The Current Landscape of Early Drug Development for Patients With Sarcoma

2017 ◽  
pp. 807-810
Author(s):  
Breelyn A. Wilky ◽  
Robin L. Jones ◽  
Vicki L. Keedy
Keyword(s):  
Clinical Trials ◽  
Growth Factor ◽  
Soft Tissue ◽  
Checkpoint Inhibitors ◽  
Growth Factor Receptor ◽  
Soft Tissue Sarcomas ◽  
Platelet Derived Growth Factor ◽  
Substantial Growth ◽  
Active Investigation ◽  
Early Drug

Until recently, advancements in the treatment of patients with adult soft tissue sarcomas have been relatively slow. This is, in part, due to their heterogeneity and rarity. A better understanding of the biology and differences among the various histologies has led to substantial growth in novel strategies. In addition to novel cytotoxic chemotherapies, agents targeting platelet-derived growth factor receptor-α (PDGFRα), mTOR, and angiogenesis are areas of active investigation. Additionally, with the success of checkpoint inhibitors in other malignancies and early encouraging results of checkpoint inhibitors in some sarcoma subtypes, this approach is being widely investigated in various sarcomas. As we increasingly recognize and treat each sarcoma histology as a separate disease, it is important to spread awareness of the exciting clinical trials available to our patients with these rare malignancies.

scholarly journals Expression of epidermal growth factor receptor,ERBB2 andKIT in adult soft tissue sarcomas

Cancer ◽  
2005 ◽  
Vol 103 (9) ◽  
pp. 1881-1890 ◽  
Author(s):  
Osamu Sato ◽  
Takuro Wada ◽  
Akira Kawai ◽  
Umio Yamaguchi ◽  
Atsushi Makimoto ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Soft Tissue ◽  
Epidermal Growth Factor ◽  
Growth Factor Receptor ◽  
Soft Tissue Sarcomas ◽  
Epidermal Growth

No relevant activity of olaratumab in patient-derived soft tissue sarcoma xenografts selected for expression of platelet-derived growth factor receptor a.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e22556-e22556
Author(s):  
Jasmien Cornillie ◽  
Britt Van Renterghem ◽  
Nathalie Van Winkel ◽  
Jasmien Wellens ◽  
Yemarshet Gebreyohannes ◽  
...  
Keyword(s):  
Growth Factor ◽  
Soft Tissue ◽  
Soft Tissue Sarcoma ◽  
Single Agent ◽  
Growth Factor Receptor ◽  
Platelet Derived Growth Factor ◽  
Phase Iii ◽  
Nerve Sheath Tumor ◽  
Antitumor Effects ◽  
Inhibition Of Proliferation

e22556 Background: Soft tissue sarcoma (STS) comprises a heterogeneous family of rare tumors of mesenchymal origin. Single-agent doxorubicin (DOX) remains the standard-of-care for advanced and inoperable STS, but response rates are < 15% and survival is generally poor. In 2016, Tap et al. reported impressive results of a phase Ib/II trial combining DOX and the platelet-derived growth factor receptor a (PDGFRA)-directed antibody olaratumab (OLA), suggesting an unprecedented survival advantage of the combination over DOX alone, without providing a mechanistic rationale for the observed activity (Lancet 2016;388:488-97). We decided to evaluate the efficacy of OLA in a panel of patient-derived STS xenografts (PDX). Methods: NMRI nu/nu mice were transplanted bilaterally with tumor tissue of models expressing PDGFRA, including PDX of leiomyosarcoma (UZLX-STS22), malignant peripheral nerve sheath tumor (STS39), myxofibrosarcoma (STS59) and undifferentiated pleomorphic sarcoma (STS84). Mice were randomly divided into 4 treatment groups: (1) control, (2) DOX (3 mg/kg once weekly), (3) anti-PDGFRA [OLA (60 mg/kg twice weekly) + mouse anti-PDGFRA antibody 1E10 (20 mg/kg twice weekly)] and (4) the combination of DOX and anti-PDGFRA (same dose/schedule as single treatment arms). Tumor volume, histopathology and Western blotting were used to assess treatment efficacy. Results: Anti-PDGFRA treatment as single agent did not reduce tumor growth and did not result in significant anti-proliferative or pro-apoptotic activity. Combining DOX and anti-PDGFRA did not reduce tumor burden, though a mild inhibition of proliferation was observed in models STS39 and STS59 and a pro-apoptotic effect was seen in all models except STS22. Antitumor effects on histology were not significantly different comparing DOX and the combination treatment. Anti-PDGFRA treatment, both as a single agent as well as with DOX, did not inhibit downstream MAPK and PI3K/AKT signaling pathways. Conclusions: In vivo findings in PDX models selected for PDGFRA expression support negative findings of the phase III trial NCT02451943 with OLA reported at this meeting.

scholarly journals Assessment of the platelet-derived growth factor receptor alpha antibody olaratumab in a panel of patient-derived soft tissue sarcoma xenografts

BMC Cancer ◽  
2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Jasmien Cornillie ◽  
Agnieszka Wozniak ◽  
Britt Van Renterghem ◽  
Nathalie Van Winkel ◽  
Jasmien Wellens ◽  
...  
Keyword(s):  
Growth Factor ◽  
Soft Tissue ◽  
Soft Tissue Sarcoma ◽  
Growth Factor Receptor ◽  
Platelet Derived Growth Factor ◽  
Receptor Alpha ◽  
Factor Receptor Alpha

Olaratumab: A Novel Platelet-Derived Growth Factor Receptor α-Inhibitor for Advanced Soft Tissue Sarcoma

2017 ◽  
Vol 51 (12) ◽  
pp. 1090-1098 ◽  
Author(s):  
Benjamin J. Andrick ◽  
Arpita Gandhi
Keyword(s):  
Growth Factor ◽  
Soft Tissue ◽  
Soft Tissue Sarcoma ◽  
Literature Search ◽  
Data Extraction ◽  
Treatment Options ◽  
Growth Factor Receptor ◽  
Soft Tissue Sarcomas ◽  
Progression Free Survival ◽  
Advanced Soft Tissue Sarcoma

Objective: To review and summarize data on olaratumab, which was approved by the US Food and Drug Administration (FDA) in October 2016, in combination with doxorubicin, for the treatment of advanced soft tissue sarcoma. Data Sources: A literature search using PubMed was conducted using the search terms olaratumab, IMC-3G3, and advanced soft tissue sarcoma from January 2005 to June 2017. Study Selection and Data Extraction: The literature search was confined to human studies published in English. Trials of olaratumab for advanced soft tissue sarcomas were prioritized. Data Synthesis: Olaratumab is a human antiplatelet-derived growth factor receptor α monoclonal antibody. Its accelerated FDA approval was based on a phase II randomized trial of olaratumab plus doxorubicin (n = 66) versus doxorubicin monotherapy (n = 67) in patients with advanced soft tissue sarcoma. Olaratumab 15 mg/kg was administered intravenously (IV) on days 1 and 8 in combination with doxorubicin 75 mg/m2 IV on day 1 every 21 days for a total of 8 cycles compared to doxorubicin 75 mg/m2 IV monotherapy. The response rate was 18.2% with combination therapy versus 11.9% with monotherapy and median progression-free survival of 6.6 and 4.1 months, respectively. Additionally, overall survival was increased by 11.8 months in the olaratumab arm (26.5 months vs 14.7 months). Clinically relevant adverse effects in the olaratumab + doxorubicin arm included neutropenia (58%), mucositis (53%), nausea (73%), vomiting (45%), and diarrhea (34%). Conclusion: Olaratumab, in combination with doxorubicin, represents a novel treatment strategy for advanced soft tissue sarcoma and provides a significant survival advantage for this rare disease state with limited treatment options.

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