Pgp to an intermediate orientation, between opened inward and open-outward. However, the conformational shift induced by saturating AMPPNP and VCR condition was less than either VBL or VRL in the presence of AMPPNP. At 150 µM, atomic force microscopy (AFM) revealed that the VAs shift Pgp population to a predominantly open-inward conformation. Additionally, STDD NMR studies revealed comparable groups in VBL, VRL, and VCR are in contact with the protein during binding. Our results, when coupled with VAs-microtubule structure-activity relationship studies, could lay the foundation for developing next-generation VAs that are effective as anti-tumor agents. A model that illustrates the intricate process of Pgp-mediated transport of the VAs is presented.

Design and Synthesis of Cyclolipopeptide Mimics of Dysoxylactam A and Evaluation of the Reversing Potencies against P-Glycoprotein-Mediated Multidrug Resistance.

Inspired by the structure of dysoxylactam A (DLA) that has been demonstrated to reverse P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) effectively, 61 structurally simplified cyclolipopeptides were thus designed and synthesized via an effective method, and their reversing P-gp-mediated MDR potentials were evaluated, which provided a series of more potent analogues and allowed us to explore their structure-activity relationship (SAR). Among them, a well-simplified compound, 56, with only two chiral centers that all derived from amino acids dramatically reversed drug resistance in KBV200 cells at 10 μM in combination with vinorelbine (VNR), paclitaxel (PTX), and adriamycin (ADR), respectively, which is more promising than DLA. The mechanism study showed that 56 reversed the MDR of tumor cells by inhibiting the transport function of P-gp rather than reducing its expression. Notably, compound 56 effectively restored the sensitivity of MDR tumors to VNR in vivo at a dosage without obvious toxicity.

Vinorelbine-loaded multifunctional magnetic nanoparticles as anticancer drug delivery systems: synthesis, characterization, and in vitro release study.

In this study, a multifunctional therapeutic agent combining chemotherapy and photothermal therapy on a single platform has been developed in the form of vinorelbine-loaded polydopamine-coated iron oxide nanoparticles. Vinorelbine (VNB) is loaded on the surface of iron oxide nanoparticles produced by a solvothermal technique after coating with polydopamine (PDA) with varying weight ratios as a result of dopamine polymerisation and covalent bonding of thiol-polyethylene glycol (SH-PEG). The VNB/PDA/Fe3O4 nanoparticles have a saturation magnetisation value of 60.40 emu/g in vibrating sample magnetometry, which proves their magnetisation. Vinorelbine, which is used as an effective cancer therapy agent, is included in the nanocomposite structure, and in vitro drug release studies under different pH conditions (pH 5.5 and 7.4) and photothermal activity at 808 nm NIR laser irradiation are investigated. The comprehensive integration of precise multifunctional nanoparticles design, magnetic response, and controlled drug release with photothermal effect brings a different perspective to advanced cancer treatment research.

The development of electrochemical DNA biosensor based on woolen ball-shaped La3+/TiO2 nanostructure coating: Nanomolar detection of Vinorelbine

Although Vinorelbine (VOB) is a powerful anticancer medication, it inevitably has a number of adverse effects. Therefore, identifying this medication in biological samples is crucial for assessing both its effectiveness and negative effects. In this study, a new DNA biosensor was created to analyze VOB within biological samples. Moreover, the sensor has been created though the modification of a pencil graphite electrode (PEG) with polypyrrole (PP), a woolen ball-shaped La3+/TiO2 nanostructure (WB–S La3+/TiO2-NS) (enhancing the conductivity of electricity), along with ds-DNA (calf thymus) (ds-DNA/PP/WB-S La3+/TiO2-NS/PGE). Alterations in electrode signal has been then utilized to determine whether VOB is present. Under optimized condition, the differential pulse voltammetry (DPV) and electrochemical impedance spectroscopy (EIS) techniques were adopted for electrochemical sensing of VOB. With a 0.37 nM detection limit, ds-DNA/PP/WB-S La3+/TiO2-NS/PGE demonstrated remarkable sensitivity for VOB at concentrations between 0.001 and 150.0 μM by DPV method. In addition, the calibration curve shows a linear range between 5.0 and 100.0 μM vanillin with a detection limit of about 0.76 μM by EIS method. Theoretical docking investigation was used to analyze the contacts among VOB and ds-DNA bases for future assessments, and the results supported the intercalation of VOB with guanine bases ds-DNA's intercalations. VOB was examined using the ds-DNA/PP/WB-S La3+/TiO2-NS/PGE method in actual samples.

Vinorelbine Alters lncRNA Expression in Association with EGFR Mutational Status and Potentiates Tumor Progression Depending on NSCLC Cell Lines' Genetic Profile.

Lung cancer remains the leading cause of cancer-related mortality worldwide, with non-small cell lung cancer (NSCLC) as the most common type. In addition, NSCLC has a high mortality rate and an overall adverse patient outcome. Although significant improvements have been made in therapeutic options, effectiveness is still limited in late stages, so the need for a better understanding of the genomics events underlying the current therapies is crucial to aid future drug development. Vinorelbine (VRB) is an anti-mitotic chemotherapy drug (third-generation vinca alkaloid) used to treat several malignancies, including NSCLC. However, despite its widespread clinical use, very little is known about VRB-associated genomic alterations in different subtypes of NSCLC. This article is an in vitro investigation of the cytotoxic effects of VRB on three different types of NSCLC cell lines, A549, Calu-6, and H1792, with a closer focus on post-treatment genetic alterations. Based on the obtained results, VRB cytotoxicity produces modifications on a cellular level, altering biological processes such as apoptosis, autophagy, cellular motility, cellular adhesion, and cell cycle, but also at a genomic level, dysregulating the expression of some coding genes, such as EGFR, and long non-coding RNAs (lncRNAs), including CCAT1, CCAT2, GAS5, MALAT1, NEAT1, NORAD, XIST, and HOTAIR, that are implicated in the mitogen-activated protein kinase (MAPK) signaling pathway. Therefore, although extensive validation is required, these results pave the way towards a better understanding of the cellular and genomic alterations underlying the cytotoxicity of VRB.

Vinorelbine as First-Line Treatment in Stage IV Canine Primary Pulmonary Carcinoma.

Vinorelbine (VRL), a semi-synthetic vinca alkaloid commonly used in humans with advanced lung cancer, reaches high concentrations in the lung tissue, has proven antineoplastic activity and a low toxicity profile in dogs. Treatment-naïve, client-owned dogs with a cyto/histological diagnosis of advanced pulmonary carcinoma, selected from a laboratory database and previously subjected to imaging, were enrolled in the study. Vinorelbine (15 mg/m2) was administered weekly for 4 weeks and then fortnightly until progressive disease was documented. Staging work-up was repeated by means of diagnostic imaging after the fourth VRL (i.e., 28 days) and monthly thereafter; response to treatment was evaluated according to the RECIST. Toxicity was graded following the VCOGC group. Ten dogs met the inclusion criteria. Partial response was documented in eight dogs. Median time to progression was 88 days (range: 7-112) and median survival time for all dogs was 100 days (range 7-635). The most common side effect was neutropenia. The main limitations of the study were the absence of histological diagnosis in eight cases and the limited number of treated dogs. VRL is well tolerated with an adequate toxicity profile and may be useful in the management of advanced lung tumours if used as a first-line treatment strategy.

Determination of Bendamustine, Gemcitabine and Vinorelbine (BEGEV) regimen in spiked human plasma using multivariate model update chemometric methods

Combination of bendamustine (BEN), gemcitabine (GEM), and vinorelbine (VIB), (BEGEV) regimen, has been proved to be a tolerable, safe and effective regimen in relapsed/refractory classical hodgkin lymphoma (R/R cHL). Two chemometric models named principal component regression (PCR) and partial least squares (PLS) were established for determination and quantification of BEN, GEM and VIB simultaneously in the ranges of 5–25 µg/mL for each of BEN and VIB, while in the range of 10 –30 µg/mL for GEM in pure and spiked plasma using their UV absorbance. The updated methods have been proven their ability to predict the concentrations of the studied drugs and validated according to FDA guidelines showing good results. There was no significant difference between the developed methods and the reported LC-MS/MS method upon statistical comparison was applied. Furthermore, the updated chemometric methods have advantages of being sensitive, accurate and cost effective for estimation of BEN, GEM and VIB and monitoring their concentration.

Fe3O4 Composite Superparticles with RGD/Magnetic Dual-Targeting Capabilities for the Imaging and Treatment of Non-Small Cell Lung Cancer.

In clinical practice, the incidence and mortality of non-small cell lung cancer are increasing year by year, which is a serious threat to the health of patients. Once the optimal surgical window is missed, the toxic side effects of chemotherapy have to be confronted. With the rapid development of nanotechnology in recent years, medical science and health have been greatly impacted. Therefore, in this manuscript, we design and prepare chemotherapeutic drug vinorelbine (VRL)-loaded polydopamine (PDA) shell-coated Fe3O4 superparticles, and further graft the targeted ligand RGD onto their surface. Because of the introduction of the PDA shell, the toxicity of the prepared Fe3O4@PDA/VRL-RGD SPs is greatly reduced. At the same time, due to the existence of Fe3O4, the Fe3O4@PDA/VRL-RGD SPs also have MRI contrast capability. Under the dual-targeting effect of RGD peptide and external magnetic field, Fe3O4@PDA/VRL-RGD SPs can accumulate into tumors effectively. The accumulated superparticles in the tumor sites can not only effectively identify and mark the location and boundary of the tumor under MRI, guideing the application of near-infrared laser, but also release the loaded VRL under the stimulation of the acidic microenvironment of the tumor to play the role of chemotherapy. On further combination with photothermal therapy under laser irradiation, A549 tumors are completely eliminated without recurrence. Our proposed RGD/magnetic field dual-targeting strategy can effectively improve the bioavailability of nanomaterials and contribute to better imaging and therapeutic effects, which has a promising application prospect in the future.

Real-World Experience of Metronomic Chemotherapy in Metastatic Breast Cancer: Results of a Retrospective Unicenter Study

Introduction: Metronomic chemotherapy (MCT) is increasingly used in oncology due to its favorable therapeutic index. There is still a lack of evidence for MCT in metastatic breast cancer (MBC). In this retrospective unicenter study, we demonstrated real-word data on MCT in MBC. Methods: MBC patients who received metronomic oral cyclophosphamide (CTX) (50 mg daily) and methotrexate (MTX) (2.5 mg every other day), CTX and capecitabine (CAPE) (500 mg thrice daily), CTX, or vinorelbine (VRL) (30 mg daily) alone for at least 4 weeks between 2009 and 2021 were included. The primary endpoint was disease control rate (DCR) ≥24 weeks. Secondary endpoints were progression-free survival (PFS) and overall survival (OS). Patient characteristics and therapy response were analyzed using χ² test. For survival analyses, Kaplan-Meier estimator and log-rank test were used. Results: Seventy-two patients were identified. Sixty-two patients received CTX/MTX, three CTX/CAPE, two CTX, and five VRL. Median age at diagnosis MBC and at start of MCT was 59.0 years and 64.5 years, respectively. 72.2% tumors were hormone receptor positive and 27.8% were triple-negative. 54.2% patients had more than two different metastases. 80.6% patients showed visceral involvement. 31.9% patients achieved DCR ≥24 weeks. Median PFS was 17.0 weeks (95% CI 14.5–19.5) and median OS was 58.0 weeks (95% CI 29.0–87.0). MCT showed similar DCR ≥24 weeks and clinically meaningful but not statistically significant shorter median PFS compared to prior therapy (31.9% versus 32.8% [p = 0.570] and 17.0 weeks versus 20.0 weeks [p = 0.093], respectively) and statistically significant higher DCR ≥24 weeks and longer median PFS compared to subsequent therapy (31.9% versus 17.4% [p = 0.038] and 17.0 weeks versus 12.0 weeks [p = 0.006], respectively). Three (4.2%) patients terminated MCT because of toxicity. Conclusion: In this real-world retrospective study, MCT was effective and well tolerated and may thus represent a valuable treatment option in selected MBC patients.

Anti-tumor effects of low-dose metronomic vinorelbine in combination with alpelisib in breast cancer cells.

In metastatic breast cancer (MBC), PIK3CA mutations, activating the phosphatidylinositol 3-kinase (PI3K) signaling pathway seem to be associated with chemotherapy resistance and poor outcome. Inhibition of the PI3K signaling pathway may lead to sensitization and prevention of the development of resistance to cytotoxic drugs. The present study aimed to investigate the anti-tumor activity of low-dose vinorelbine (VRL) combined with alpelisib, an α-selective PI3K inhibitor and degrader, in breast cancer (BC) cells. Human BC cell lines MCF-7, T-47D [both hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, PIK3CA-mutated], MDA-MB-231 and BT-549 (both triple-negative, wild-type PIK3CA) were exposed to a combination of low-dose VRL and alpelisib for 3 and 7 days. Cell viability was detected by the Alamar blue assay, and cell proliferation was determined by the BrdU incorporation. The effect of the substances on the p110α protein expression that is encoded by PIK3CA gene was investigated by Western blot. Low-dose VRL plus alpelisib showed synergistic anti-tumor effects and significantly inhibited cell viability and proliferation of MCF-7 and T-47D cells. Even lower alpelisib concentrations (10 ng/ml and 100 ng/ml) combined with low-dose metronomic VRL led to a significant reduction of cell viability of PIK3CA-mutated cells, and the anti-tumor activity was comparable with the effects at 1000 ng/ml alpelisib. Cell viability and proliferation of MDA-MB-231 and BT-549 cells were inhibited by VRL but not by alpelisib alone. This indicates that alpelisib did not significantly affect the cell growth of triple-negative, PIK3CA wild-type BC cells. The p110α expression was downregulated or not affected in PIK3CA-mutated cell lines, and not significantly upregulated in PIK3CA wild-type cell lines. In conclusion, combination of low-dose metronomic VRL and alpelisib showed synergistic anti-tumor effects and significantly inhibited the growth of HR-positive, HER2-negative, PIK3CA-mutated BC cells, providing a rationale for further efforts to evaluate this combination in vivo.

Effect of Growth Regulators on Callus Formation and Alkaloids Production on Vinca Rosea Plant (Catharanthus roseus L.)

Vinca alkaloids are a subset of drugs obtained from the periwinkle plant they are naturally extracted from the pink periwinkle plant (Catharanthus roseus), and they have been used to treat diabetes, high blood pressure and have been used as disinfectant. The vinca alkaloids are also important for being Cancer resistant there are four major vinca alkaloids in clinical use: Vinblastine (VBL), vinorelbine (VRL), vincristine (VCR) and vindesine (VDS). Vinca alkaloids are the second most used class of cancer drugs and will stay among the original cancer therapies. Catharanthus roseus is still source used for the powerful antitumor drugs. Callus culture had been done on MS-medium containing Different Concentrations from BA – 2,4-D – NAA – IAA. Where the different effects of growth regulators were studied when different parts of the plant have been cultured from leaves and stems this is to induce callus formation and encourage growth and the concentrations that were prepared: BA (0,1 – 0,3 – 1 – 2 mg/l) - NAA (0,1 – 1 mg/l) - IAA (0,1 mg/l) - 2,4-D (0,75 – 1 mg/l). And after culture the explants we transferred it to the growth room with a temperature ranging from 27 to 29 ° C relative humidity around 80% And in complete darkness. The results from HPLC analysis for the dry weight of callus were as follows ajmalicine (0.18 mg/g DW), catharanthine (0.07 mg/g DW), serpentine (0.37mg/g DW), vindoline (0.11 mg/g DW).

Chemotherapy-induced phlebitis via the GBP5/NLRP3 inflammasome axis and the therapeutic effect of aescin.

Intravenous infusion of chemotherapy drugs can cause severe chemotherapy-induced phlebitis (CIP) in patients. However, the underlying mechanism of CIP development remains unclear. RNA-sequencing analysis was used to identify potential disease targets in CIP. Guanylate binding protein-5 (GBP5) genetic deletion approaches also were used to investigate the role of GBP5 in NLR family pyrin domain containing 3 (NLRP3) inflammasome activation in lipopolysaccharide (LPS) primed murine bone-marrow-derived macrophages (BMDMs) induced by vinorelbine (VIN) in vitro and in mouse models of VIN-induced CIP in vivo. The anti-CIP effect of aescin was evaluated, both in vivo and in vivo. Here, we show that the expression of GBP5 was upregulated in human peripheral blood mononuclear cells from CIP patients. Genetic ablation of GBP5 in murine macrophages significantly alleviated VIN-induced CIP in the experimental mouse model. Mechanistically, GBP5 contributed to the inflammatory responses through activating NLRP3 inflammasome and driving the production of the inflammatory cytokine IL-1β. Moreover, aescin, a mixture of triterpene saponins extracted from horse chestnut seed, can alleviate CIP by inhibiting the GBP5/NLRP3 axis. These findings suggest that GBP5 is an important regulator of NLRP3 inflammasome in CIP mouse model. Our work further reveals that aescin may serve as a promising candidate in the clinical treatment of CIP.

Remarkable Remission Rate and Long-Term Efficacy of Upfront Metronomic Chemotherapy in Elderly and Frail Patients, with Diffuse Large B-Cell Lymphoma.

The upfront treatment of very elderly and frail patients with diffuse large B-cell lymphoma (DLBCL) is still a matter of debate. Herein, we report results of the metronomic all-oral DEVEC [prednisolone/deltacortene®, vinorelbine (VNR), etoposide (ETO), cyclophosphamide] combined with i.v. rituximab (R). This schedule was administered as a first line therapy in 22 elderly/frail DLBCL subjects (median age = 84.5 years). In 17/22 (77%) patients, the Elderly-IPI-score was high. After a median follow-up of 24 months, 15 patients had died: seven (50%) for causes unrelated to DLBCL or its treatment, six (40%) for progression, and two (13%) for multiorgan failure. Six treatment-pertinent serious-adverse-events occurred. At the end of induction, 14/22 (64%) achieved complete remission; overall survival and event-free survival at 24 months were both 54% (95% CI = 32−72%), while the time to progression was 74% (95% CI = 48−88%). Furthermore, antiproliferative and proapoptotic assays were performed on DLBCL/OCI-LY3 cell-line using metronomic VNR and ETO and their combination. Both metronomic VNR and ETO had concentration-dependent antiproliferative (IC50 = 0.036 ± 0.01 nM and 7.9 ± 3.6 nM, respectively), and proapoptotic activities in DLBCL cells. Co-administration of the two drugs showed a strong synergism (combination index < 1 and dose reduction index > 1) against cell proliferation and survival. This low-dose schedule seems to compare favourably with intravenous-CHEMO protocols used in the same subset. Indeed, the high synergism shown by metronomic VRN+ETO in in vitro studies, explains the remarkable clinical responses and it allows significant dose reductions.

Effect of Growth Regulators and Nacl Stress on Callus Formation and Alkaloids Production on Vinca Rosea Plant (Catharanthus Roseus L)

Vinca alkaloids are a subset of drugs obtained from the periwinkle plant they are naturally extracted from the pink periwinkle plant (Catharanthus roseus), and they have been used to treat diabetes, high blood pressure and have been used as disinfectant. The vinca alkaloids are also important for being Cancer resistant there are four major vinca alkaloids in Clinical Use: Vinblastine (VBL), vinorelbine (VRL), vincristine (VCR) and vindesine (VDS). Vinca alkaloids are the second most used class of cancer drugs and will stay among the original cancer therapies. Catharanthus roseus is still source used for the powerful antitumor drugs. Callus culture had been done on MS-medium containing Different Concentrations from BA-2, 4-D-NAA-IAA. Where the different effects of growth regulators were studied when different parts of the plant have been cultured from leaves and stems this is to induce callus formation and encourage growth and the concentrations that were prepared: BA (0,1-0, 3-1-2 mg/l)-NAA (0,1-1mg/l)-IAA (0,1 mg/l)-2, 4-D (0,75-1mg/l). And after culture the explants we transferred it to the growth room with a temperature ranging from 27 to 29°C relative humidity around 80% And in complete darkness then we applied the resulting callus tissue under the influence of different concentrations of NaCl as (50-75-100-150mM/L). The results from HPLC analysis for the dry weight of callus were as follows ajmalicine (0.18 mg/g DW), catharanthine (0.07 mg/g DW), serpentine (0.37mg/g DW), vindoline (0.11 mg/g DW).

Glucocorticoids enhance chemotherapy-driven stress granule assembly and impair granule dynamics, leading to cell death.

ABSTRACTStress granules (SGs) can assemble in cancer cells upon chemotoxic stress. Glucocorticoids function during stress responses and are administered with chemotherapies. The roles of glucocorticoids in SG assembly and disassembly pathways are unknown. We examined whether combining glucocorticoids such as cortisone with chemotherapies from the vinca alkaloid family, which dismantle the microtubule network, affects SG assembly and disassembly pathways and influences cell viability in cancer cells and human-derived organoids. Cortisone augmented SG formation when combined with vinorelbine (VRB). Live-cell imaging showed that cortisone increased SG assembly rates but reduced SG clearance rates after stress, by increasing protein residence times within the SGs. Mechanistically, VRB and cortisone signaled through the integrated stress response mediated by eIF2α (also known as EIF2S1), yet induced different kinases, with cortisone activating the GCN2 kinase (also known as EIF2AK4). Cortisone increased VRB-induced cell death and reduced the population of cells trapped in mitotic catastrophe. These effects were mediated by the core SG proteins G3BP1 and G3BP2. In conclusion, glucocorticoids induce SG assembly and cell death when administered with chemotherapies, suggesting that combining glucocorticoids with chemotherapies can enhance cancer cell chemosensitivity.

Preliminary Study on Drug-Loaded Chondroitin Sulfate-Modified Micelles Targeting Golgi Apparatus in Tumor Cells for the Treatment of Tumor Metastasis

To make preliminary exploration into the Golgi apparatus targeting of chondroitin sulfate-modified micelles (CSmicelles) co-loaded with pirarubicin (THP) and vinorelbine (VRL) in tumor cells, as well as their in vitro anti-tumor metastasis effect. The cellular uptake efficiency and internalization mechanism of CSmicelles in 4T1 mouse breast cancer cell line were investigated by flow cytometry. Preliminary study of the Golgi apparatus targeting CSmicelles in tumor cells was conducted by co-localization experiment. Then, the effect of CSmicelles co-loaded with THP and VRL (THP+VTL-CSmicelles) on the structure of Golgi apparatus was investigated by GM130 immunofluorescence experiment. Finally, the i n vitro anti-tumor metastasis ability of THP+VTL-CSmicelles was evaluated by wound healing assay and Transwell migration/invasion assay. It was found that CSmicelles could significantly increase cellular uptake of drugs. CSmicelles were internalized into cells through clathrin-mediated and caveolin-mediated endocytosis, which was energy-dependent active transport and exhibited substantial ability of targeting Golgi apparatus in tumor cells. THP+VTL-CSmicelles could break down the structure of Golgi apparatus and significantly inhibit the migration and invasion of tumor cells. THP+VTL-CSmicelles demonstrate high affinity towards Golgi apparatus in tumor cells, exert targeted effects and inhibit tumor cell metastasis, which provides a novel idea and method for the treatment of cancer metastasis.

Abstract 2022: Model-informed pediatric drug development: oral vinorelbine in low-grade glioma as a case study

Abstract Objectives:Defining a safe and effective dose in children is one of the biggest challenges in pediatric drug development. Pharmacometric tools are proposed as powerful quantitative techniques to leverage and integrate the collected data from pediatric clinical trials. Here we demonstrate and discuss the applications of nonlinear mixed effects (NLME) models through a detailed example of oral vinorelbine (VNR) in pediatric cancers.Methods:A multicentric, open-label, single-arm intervention phase II study was conducted. Patients with recurrent/progressive Low-Grade Glioma (LGG), were included. Patients received 60 mg/m² of oral VNR on days 1, 8 and 15 during the first 28-day treatment cycle and 80 mg/m² from cycle 2 to 12. Population pharmacokinetic (PK) analysis was performed using a NLME modeling approach on Monolix®. Fifty SNPs on PK-related genes were genotyped. The Influence of demographic, biological and pharmacogenetic covariates on VNR PK parameters was investigated using a stepwise multivariate procedure.Results:PK analysis included 36 patients with a median age (range) of 11 (6-17) years. A three-compartments model, with a delayed double zero-order absorption and a linear elimination, best described VNR pharmacokinetics. Typical population estimates (between-subject variability, between-occasion variability) for the apparent central volume of distribution (Vc/F) and elimination rate constant (k10) were 803 L (47%, 41%) and 0.60 h-1 (18%, 16%), respectively. Lower area under the concentration-time curve (AUC) levels were observed among children in comparison to adults. Following covariate analysis, BSA, leukocytes count, and ABCB1-rs2032582 SNP showed a dramatic impact on Vc/F. Additionally, ABCG2-rs2725264 A/G or G/G carriers and UGT2B7-rs7668258 T/T carriers showed higher k10 values. Conversely, age and sex had no significant effect on VNR PK.Conclusion:Higher doses may be necessary for children with LGG. A personalized dosing strategy, using BSA, leukocytes and ABCB1-rs2032582 SNP, could help to optimize the efficacy/toxicity balance of VNR in children. Model-informed drug development enabled efficiently a better understanding of PK of oral VNR in children and identifying several factors likely to explain the variability in VNR exposure and subsequent clinical outcomes. Citation Format: Mourad HAMIMED, Pierre LEBLOND, Aurélie DUMONT, Florence GATTACCECA, Emmanuelle TRESCH-BRUNEEL, Alicia PROBST, Pascal CHASTAGNER, Anne PAGNIER, Emilie DE CARLI, Natacha ENTZ-WERLÉ, Jacques GRILL, Isabelle AERTS, Didier FRAPPAZ, Anne-Isabelle BERTOZZI-SALAMON, Caroline SOLAS, Nicolas ANDRÉ, Joseph Ciccolini. Model-informed pediatric drug development: oral vinorelbine in low-grade glioma as a case study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2022.

ARST2031: A study to compare early use of vinorelbine and maintenance therapy for patients with high risk rhabdomyosarcoma.

TPS11591 Background: Patients with high-risk rhabdomyosarcoma (HR-RMS) continue to have poor outcomes with 3-year event free survival (EFS) rates of 30% or less despite chemotherapy dose intensification on recent cooperative group RMS trials. Vinorelbine (VINO) has demonstrated clinical activity in RMS patients with relapsed/refractory disease and shown to provide a survival benefit when given with oral cyclophosphamide as maintenance chemotherapy for a select group of patients that achieved first complete remission. Methods: ARST2031 is a randomized Phase 3 trial with the primary aim to compare event-free survival (EFS) of patients with HR-RMS treated with vincristine, dactinomycin and cyclophosphamide (VAC) followed by maintenance with vinorelbine and oral cyclophosphamide (VINO-CPO) or vinorelbine, dactinomycin and cyclophosphamide (VINO-AC) followed by maintenance with VINO-CPO. Patients are stratified by histology and randomly assigned to VAC followed by VINO-CPO maintenance or VINO-AC followed by VINO-CPO maintenance. To be eligible, patients must be ≤ 50 years of age at the time of enrollment with newly diagnosed RMS except adult-type pleomorphic, based upon institutional histopathologic classification. All patients must have Stage 4 disease and patients diagnosed with embryonal RMS (ERMS) must be ≥ 10 years of age. Patients with malignant cytology in cerebrospinal fluid, intra-parenchymal brain metastases, or diffuse leptomeningeal disease are excluded. The study was activated on September 13, 2021 and is anticipated to enroll approximately 4 patients per month. The planned sample size is 100 patients, with approximately 50 patients randomized to each arm. Safety and feasibility of VINO-AC will be assessed in the first 8 patients prior to randomization. The study will have power of 0.8 to detect a hazard ratio of 0.61 (74 events in total) when the one-sided Type I error rate is 0.10, with 30 months of accrual and 2 years of follow-up. The hazard ratio of 0.61 was determined by assuming piecewise exponential distributions and specifying the 2-year EFS of 46% vs. 28% and long-term EFS of 32% vs. 16%, based on prior outcome data. Biospecimens will be collected and banked for future use. Clinical trial information: NCT04994132.

188P Pooled analysis of two phase II randomised studies (NorBreast-231 & TEMPO Breast) evaluating weekly oral vinorelbine (VNR) as first-line chemotherapy in patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC)

Single-agent chemotherapy is a valuable option for patients with ABC, and weekly oral VNR is a recommended treatment. NorBreast-231 evaluated activity and tolerability of paclitaxel and oral VNR, while TEMPO Breast explored weekly versus metronomic VNR. The results of TEMPO Breast showed numerically higher disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) for standard weekly VNR in this setting, possibly due to a ‘peak effect’ with weekly dosing. We performed a pooled analysis of the weekly arm of these two trials.

Efficacy of cisplatin plus vinorelbine adjuvant chemotherapy with split-dose administration of cisplatin after complete resection of stage II-IIIA non-small cell lung cancer.

Although co-administration of cisplatin (CDDP) and vinorelbine (VNR) has been established as a standard of care adjuvant chemotherapy for non-small cell lung cancer (NSCLC), there is a lack of clinical data on its safety and efficacy in Japanese patients receiving split-dose administration of CDDP. The present study analyzed patients who received CDDP + VNR with split-dose administration of CDDP after undergoing complete resection of NSCLC. Patients received four courses of CDDP (40 mg/m2) and VNR (25 mg/m2) on days 1 and 8, every 3 weeks. There were 27 male and 13 female patients; the mean age was 65 years (range 38-78 years), the postoperative disease staging distribution was IIA/IIB/IIIA: 14/8/18 patients, and histological distribution was adenocarcinoma/squamous cell carcinoma/others: 24/12/4 patients, respectively. Of the 40 patients, 28 (70%) completed the four courses of treatment. The mean total dose administered was 279 mg/m2 CDDP (87.2%) and 172 mg/m2 VNR (86%). The major adverse events included Grade (G) 3 or higher neutropenia (80%), G3 phlebitis (5%) and vomiting (2.5%). There was no G2 or higher serum creatinine level elevation, G3 or higher anorexia and nausea, or any treatment-related deaths. The overall completion rate of four courses was 70 and 62.5% for patients aged 70 years and older, whereas the overall percentage of patients that could complete three or more courses was 85 and 87.5% for patients aged 70 years and older. The relapse-free survival rate was 60% at 3 years and 57.5% at 5 years. Overall survival rate was 80% at 3 years and 60% at 5 years. The present study demonstrated the sufficient tolerability, safety and efficacy of combined CDDP + VNR adjuvant chemotherapy with split-dose administration of CDDP, with a low risk of gastrointestinal toxicities or nephrotoxicity.