Study protocol of REGOSARC trial: activity and safety of regorafenib in advanced soft tissue sarcoma: a multinational, randomized, placebo-controlled, phase II trial

Brodowicz, Thomas; Liegl-Atzwager, Bernadette; Tresch, Emmanuelle; Taïeb, S.; Kramar, Andrew; Gruenwald, Viktor; Vanseymortier, Marie; Clisant, Stéphanie; Blay, Jean‐Yves; Cesne, Axel Le; Penel, Nicolas

doi:10.1186/s12885-015-1143-y

Cited by 21 publications

(11 citation statements)

References 20 publications

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“…Generally, anti-angiogenesis TKIs therapy with pazopanib has been a hallmark for all non-adipocytic soft tissue sarcoma after phase II and III trial verification, with median PFS 4.6 months (3.7–4.8 m; 95% CI) and best overall objective response rate of 6% (14/246) [ 14 , 29 ]. Thomas et al [ 30 ] reported that regorafenib, which is an inhibitor of VEGFR-1, − 2 and − 3 and tumor cell signaling kinases (RET, KIT, PDGFR, and Raf), yielded median PFS of 4.6 months in advanced sarcoma patients, which was almost the same as with pazopanib. Recently, the US Food and Drug Administration approved olaratumab [ 31 ], a human antiplatelet-derived growth factor receptor α monoclonal antibody, together with doxorubicin as first-line therapy for unresectable or metastatic soft tissue sarcoma.…”

Section: Discussionmentioning

confidence: 99%

Apatinib for advanced sarcoma: results from multiple institutions’ off-label use in China

Xie

Wang

et al. 2018

BMC Cancer

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BackgroundAnti-angiogenesis Tyrosine kinase inhibitors (TKIs) have been proved to show promising effects on prolonging progression-free survival (PFS) for advanced sarcoma after failure of standard multimodal Therapy. Methylsulfonic apatinib is one of those TKIs which specifically inhibits VEGFR-2. This paper summarizes the experience of three Peking University affiliated hospitals in off-label use of apatinib in the treatment of extensively pre-treated sarcoma.MethodsWe retrospectively analysed files of patients with advanced sarcoma not amenable to curative treatment, who were receiving an apatinib-containing regimen between June 1, 2015 and December 1, 2016. Fifty-six patients were included: 22 osteosarcoma, 10 Ewing’s sarcoma, 3 chondrosarcoma and 21 soft tissue sarcoma.ResultsWith median follow-up time of 6 months (range, 0.7–18.0 m), thirty-five (62.5%) patients had partial response, and disease was stable in 11 (19.6%). The 4-month and 6-month progression-free survival rates were 46.3 and 36.5%, respectively. The median duration of response was 3.8 months (95% CI 1.9–5.6 m), with much variability among disease subtypes. The median overall survival was 9.9 months (95% CI 7.6–12.2 m). Grade 3 and 4 toxicities were observed in 8 (14.3%) patients, the most common being hypertension, pneumothorax, wound-healing problems, anorexia, and rash or desquamation.ConclusionsApatinib might be effective, with a high objective response rate, in an off-label study of sarcoma patients with advanced, previously treated disease. The duration of response was consistent with reports in different subtypes of sarcomas. Prospective trials of apatinib in the treatment of selected subtypes of sarcomas are needed.Trial registrationRetrospectively registered in the Medical Ethics Committee of Peking University People’s Hospital, Peking University Shougang Hospital and Peking University International Hospital. The trial registration number is 2017PHB176–03 and the date of registration is January 20th 2017.

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Section: Discussionmentioning

confidence: 99%

Apatinib for advanced sarcoma: results from multiple institutions’ off-label use in China

Xie

Wang

et al. 2018

BMC Cancer

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“…Regorafenib is an orally administered small molecular multikinase inhibitor that targets tumor cells, vasculature, and tumor microenvironment (8,28). To date, preclinical studies with orthotopic colon cancer xenografts have revealed that regorafenib reduced tumor angiogenesis and inhibited tumor growth (20).…”

Section: Discussionmentioning

confidence: 99%

Regorafenib as a potential adjuvant chemotherapy agent in disseminated small colon cancer: Drug selection outcome of a novel screening system using nanoimprinting 3-dimensional culture with HCT116-RFP cells

Yoshii¹,

Furukawa²,

Aoyama³

et al. 2016

International Journal of Oncology

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Colon cancer is one of the leading causes of cancer death worldwide. Adjuvant chemotherapy following primary surgical treatment is suggested to be beneficial in eradicating invisible disseminated small tumors in colon cancer; however, an effective drug remains to be developed. Recently, we reported a novel drug screening system using a nanoimprinting 3-dimensional (3D) culture that creates multicellular spheroids, which simulate in vivo conditions and, thereby, predict effective drugs in vivo. This study aimed to perform drug selection using our recently developed 3D culture system in a human colon cancer HCT116 cell line stably expressing red fluorescent protein (HCT116-RFP), to determine the most effective agent in a selection of clinically used antitumor agents for colon cancer. In addition, we confirmed the efficacy of the selected drug regorafenib, in vivo using a mouse model of disseminated small tumors. HCT116-RFP cells were cultured using a nanoimprinting 3D culture and in vitro drug selection was performed with 8 clinically used drugs [bevacizumab, capecitabine, cetuximab, 5-fluorouracil (5-FU), irinotecan, oxaliplatin, panitumumab and regorafenib]. An in vivo study was performed in mice bearing HCT116-RFP intraperitoneally disseminated small tumors using 3'-[18F]-fluoro-3'-deoxythymidine-positron emission tomography and fluorescence microscopy imaging to evaluate the therapeutic effects. Regorafenib was determined to be the most effective drug in the 3D culture, and significantly inhibited tumor growth in vivo, compared to the untreated control and 5-FU-treated group. The drug 5-FU is commonly used in colon cancer treatment and was used as a reference. Our results demonstrate that regorafenib is a potentially efficacious adjuvant chemotherapeutic agent for the treatment of disseminated small colon cancer and, therefore, warrants further preclinical and clinical studies.

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“…Regorafenib is another multitargeted TKI, with activity against angiogenic, stromal (VEGFR1–3, TIE2, FGFR1, and PDGFR-β), oncogenic (KIT and RET), and intracellular signaling (RAF1 and B-RAF) kinases among others, currently in Phase II trial (REGOSARC) for STS83 after showing activity in both colorectal cancer and GIST in Phase III trials 84,85. Preliminary results from REGOSARC demonstrated improved PFS and OS in patients with leiomyosarcoma and improved PFS in those with other sarcomas 86.…”

Section: Tkismentioning

confidence: 99%

Targeted therapy for soft tissue sarcomas in adolescents and young adults

Steppan

Pratilas

Loeb

2017

AHMT

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Soft tissue sarcomas (STSs) are a heterogeneous group of tumors originating from the mesenchyme. Even though they affect individuals in all age groups, the prevalence of subtypes of STSs changes significantly from childhood through adolescence into adulthood. The mainstay of therapy is surgery, with or without the addition of chemotherapy and/or radiation therapy. These treatment modalities are associated, in many cases, with significant morbidity and, given the heterogeneity of tumor histologies encompassed by the term “STS”, have not uniformly improved outcomes. Moreover, some subgroups of STSs appear to be more, and others less, responsive to conventional chemotherapy agents. Over the last two decades, our understanding of the biology of STSs is slowly increasing, allowing for the development of more targeted therapies. We review the new treatment modalities that have been tested on patients with STSs, with a special focus on adolescents and young adults, a group of patients that is often underrepresented in clinical trials and has not received the dedicated attention it deserves, given the significant differences in biology and treatment response in comparison to children and adults.

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Study protocol of REGOSARC trial: activity and safety of regorafenib in advanced soft tissue sarcoma: a multinational, randomized, placebo-controlled, phase II trial

Cited by 21 publications

References 20 publications

Apatinib for advanced sarcoma: results from multiple institutions’ off-label use in China

Apatinib for advanced sarcoma: results from multiple institutions’ off-label use in China

Regorafenib as a potential adjuvant chemotherapy agent in disseminated small colon cancer: Drug selection outcome of a novel screening system using nanoimprinting 3-dimensional culture with HCT116-RFP cells

Targeted therapy for soft tissue sarcomas in adolescents and young adults

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