多维替尼Dovitinib相关信息

                                                                   多维替尼Dovitinib相关信息
基本简介：
Dovitinib一种具有口服活性的小分子，强效抑制III，IV和V型受体酪氨酸激酶抑制剂，作用于FGFR1(IC50=8 nM)，FGFR3(IC50=9 nM)，VEGFR1(IC50=10 nM)，VEGFR2(IC50=13 nM)， VEGFR3(IC50=8 nM)，PDGFRβ(IC50=27 nM)，FLT3(IC50=1 nM)，c-KIT(IC50=2 nM)和 CSF-1R/c-fms(IC50=36 nM) 。在SK-HEP1细胞中，dovitinib诱导细胞周期捕获，抑制细胞在集落的形成，同时抑制bFGF诱导的细胞迁移。Dovitinib强效抑制肝细胞癌（HCC）移植瘤模型中肿瘤生长，并具有抗迁移活性。Dovitinib还可以降低肿瘤细胞中磷酸化的PDGFRB和磷酸化的ERK。Dovitinib与bortezomib，melphalan和dexamethasone等药物联合作用于WM细胞，可以产生累加效应，显著诱导凋亡反应并抑制WM细胞增殖。
Dovitinib最初是由Chiron研究的，后来是由Novartis在研究。

产品结构：

基本特性：
CAS号：405169-16-6，分子式：C21H21FN6O，分子量：392.43

药代动力学：
多维替尼主要通过肝P450 酶CYP1A1/2代谢，4小时后到达血药峰值，半衰期在第1天时为24小时，在第15天时为13小时；400mg组在服药第15天时平均AUC0–t为 2800 (ng/mLh），略低于第1天；500mg组在服药第15天时平均AUC0–t为 3400 (ng/mLh），高于第1天，有40%的病人出现血药浓度蓄积。

服用方案：
500mg每天一次，空腹，吃5天停2天。胃溶胶囊。

相关临床试验结果：
（1）Phase I/II and pharmacodynamic study of dovitinib (TKI258), an inhibitor of fibroblast growth factor receptors and VEGF receptors, in patients with advanced melanoma.
http://www.ncbi.nlm.nih.gov/pubmed/21976540
RESULTS: Forty-seven patients were enrolled. The most frequently reported adverse events were fatigue (77%; grade ≥3, 28%), diarrhea (77%; grade ≥3, 11%), and nausea (77%; grade ≥3, 9%). Six dose-limiting toxicities were observed in the 400-mg and 500-mg dose cohorts, which consisted of grade 3 nausea, fatigue, and diarrhea and grade 4 fatigue events. The maximum tolerated dose was 400 mg/d. The best tumor response was stable disease, which was observed in 12 patients. Increases in plasma FGF23, VEGF, and placental growth factor and decreases in soluble VEGF receptor 2 were noted during the first cycle of treatment, consistent with FGF receptor (FGFR) and VEGF receptor (VEGFR) inhibition. Dynamic contrast-enhanced MRI analysis showed a dose-dependent decrease in tumor blood flow and vascular permeability with dovitinib therapy. A decrease in FGFR phosphorylation was observed in paired tumor biopsy samples from a patient treated with dovitinib at a dose of 400 mg/d.
结果：一共有47名晚期黑色素瘤病人入组。最主要的副作用包括疲劳（77%；3级以上，28%），腹泻（77%；3级以上，11%），恶心（77%；3级以上，9%）。6次剂量限制毒性事件发生在400mg和500mg剂量组，包括3级恶心、疲劳、腹泻和4级疲劳。最大耐受剂量是400mg每天。共有12名病人稳定，没有一名有效缓解。第一个疗程后，血清中FGF23、VEGF和PIGF增高，VEGFR2降低。动态增强MRI显示服用多维替尼后，肿瘤的肿瘤血流量和血管通透性降低。多维替尼400mg每天剂量组观察到病人肿瘤组织取样的磷酸化FGFR降低。
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（2）A phase I pharmacokinetic and pharmacodynamic study of TKI258, an oral, multitargeted receptor tyrosine kinase inhibitor in patients with advanced solid tumors.
http://www.ncbi.nlm.nih.gov/pubmed/18381947
PURPOSE: To determine the maximum tolerated dose (MTD) dose-limiting toxicity, and pharmacokinetic and pharmacodynamic profile of TKI258 (formerly CHIR-258).
EXPERIMENTAL DESIGN: A phase I dose escalating trial in patients with advanced solid tumors was performed. Treatment was initially as single daily doses on an intermittent 7-day on/7-day off schedule. Following a protocol amendment, a second schedule comprised, during cycle 1, 7-day on/7-day off treatment followed by 14 days of continuous daily dosing; subsequent cycles comprised 28 days of daily dosing. Pharmacokinetics and evaluation of phosphorylated extracellular signal-regulated kinase (ERK) in peripheral blood mononuclear cells were done during the first 28 days of each schedule.
RESULTS: Thirty-five patients were treated in four intermittent (25-100 mg/d) and three continuous (100-175 mg/d) dosing cohorts. Observed drug-related toxicities were nausea and vomiting, fatigue, headache, anorexia, and diarrhea. Dose-limiting toxicities were grade 3 hypertension in one patient at 100 mg continuous dosing, grade 3 anorexia in a second patient at 175 mg, and grade 3 alkaline phosphatase elevation in a third patient at 175 mg. One patient had a partial response (melanoma) and two patients had stable disease >6 months. TKI258 pharmacokinetics were linear over the dose range of 25 to 175 mg. Five of 14 evaluable patients had modulation of phosphorylated ERK levels.
CONCLUSIONS: The MTD was defined as 125 mg/d. Evidence of antitumor activity in melanoma and gastrointestinal stromal tumors warrants further investigation, and other phase I studies are ongoing. Further pharmacodynamic evaluation is required in these studies to evaluate the biological effects of TKI258.
（3）Phase I study of dovitinib (TKI258), an oral FGFR, VEGFR, and PDGFR inhibitor, in advanced or metastatic renal cell carcinoma.
http://www.ncbi.nlm.nih.gov/pubmed/23339124
PURPOSE: Signaling through the fibroblast growth factor (FGF) pathway may account for tumor resistance to antiangiogenic therapies targeting the VEGF pathway. Here, dovitinib (TKI258), a potent oral inhibitor of FGF receptor, VEGF receptor (VEGFR), and platelet-derived growth factor receptor tyrosine kinases, is studied in a dose escalation trial.
EXPERIMENTAL DESIGN: Patients with advanced or metastatic renal cell carcinoma (RCC) with predominant clear cell histology were treated with oral dovitinib 500 or 600 mg/day (5-days-on/2-days-off schedule).
RESULTS: Twenty heavily pretreated patients (median 3 prior regimens) were enrolled, with 16, 11, and 12 patients having previously received at least 1: VEGFR inhibitor, mTOR inhibitor, and immunotherapy, respectively. Fifteen and 5 patients were treated in 500- and 600-mg cohorts, respectively. Three patients experienced dose-limiting toxicities: grade 2 bradycardia (500 mg), grade 4 hypertensive crisis (600 mg), and grade 3 asthenia with grade 2 nausea and vomiting (600 mg). The most common adverse events related to dovitinib were nausea (75%), diarrhea (70%), vomiting (70%), and asthenia (50%), the majority of which were mild (grade 1 or 2), with grade 3 events 5% or less (except asthenia, 15%) and only one grade 4 event (hypertensive crisis). Two patients achieved a partial response (500 mg), and 12 patients had stable disease, including 2 patients with long lasting disease stabilizations (>1 year) in the 500-mg cohort.
CONCLUSIONS: Dovitinib was tolerable and showed antitumor activity at a maximum tolerated dose of 500 mg on a 5-days-on/2-days-off schedule in heavily pretreated RCC patients.
结果：20名三线治疗后的肾细胞癌病人入组，16名至少接受过一次抗血管生成药治疗，11名至少接受过1次mTOR抑制剂治疗，12名至少接受过一次免疫治疗。500mg组（吃5天停2天）有15名病人，600mg组（吃5天停2天）有5名病人。3名病人出现剂量限制性毒性：1名出现2级心动过缓（500mg）；1名出现4级高血压危象（600mg），1名出现3级乏力、2级疲劳和呕吐（600mg）。最常见的副作用包括疲劳（77%），腹泻（70%），呕吐（70%）和乏力（50%），其中大部分为轻度副作用（1级或者2级），3级副作用小于5%（除了乏力，15%）只有1名病人出现4级高血压危象。2名病人有效缓解（500mg），12名病人肿瘤稳定，包括2名病人肿瘤稳定超过1年（500mg）。
结论：多维替尼最大剂量为500mg吃5天停2天，该方案对于三线治疗后的肾细胞癌病人有抗肿瘤活性。

Experimental Dovitinib Seems to Offer No Benefits for Metastatic, HER2-Negative Disease
http://www.breastcancer.org/research-news/20110610c
A very small, very early study found that the experimental targeted therapy dovitinib didn't benefit women diagnosed with metastatic, HER2-negative breast cancer.

Metastatic breast cancer is cancer that has spread to a part of the body away from the breast, such as the bones or the liver. The research was published in the Journal of Clinical Oncology and presented at the 2011 annual meeting of the American Society of Clinical Oncology (ASCO).

About one out of every four breast cancers is HER2-positive, so three out of four are HER2-negative. HER2-positive breast cancers make too much of the HER2 protein. The HER2 protein sits on the surface of cancer cells and receives signals that tell the cancer to grow and spread. HER2-positive cancers tend to be more aggressive and harder to treat than breast cancers that are HER2-negative. Still, targeted therapies such as Herceptin (chemical name: trastuzumab) and Tykerb (chemical name: lapatinib), which can help treat HER2-positive breast cancers, don't work on HER2-negative breast cancers. Researchers are looking for targeted therapies for HER2-negative breast cancer, especially for metastatic HER2-negative breast cancer.

Like the HER2 protein, FGFR1 (fibroblast growth factor receptor 1) is a protein that sits on the surface of cells. On breast and other cancer cells, the FGFR1 protein receives signals that can encourage the cancer cells to grow and spread. Some breast cancers make too much of the FGFR1 protein and are called FGFR1-positive. It's also said that these cancer cells overexpress FGFR1 or have FGFR1 amplification. Right now, doctors don't routinely test to see if a breast cancer is FGFR1-positive or FGFR1-negative. Still, researchers have found that about 8% to 10% of breast cancers are FGFR1-positive. Breast cancers that are FGFR1-positive tend to be more resistant to treatments, including hormonal therapy if the cancer also is hormone-receptor-positive.

The experimental targeted therapy dovitinib was created to attach to the FGFR1 protein and block it from receiving growth signals. Researchers also are doing very early studies on using dovitinib to treat skin cancer (melanoma), kidney cancer, as well as breast cancer, whether or not the cancer is FGFR1-positive. Dovitinib is a pill taken by mouth.

In this study:

•61% of 68 women were diagnosed with HER2-negative, metastatic breast cancer that had spread to three or more parts of the body away from the breast.
•78% of the women had cancer that had spread to the liver.
•All the women already had received one or more metastatic breast cancer treatments.
•21 women had cancers that were FGFR1-positive and hormone-receptor-positive.
All the women were treated with dovitinib. Response to treatment was recorded 4 to 6 weeks after the women started taking dovitinib and again 20 or more weeks later. Treatment response was measured in terms of clinical benefit: either the cancer showed signs of being weakened by the treatment (partial response) or the cancer didn't grow while the women took the treatment (stable disease).

Dovitinib seemed to offer the most benefits to the 21 women diagnosed with FGFR1-positive AND hormone-receptor-positive breast cancer:

•55% of the women had stable disease and 15% (3 women) had partial response 4 to 6 weeks after treatment started.
None of the other women had a partial response to treatment after 4 to 6 weeks, though many had stable disease.

Only a few women showed any clinical benefit from dovitinib 24 or more weeks after they started taking dovitinib. Women with FGFR1-positive and hormone-receptor-positive cancer showed the greatest clinical benefit; still, it was only 15% of those women.

Despite the less-than-promising results, the researchers think that dovitinib may still be a good treatment for some women diagnosed with advanced-stage breast cancer. It's possible that women diagnosed with metastatic breast cancer might get more benefits from dovitinib if it's used earlier in the treatment plan or if the cancer hasn't spread as much. Much more research is needed before doctors can understand which group of women may benefit from dovitinib and when and how it might be best used to treat metastatic breast cancer.

If you're being treated for metastatic breast cancer, you and your doctor may be considering a number of options, especially if the cancer is HER2-negative and/or has stopped responding to standard treatments. Despite the weak results seen in this study, treatment with an experimental regimen that includes a targeted therapy like dovitinib may be an option if you're willing to participate in a clinical trial. Ask your doctor if there are any clinical trials that might be a good fit for you and your unique situation. Visit the Breastcancer.org Clinical Trials pages for more information.

（4）Phase II Study of Dovitinib and Pilot Study of Fibroblast Growth Factor Receptor Biomarkers in Advanced Non-Small Cell Lung Cancer or Advanced Colorectal Cancer Previously Treated With Anti-Vascular Endothelial Growth Factor Therapy
http://www.clinicaltrial.gov/ct2 ... b++nsclc&rank=3
（5）Phase II Study of Dovitinib for FGFR1 Amplified Squamous Non-small Cell Lung Cancer
http://www.clinicaltrial.gov/ct2 ... b++nsclc&rank=2
（6）A Study of Dovitinib Versus Sorafenib in Adult Patients With Hepatocellular Carcinoma (HCC) as a First Line Treatment
http://www.clinicaltrial.gov/ct2 ... inib+hcc&rank=1

Population Pharmacokinetic/Pharmacodynamic Modeling to Assist Dosing Schedule Selection for Dovitinib
http://lib.bioinfo.pl/pmid:22287694
Dovitinib is an oral multitargeted kinase inhibitor with potent activity against receptors for vascular endothelial growth factor, platelet-derived growth factor, and basic fibroblast growth factor. Initial phase 1 to 2 studies of dovitinib using a continuous daily dosing schedule has shown that dovitinib exhibits a prolonged and overproportional increase in dose and exposure relationship above 400 mg/d. To address this, intermittent dosing schedules were explored using a model-based approach. A semi-mechanistic population pharmcokinetic/pharmacodynamic (PD) model was developed from 4 dovitinib phase 1 studies with daily dosing schedules. Autoinduction of cytochrome P450 1A (CYP1A) responsible for dovitinib metabolism was described using an indirect response model. Simulation of dovitinib plasma concentration profiles following 4 intermittent dosing schedules suggested that intermittent dosing could prevent prolonged drug accumulation. Based on the simulated plasma profiles, PD response, and patient compliance, a 5-days-on/2-days-off intermittent dosing schedule was selected for a phase 1 to 2 clinical study. The observed dovitinib plasma concentrations in this study confirmed the model predictions. Furthermore, dovitinib was well tolerated, and antitumor activity was observed as well in this new study. The 5-days-on/2-days-off dosing schedule is currently used in a dovitinib registration trial and other clinical trials.

What the “eff” with FGF and IGF inhibitors?

While the F “Family”, namely VEGF and EGF, have yielded successful commercial products (though not always in line with early biologic hypotheses), the same cannot be said of the other members of the growth factor family, namely FGF (fibroblast growth factor) an IGF (insulin-like growth factor). We would throw PDGF (platelet-derived growth factor) onto that pile as well. Despite early expectations of clinical success with inhibitors of these factors, whether they be small molecule or large, receptor or ligand, positive clinical results have been fleeting. Perhaps this is because of the nature of the underlying biology whereby they play more of an accessory, rather than principal, role. In addition, the level of driver mutations and/or overexpression does not seem to have tracked that of VEGF and EGF. Despite the disappointment to date, this may be the year in which FGF (in its various forms) finally emerges as a validated drug target. Several presentations will speak to the biologic validity of the members of the FGF family. Taking them in numerical order, FGFR1 appears to play a key role in a variety of squamous cancer subtypes like SCLC, while FGFR2 may participate in the pathogenesis of breast, prostate and papillary renal cancer. FGF2 also is the subject of a presentation tying its role to the development of resistance to ABL kinase inhibitors in CML (good for Iclusig?). Finally, the link between mutations in FGFR3 and bladder cancer is once again discussed in a paper that describes the activation of FGFR3 to a genomic fusion product. Obviously, wherever a potential target exists, chemical matter will emerge to interact with it. Of interest to us will be a human antibody to FGFR2 IIIc from a company called Attogen Bio, as well as a handful of specific and less-specific (a/k/a “dirty”) kinase inhibitors such as AZD4547 and PD173074 in the former category, and dovitinib (can you believe it’s still alive?) and ponatinib (Iclusig).

老马辛苦了！谢谢！！

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谢谢马！太及时了，不知价格如何？