Optimizing Molecularly Targeted Agents
Ying Yuan, Hoang Q. Nguyen, Peter F. Thall in Bayesian Designs for Phase I–II Clinical Trials, 2017
Pishvaian et al. (2012) reported a phase I trial for the combination of imatinib and paclitaxel in patients with advanced solid tumors refractory to standard therapy. Imatinib is a tyrosine kinase inhibitor used in the treatment of multiple cancers, most notably chronic myelogenous leukemia (CML). Imatinib works by inhibiting the activity of the BCR-Abl tyrosine kinase enzyme that is necessary for cancer development, thus preventing the growth of cancer cells and leading to their death by apoptosis. Because the BCR-Abl tyrosine kinase enzyme exists only in cancer cells and not in healthy cells, imatinib works effectively as an MTA killing only cancer cells. The goal of the trial was to evaluate the safety of combining imatinib with the traditional cytotoxic chemotherapeutic agent paclitaxel, and to determine whether that combination improved the Efficacy of imatinib. In the trial, four doses, 300, 400, 600, 800 mg, of imatinib and three doses, 60, 80, 100 mg/m2, of paclitaxel were investigated. Most of the grade 3 or 4 toxicities related to therapy were neutropenia, flu-like symptoms, or pain. Treatment response was evaluated using the RECIST criteria (Eisenhauer et al., 2009).
Chemotherapy in pregnancy
Hung N. Winn, Frank A. Chervenak, Roberto Romero in Clinical Maternal-Fetal Medicine Online, 2021
Imatinib is a specific inhibitor of a number of tyrosine kinase enzymes and is indicated for the treatment of chronic myelogenous leukemia. It has been associated with a high rate of teratogenicity (108). However, Skoumalova et al. reported on its administration throughout the first trimester of pregnancy, followed by the use of interferon for the remainder of the gestation, with the delivery of a normal and healthy child (108). Neither the drug nor its active metabolite appears to cross the placenta in significant concentrations (109). Nonetheless, Pye et al. reported on the evaluation of 125 pregnancies complicated by the use of imatinib (110). They reported that 3 of the 35 patients who terminated their pregnancies did so because of detected fetal malformations. Of the remaining infants delivered, 12 had malformations, and 3 of them had similar complex malformations including renal and vertebral anomalies.
Chronic Myeloid Leukemia
Wojciech Gorczyca in Atlas of Differential Diagnosis in Neoplastic Hematopathology, 2014
An HR indicates a return of peripheral blood cell counts and BM morphology to normal. CyR can be divided into complete, major, minor, and minimal. CCyR indicates the disappearance of the Ph and major cytogenetic response (MCyR) indicates <35% Ph+ cells in the BM. Major molecular response (MMR) is defined as 3-log reduction in BCR–ABL1 transcript (≤0.10 BCR/ABL1 ratios, according to the International Scale) and complete molecular response (CMR) is synonymous with undetectable transcripts by quantitative real-time (qRT)-PCR (RQ-PCR). The preferred initial treatment is daily dose of imatinib [8]. A dose increase of imatinib, allogeneic stem cell transplantation, or investigational treatments are recommended for cases of failure and could be considered in case of suboptimal response. European LeukemiaNet suggested the following definitions for failure: no HR at 3 months, incomplete HR or no CyR (Ph+ > 95%) at 6 months, less than partial CyR (Ph+ > 35%) at 12 months, less than complete CyR at 18 months, and (at any time) loss of CCyR/complete HR or appearance of highly imatinib-resistant BCR–ABL1 mutations [8]. Optimal response is defined as complete HR at 3 months, at least a partial CyR at 6 months, CCyR at 12 months, and MMR at 18 months [71].
Drugs repurposing for SARS-CoV-2: new insight of COVID-19 druggability
Published in Expert Review of Anti-infective Therapy, 2022
Sujit Kumar Debnath, Monalisha Debnath, Rohit Srivastava, Abdelwahab Omri
Imatinib is a tyrosine kinase receptor inhibitor used in diseases like gastrointestinal stromal tumors and chronic myelogenous leukemia. Unregulated cell growth has been observed in abnormal and constitutive expressed tyrosine kinase. An in-vitro study confirmed that imatinib hindered the early stages of the virus life cycle. However, the inhibitory activity of this drug COVID-19 is debatable due to unpredictable outcomes from preclinical studies [109]. This drug does not impair the virus-host interactions directly. It has been hypothesized that this drug acts on the upregulation of genes involved in virus response. It perhaps also acts as an immunomodulatory that reduce pro-inflammatory cytokines and chemokines. In a randomized clinical trial, imatinib could not reduce the time to discontinue mechanical ventilation, and supplemental oxygen in COVID-19 patients needed supplementary oxygen [110]. C-ABL-1 kinase signaling pathways serve a crucial role in the egress of poxviruses and Ebola viruses. This kinase is signaling equally critical in the replication of MERS-CoV and SARS-CoV. A phase 3 clinical trial is currently underway for hospitalized COVID-19 patients. This trial’s hypothesis is to decrease the SARS-CoV-3 by increasing endosomal pH, interfering with the replication of SARS-CoV-2 and clinical outcome of COVID-19 patients in the intensive care unit.
Role of therapeutic agents on repolarisation of tumour-associated macrophage to halt lung cancer progression
Published in Journal of Drug Targeting, 2020
Hibah M. Aldawsari, Bapi Gorain, Nabil A. Alhakamy, Shadab Md
Imatinib is a tyrosine kinase inhibitor (TKI), which has an anti-cancer activity on numerous solid tumours. Its anti-cancer action is partly dependent on immune cells including T cells [61]. In vitro studies using Lewis Lung cancer (LLC) cells showed that imatinib averted M2-like polarisation initiated by IL-4 or IL-13; imatinib repressed STAT6 phosphorylation and nuclear translocation, resulting in the arrest of M2-like polarisation [14]. In vivo, the percentage of M2-like macrophages in tumour and lung tissues was reduced after one-week of imatinib administration. Taken together, these results indicate that imatinib restrains M2-like polarisation both in the cell line and in the in vivo animal model; this may contribute to its anti-metastatic action in lung cancer [14]. However, these studies used a single animal model of primary and metastatic lung cancer, and further exploration of imatinib using other metastatic models is required to confirm the potential application of imatinib in the treatment of lung cancer [14].
Emerging alternatives to tyrosine kinase inhibitors for treating chronic myeloid leukemia
Published in Expert Opinion on Emerging Drugs, 2018
Simon Kavanagh, Aisling Nee, Jeffrey H. Lipton
The first clinically useful TKI for CML therapy, imatinib, is a TKI with activity against ABL, c-Kit, and platelet-derived growth factor receptors α and β [24]. The efficacy of imatinib was first demonstrated in a phase I trial of patients with chronic phase CML who had lost response to interferon-α (IFN-α) [29]. Impressive rates of complete hematological response (CHR) were seen in this dose-escalation study with 53 of 54 patients who received a dose of 300 mg or more reaching this milestone. A phase 3 study, randomizing 1106 patients to either imatinib or IFN-α with cytarabine, followed. This landmark study demonstrated superior freedom from progression with imatinib, higher rates of major and complete cytogenetic response (CCyR), and better tolerability [16]. Common side effects with imatinib, seen in this trial and in subsequent follow-up, include edema, nausea, diarrhea, and muscle cramps. While usually of minor grade, these side effects can still be treatment-limiting in a proportion of patients due to their chronic nature. Following routine use of imatinib, the rates of allogeneic transplantation for chronic phase CML have declined markedly [30] with this strategy now more commonly used in advanced phases of disease.
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