Receptor tyrosine kinase inhibitors for the treatment of osteosarcoma and Ewing sarcoma

Just, Marissa A.; Mater, David Van; Wagner, Lars M.

doi:10.1002/pbc.29084

Cited by 12 publications

(10 citation statements)

References 73 publications

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“…Many of the TKIs currently being evaluated have multiple targets, including receptor and intracellular tyrosine kinases that drive pro-tumorigenic pathways, such as angiogenesis and proliferation [ 83 ]. Data from clinical trials evaluating TKIs for sarcoma suggest that inhibition of multiple tyrosine kinases is more effective than targeting a single kinase [ 84 ].…”

Section: Results Of Published Trialsmentioning

confidence: 99%

Recent and Ongoing Research into Metastatic Osteosarcoma Treatments

Harris

Hawkins

2022

IJMS

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The survival rate for metastatic osteosarcoma has not improved for several decades, since the introduction and refinement of chemotherapy as a treatment in addition to surgery. Over two thirds of metastatic osteosarcoma patients, many of whom are children or adolescents, fail to exhibit durable responses and succumb to their disease. Concerted efforts have been made to increase survival rates through identification of candidate therapies via animal studies and early phase trials of novel treatments, but unfortunately, this work has produced negligible improvements to the survival rate for metastatic osteosarcoma patients. This review summarizes data from clinical trials of metastatic osteosarcoma therapies as well as pre-clinical studies that report efficacy of novel drugs against metastatic osteosarcoma in vivo. Considerations regarding the design of animal studies and clinical trials to improve survival outcomes for metastatic osteosarcoma patients are also discussed.

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Section: Results Of Published Trialsmentioning

confidence: 99%

Recent and Ongoing Research into Metastatic Osteosarcoma Treatments

Harris

Hawkins

2022

IJMS

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“…Adult phase 3 data of pazopanib in metastatic soft tissue sarcoma also failed to show a significant objective response rate (6%) or improvement in overall survival; rather, it was the statistically significant improvement in progression-free survival (PFS) that led to regulatory approval [ 12 ]. The results of several phase II trials of receptor tyrosine kinase inhibitors in the treatment of bone sarcomas also suggest that objective response rate in the setting of relapsed or refractory disease may be of less relevance in evaluating their efficacy, raising the potential for their role as maintenance therapy [ 30 ].…”

Section: Discussionmentioning

confidence: 99%

Low-Dose Metronomic Topotecan and Pazopanib (TOPAZ) in Children with Relapsed or Refractory Solid Tumors: A C17 Canadian Phase I Clinical Trial

Manji

Samson

Deyell

et al. 2022

Cancers

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Oral metronomic topotecan represents a novel approach to chemotherapy delivery which, in preclinical models, may work synergistically with pazopanib in targeting angiogenesis. A phase I and pharmacokinetic (PK) study of this combination was performed in children with relapsed/refractory solid tumors. Oral topotecan and pazopanib were each administered daily without interruption in 28-day cycles at five dose levels (0.12 to 0.3 mg/m2 topotecan and 125 to 160 mg/m2 pazopanib powder for oral suspension (PfOS)), with dose escalation in accordance with the rolling-six design. PK studies were performed on day 1 and at steady state. Thirty patients were enrolled, with 26 evaluable for dose-limiting toxicity (DLT), with median age 12 years (3–20). Toxicities were generally mild; the most common grade 3/4 adverse events related to protocol therapy were neutropenia (18%), thrombocytopenia (11%), lymphopenia (11%), AST elevation (11%), and lipase elevation (11%). Only two cycle 1 DLTs were observed on study, both at the 0.3/160 mg/m2 dose level comprising persistent grade 3 thrombocytopenia and grade 3 ALT elevation. No AEs experienced beyond cycle 1 required treatment discontinuation. The best response was stable disease in 10/25 patients (40%) for a median duration of 6.4 (1.7–45.1) months. The combination of oral metronomic topotecan and pazopanib is safe and tolerable in pediatric patients with solid tumors, with a recommended phase 2 dose of 0.22 mg/m2 topotecan and 160 mg/m2 pazopanib. No objective responses were observed in this heavily pre-treated patient population, although 40% did achieve stable disease for a median of 6 months. While this combination is likely of limited benefit for relapsed disease, it may play a role in the maintenance setting.

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“…Supporting this was the potential importance of angiogenesis in osteosarcoma and Ewing sarcoma [ 90 , 91 ], as well as the expression of targetable RTKs such as RET, MET, PDGFR, KIT, AXL, and FGFR. The experience of several recent phase II trials of multi-targeted RTK inhibitors for the treatment of recurrent osteosarcoma and Ewing sarcoma has been summarized [ 92 ]. The drugs studied included sorafenib, apatinib, lenvatinib, cabozantinib, and regorafenib [ 35 , 37 , 38 , 40 , 42 , 44 ].…”

Section: Key Clinical Trials Of Rtk Inhibitors To Treat Pediatric Solid Tumorsmentioning

confidence: 99%

“…The incidence of toxicities may be related to the extent of various kinases inhibited. For example, highly-specific inhibitors such as larotrectinib and selpercatinib require dose reductions in less than 10% of patients [ 25 , 33 ], while one-third or more of patients receiving multi-RTK inhibitors require treatment modifications [ 92 ].…”

Section: Toxicity Dosing and Pharmacokinetic Considerationsmentioning

confidence: 99%

Pursuing Precision: Receptor Tyrosine Kinase Inhibitors for Treatment of Pediatric Solid Tumors

Bellantoni

Wagner

2021

Cancers

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Receptor tyrosine kinases are critical for the growth and proliferation of many different cancers and therefore represent a potential vulnerability that can be therapeutically exploited with small molecule inhibitors. Over forty small molecule inhibitors are currently approved for the treatment of adult solid tumors. Their use has been more limited in pediatric solid tumors, although an increasing number of single-agent and combination studies are now being performed. These agents have been quite successful in certain clinical contexts, such as the treatment of pediatric tumors driven by kinase fusions or activating mutations. By contrast, only modest activity has been observed when inhibitors are used as single agents for solid tumors that do not have genetically defined alterations in the target genes. The absence of predictive biomarkers has limited the wider applicability of these drugs and much work remains to define the appropriate patient population and clinical situation in which receptor tyrosine kinase inhibitors are most beneficial. In this manuscript, we discuss these issues by highlighting past trials and identifying future strategies that may help add precision to the use of these agents for pediatric extracranial solid tumors.

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Receptor tyrosine kinase inhibitors for the treatment of osteosarcoma and Ewing sarcoma

Cited by 12 publications

References 73 publications

Recent and Ongoing Research into Metastatic Osteosarcoma Treatments

Recent and Ongoing Research into Metastatic Osteosarcoma Treatments

Low-Dose Metronomic Topotecan and Pazopanib (TOPAZ) in Children with Relapsed or Refractory Solid Tumors: A C17 Canadian Phase I Clinical Trial

Pursuing Precision: Receptor Tyrosine Kinase Inhibitors for Treatment of Pediatric Solid Tumors

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