Abstract
BackgroundClinical outcomes of patients with osteosarcoma remain unsatisfactory, with little improvement in a 5-year overall survival over the past three decades. There is a substantial need for further research and development to identify and develop more efficacious agents/regimens in order to improve clinical outcomes of patients for whom the prognosis is unfavorable. Recently, mycophenolate mofetil, a prodrug of mycophenolic acid, has been found to have anticancer activity against osteosarcoma in both in vitro and animal experiments, so that further investigation in humans is warranted.MethodsA total of 27 patients with high-grade locally advanced or metastatic osteosarcoma will be enrolled into this phase II, multi-center, open-label, single-arm, two-stage clinical trial. The main objectives of this study are to determine the efficacy and safety of mycophenolate mofetil in the patients. The primary endpoint is progression-free survival at 16 weeks; the secondary endpoints include progression-free survival, overall survival, overall response rate, safety parameters, pharmacokinetic parameters, biomarkers, pain score, and quality of life. Mycophenolate mofetil at the initial dose of 5 g/day or lower will be administered for 4 cycles (28 days/cycle) or until disease progression or unacceptable toxicity. The dose of mycophenolate mofetil may be reduced by 1–2 g/day or withheld for some Grade 3 or Grade 4 toxicities whenever clinically needed. The duration of study participation is approximately 4–5 months, with a minimum of 12 study visits. If mycophenolate mofetil proves beneficial to some patients, as evidenced by stable disease or partial response at 16 weeks, administration of mycophenolate mofetil will continue in the extension period.DiscussionThis trial is the first step in the translation of therapeutic potential of mycophenolate mofetil emerging from in vitro and animal studies into the clinical domain. It is designed to assess the efficacy and safety of mycophenolate mofetil in patients with high-grade locally advanced or metastatic osteosarcoma. The results will provide important information about whether or not mycophenolate mofetil is worth further development.Trial registrationThis trial was prospectively registered on Thai Clinical Trials Registry (registration number: TCTR20190701001). The posted information will be updated as needed to reflect protocol amendments and study progress.
Highlights
Clinical outcomes of patients with osteosarcoma remain unsatisfactory, with little improvement in a 5-year overall survival over the past three decades
The present study aims to explore the pharmacokinetics of mycophenolate mofetil, biomarkers, and the quality of life in patients with highgrade locally advanced or metastatic osteosarcoma
Any modifications to the protocol and related documents will be submitted to ethics committees for approval of such amendments prior to implementation. This is the first prospective phase II clinical trial which is designed to assess the efficacy and safety of mycophenolate mofetil in patients with high-grade locally advanced or metastatic osteosarcoma. The results of this trial will reveal the therapeutic potential of mycophenolate mofetil against osteosarcoma in humans for the first time
Summary
Clinical outcomes of patients with osteosarcoma remain unsatisfactory, with little improvement in a 5-year overall survival over the past three decades. Mycophenolate mofetil, a prodrug of mycophenolic acid, has been found to have anticancer activity against osteosarcoma in both in vitro and animal experiments, so that further investigation in humans is warranted. The substantial advance in the treatment of osteosarcoma occurs in the 1970s and 1980s, when chemotherapy was shown to significantly improve the survival outcome of the patients with localized disease undergoing surgical resection [5, 6]. Mycophenolate mofetil is an immunosuppressive agent currently being used for the prophylaxis of organ rejection following transplantation [12, 13] It is a prodrug of mycophenolic acid (MPA), a potent inhibitor of inosine monophosphate dehydrogenase (IMPDH) [14, 15]. Mycophenolate mofetil has been recently proposed to be a promising new drug candidate for the treatment of osteosarcoma [19]
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