Multicenter Phase 2 Trial of Gemcitabine, Carboplatin, and Sorafenib in Patients With Metastatic or Unresectable Transitional-Cell Carcinoma

Hurwitz, Michael; Markowski, Paul; Yao, Xiaopan; Deshpande, Hari A.; Patel, Jaymin; Mortazavi, Amir; Donadio, Alessia; Stein, Mark N.; Kelly, William Kevin; Petrylak, Daniel P.; Mehnert, Janice M.

doi:10.1016/j.clgc.2018.07.021

Cited by 4 publications

(4 citation statements)

References 29 publications

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“…A phase I clinical trial of the combination of sorafenib and vinflunine was notable for an overall response rate of 41% in patients with post-platinum metastatic UC [ 139 ]. A phase II trial assessed sorafenib in combination with gemcitabine and carboplatin as first-line therapy in metastatic or unresectable UC [ 140 ]. While this study reports a median progression-free survival of 9.5 months, there were significant toxicities with the regimen leading to 65% of the cohort discontinuing treatment [ 140 ].…”

Section: Mapk Pathwaymentioning

confidence: 99%

“…A phase II trial assessed sorafenib in combination with gemcitabine and carboplatin as first-line therapy in metastatic or unresectable UC [ 140 ]. While this study reports a median progression-free survival of 9.5 months, there were significant toxicities with the regimen leading to 65% of the cohort discontinuing treatment [ 140 ]. Further evaluation with phase III studies of sorafenib in combination with vinflunine or gemcitabine/carboplatin is warranted.…”

Section: Mapk Pathwaymentioning

confidence: 99%

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Molecularly Targeted Therapy towards Genetic Alterations in Advanced Bladder Cancer

Thomas

Sonpavde

2022

Cancers

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Despite the introduction of immune checkpoint inhibitors and antibody–drug conjugates to the management of advanced urothelial carcinoma, the disease is generally incurable. The increasing incorporation of next-generation sequencing of tumor tissue into the characterization of bladder cancer has led to a better understanding of the somatic genetic aberrations potentially involved in its pathogenesis. Genetic alterations have been observed in kinases, such as FGFRs, ErbBs, PI3K/Akt/mTOR, and Ras-MAPK, and genetic alterations in critical cellular processes, such as chromatin remodeling, cell cycle regulation, and DNA damage repair. However, activating mutations or fusions of FGFR2 and FGFR3 remains the only validated therapeutically actionable alteration, with erdafitinib as the only targeted agent currently approved for this group. Bladder cancer is characterized by genomic heterogeneity and a high tumor mutation burden. This review highlights the potential relevance of aberrations and discusses the current status of targeted therapies directed at them.

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Section: Mapk Pathwaymentioning

confidence: 99%

Section: Mapk Pathwaymentioning

confidence: 99%

Molecularly Targeted Therapy towards Genetic Alterations in Advanced Bladder Cancer

Thomas

Sonpavde

2022

Cancers

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“…To increase the efficacy of treating advanced breast cancer gemcitabine is combined with carboplatin 16 . To improve the efficacy of treating germ cell cancer, as well as metastatic and unresectable transitional cell carcinoma gemcitabine is combined with sorafenib 17 , 18 . To heighten the efficacy of treating urothelial carcinoma of the bladder gemcitabine is combined with paclitaxel 19 .…”

Section: Introductionmentioning

confidence: 99%

Exploring the action of RGDV-gemcitabine on tumor metastasis, tumor growth and possible action pathway

Zhang

et al. 2020

Sci Rep

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The coupling of Arg-Gly-Asp-Val (RGDV) and gemcitabine led to a hypothesis that the conjugate (RGDV-gemcitabine) could inhibit tumor metastasis. To confirm this hypothesis the activities of RGDV-gemcitabine inhibiting tumor metastasis in vitro and in vivo were presented for the first time. AFM (atomic force microscopy) imaged that RGDV-gemcitabine was able to adhere onto the surface of serum-starved A549 cells, to block the extending of the pseudopodia. Thereby RGDV-gemcitabine was able to inhibit the invasion, migration and adhesion of serum-starved A549 cells in vitro. On C57BL/6 mouse model RGDV-gemcitabine dose dependently inhibited the metastasis of planted tumor towards the lung and the minimal dose was 0.084 µmol/kg/3 days. The decrease of serum TNF-α (tumor necrosis factor), IL-8 (interleukin-8), MMP-2 (matrix metalloprotein-2) and MMP-9 (matrix metalloprotein-9) of the treated C57BL/6 mice was correlated with the action pathway of RGDV-gemcitabine inhibiting the metastasis of the planted tumor towards lung.

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“…The combinations of gemcitabine with the other drugs including oxaliplatin, irinotecan, miR-345, nab-paclitaxel, RT11-i antibody, metformin, ginkgolide B and melatonin are approved been able to enhance the efficacy of gemcitabine in the treatment of pancreatic cancer 7–13. Thus the combination of gemcitabine with platinum, carboplatin, sorafenib, paclitaxel, cisplatin plus bevacizumab and docetaxel is used for bladder cancer and muscle-invasive bladder cancer,7,14 advanced breast cancer,15 germ cell cancer,16 metastatic or unresectable transitional-cell carcinoma,17 recurrent urothelial carcinoma of bladder,18 concomitant primary lung cancer and metastatic pulmonary colorectal cancer19 and soft tissue sarcomas,20 respectively.…”

Section: Introductionmentioning

confidence: 99%

<p>RGDV-modified gemcitabine: a nano-medicine capable of prolonging half-life, overcoming resistance and eliminating bone marrow toxicity of gemcitabine</p>

Liu¹,

Mao²,

Zhang³

et al. 2019

IJN

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BackgroundGemcitabine has been widely used as a chemotherapeutic drug. However, drug resistance, short half-life and side effects seriously decrease its chemotherapeutic efficacy.PurposeThe object of preparing RGDV-gemcitabine was to prolong the half-life, to overcome drug resistance and to eliminate bone marrow toxicity of gemcitabine.MethodsArg-Gly-Asp-Val was coupled with gemcitabine, forming 4-(Arg-Gly-Asp-Val-amino)-1-[3,3-difluoro-4-hydroxy-5-(hydroxylmethyl)oxo-lan-2-yl]pyrimidin-2-one (RGDV-gemcitabine) involving 9-step reactions. The advantages of RGDV-gemcitabine to gemcitabine were demonstrated by a series of assays, such as in vitro half-life assay, in vitro drug resistance assay, in vivo anti-tumor assay, in vivo kidney toxicity assay, in vivo liver toxicity assay and in vivo marrow toxicity assay. The nano-features of RGDV-gemcitabine were visualized by TEM, SEM and AFM images. The tumor-targeting action and release of RGDV-gemcitabine were evidenced by FT-MS spectra.ResultsHalf-life and anti-tumor activity of RGDV-gemcitabine were 17-fold longer and 10-fold higher than that of gemcitabine, respectively. RGDV-gemcitabine, but not gemcitabine, showed no kidney toxicity, no liver toxicity, no marrow toxicity and no drug resistance. The advantages attributed to the nanofeatures of RGDV-gemcitabine were targeting tumor tissue and releasing gemcitabine in tumor tissue.ConclusionRGDV-gemcitabine successively overcame the defects of gemcitabine and provided a practical strategy of nano-medicine.

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Multicenter Phase 2 Trial of Gemcitabine, Carboplatin, and Sorafenib in Patients With Metastatic or Unresectable Transitional-Cell Carcinoma

Cited by 4 publications

References 29 publications

Molecularly Targeted Therapy towards Genetic Alterations in Advanced Bladder Cancer

Molecularly Targeted Therapy towards Genetic Alterations in Advanced Bladder Cancer

Exploring the action of RGDV-gemcitabine on tumor metastasis, tumor growth and possible action pathway

<p>RGDV-modified gemcitabine: a nano-medicine capable of prolonging half-life, overcoming resistance and eliminating bone marrow toxicity of gemcitabine</p>

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