Dose–Schedule Finding in Early-Phase Clinical Trials
John O’Quigley, Alexia Iasonos, Björn Bornkamp in Handbook of Methods for Designing, Monitoring, and Analyzing Dose-Finding Trials, 2017
In oncology, several preclinical and clinical studies have established a relationship between toxicity, as well as efficacy, and schedule [14–18]. A very useful example that emphasizes this association is described in Guo et al. [9]. The authors point out that Shah et al. [19] demonstrated that dasatinib for treating chronic myelogenous leukemia was developed using a suboptimal course of therapy. A 70-mg twice-daily dosing schedule, approved by the FDA in 2006, was initially used due to its relatively short half-life, in an attempt to obtain sustained kinase inhibition and minimal toxicity [19]. A subsequent phase III trial of dasatinib in 670 patients with chronic myelogenous leukemia showed that a once-daily administration demonstrated similar efficacy to the twice-daily regimen, but the once-daily regimen significantly reduced the occurrence of treatment-related adverse events, improving the safety profile of the treatment. This example emphasizes the impact of accounting for scheduling in phase I–II trials. The methods of Li et al. [8] and Guo et al. [9] aim to find an optimal dose–schedule combination based on toxicity and efficacy in the phase I–II setting.
Pulmonary hypertension induced by drugs and toxins
Philippe Camus, Edward C Rosenow in Drug-induced and Iatrogenic Respiratory Disease, 2010
Dasatinib is an oral selective tyrosine kinase inhibitor approved by the FDA for treatment of chronic myelogenous leukaemia after failure of imatinib (unsatisfactory response or toxicity).73 In a study, pleural effusion was observed in 35 per cent of patients (48/138).74 When an echocardiogram was done at the onset of pleural effusion, an increase in right ventricular systolic pressure, a non-invasive surrogate marker of pulmonary artery pressure, was observed. Two cases of PAH, confirmed by right heart catheterization, were also reported at 6 and 26 months after the initiation of dasatinib.75,76 Right ventricular size and systolic function had normalized 6 weeks and 6 months after its discontinuation. Interestingly, imatinib, which is also a tyrosine kinase inhibitor, was reported being effective in treating idiopathic PAH.77 This stresses the complexity of the pathophysiology in inducing PAH by dasatinib.
New Drugs in Myeloproliferative Disorders
Richard T. Silver, Ayalew Tefferi in Myeloproliferative Disorders, 2007
Imatinib mesylate is an inhibitor of the tyrosine kinase activity of ABL, PDGFR, KIT, and ARG (61). The employment of imatinib for the therapy of patients with PMF was based on its inhibitory activity against PDGF-mediated signaling and the reduction of bone marrow fibrosis and microvessel density observed in patients with chronic myeloid leukemia , for which imatinib is a standard therapy (62). Results from all the phase II trials of imatinib in patients with PMF reported to date are modest (63,64). Only one study showed significant improvement in splenomegaly, including 4 (29%) patients who had normalization of spleen span (65). Imatinib was administered at doses ranging from 200 to 800 mg daily, but dropout rates were in excess of 50% across all trials due to adverse events (63,64). Recently, imatinib has been shown to increase the number of clonogenic megakaryocytic progenitors in bone marrow, indicating that imatinib may restore megakaryocyte differentiation and be effective for the treatment of thrombocytopenia in PMF (66). Dasatinib (BMS-354825) is a dual SRC-and ABL-kinase inhibitor, 300-fold more potent ABL kinase inhibitor than imatinib (67). In addition, dasatinib effectively inhibits PDGFR-β (IC50 28 nM) (67). Based on these preclinical data and on the results obtained with imatinib, results from an ongoing clinical trial of dasatinib in patients with PMF are eagerly awaited.
Dasatinib-induced colitis: clinical, endoscopic and histological findings
Published in Scandinavian Journal of Gastroenterology, 2022
Kenji Yamauchi, Tomoki Inaba, Hugh Shunsuke Colvin, Ichiro Sakakihara, Kumiko Yamamoto, Koichi Izumikawa, Sakuma Takahashi, Shigetomi Tanaka, Shigenao Ishikawa, Masaki Wato, Midori Ando, Masato Waki
Dasatinib, a second-generation tyrosine kinase inhibitor, is widely used in patients with chronic myeloid leukaemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukaemia (Ph + ALL). Dasatinib inhibits not only breakpoint cluster region-abelson (BCR-ABL) tyrosine kinase, but it also has an off-target inhibitory effect on Src family kinases. Src family kinases are an important component of the immune response, and their inhibition leads to the suppression of the regulatory T cell response [1], leading to reactivation of cytomegalovirus (CMV) [2]. An increase in lymphocytes, called large granular lymphocytes (LGLs), was observed in some patients with CML who had received dasatinib. Patients with an increase in LGL had better outcomes but with more side effects, such as pleural effusion and colitis [3]. Subsequent studies reported that LGLs are composed of NK cells and CD8+ T cells and are increased only in dasatinib-treated patients with pre-existing CMV infection, but not in CMV-naive patients or in patients treated with other TKIs. NK cells express a number of receptors, and increased activation and maturation of NK cells associated with CMV were revealed in a study on LGLs related to dasatinib [4]. These reports suggest that dasatinib in CMV-positive CML patients promotes CMV reactivation and activation of NK cells against CMV, leading to enhanced antitumor effects of CML cells expressing CMV antigens, together with some autoimmune side effects [5].
The role of Eph receptors in cancer and how to target them: novel approaches in cancer treatment
Published in Expert Opinion on Investigational Drugs, 2020
Oscar J Buckens, Btissame El Hassouni, Elisa Giovannetti, Godefridus J Peters
Dasatinib is a multi-kinase inhibitor and is used for the treatment of chronic myelogenous leukemia by inhibiting BCR-ABL1, but it is also known to inhibit various Eph receptors. In breast cancer cell lines, both EphA2 expression levels and EphA2 phosphorylation levels are down regulated as a response to dasatinib treatment [150]. In melanoma cell lines dasatinib was not able to induce an effect on EphA2 phosphorylation, indicating that both the cell line and the type of cancer are important [151]. Huang et al. [150] demonstrated that dasatinib can inhibit the kinase activity of EphA2 directly with an IC50 value of 17 nM in an EphA2-expressing baculovirus system. Next to this direct inhibition, dasatinib might induce down regulation of EphA2 through inhibition of SRC family kinases (SFK), since SFK can regulate EphA2 expression [150]. Dasatinib can also inhibit EphB4 in vitro with an IC50 of 5.5 nM [152]. Bantscheff et al. [152] showed that imatinib and bosutinib have an affinity for EphB4 as well with IC50 values of 5 μM and 5.5 nM, respectively. All three IC50 values were obtained in K562 cells. In pancreatic cancer, dasatinib can inhibit ligand-induced EphA2 internalization as well as degradation of the receptor [153].
Dasatinib ameliorates thioacetamide-induced liver fibrosis: modulation of miR-378 and miR-17 and their linked Wnt/β-catenin and TGF-β/smads pathways
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Mai A. Zaafan, Amr M. Abdelhamid
Dasatinib is a second-generation oral multitarget inhibitor of many tyrosine kinases10,20. Dasatinib was designed to treat some types of cancers including chronic myeloid leukaemia (CML)21. Dasatinib has recently been studied for its anti-fibrotic effects in a variety of fibrous diseases, including systemic sclerosis, lung fibrosis, and chronic pancreatitis. Through the TKs/GSK3/β-catenin pathway, dasatinib inhibits the proliferation and activation of pancreatic stellate cells (PSCs)21,22. The current study aims to investigate the potential efficacy and the molecular mechanisms of dasatinib in the treatment of thioacetamide-induced liver fibrosis by modulating miR-378 and miR-17 via the Wnt/β catenin and TGF-/smad pathways.
Related Knowledge Centers
- Adverse Effect
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- Leukopenia
- Targeted Therapy
- Chronic Myelogenous Leukemia
- Acute Lymphoblastic Leukemia
- Oral Administration
- Thrombocytopenia