Mycophenolate mofetil, an immunosuppressive agent, is under investigation in a Phase II clinical trial for its potential to treat high-grade locally advanced or metastatic osteosarcoma. The multi-center, open-label, single-arm study is being conducted in Thailand and aims to assess the drug's efficacy and safety in patients who have limited treatment options. The primary endpoint is progression-free survival (PFS) at 16 weeks.
Rationale for Mycophenolate Mofetil in Osteosarcoma
Osteosarcoma is a primary malignant bone tumor predominantly affecting adolescents and young adults, with a global incidence of 2-4 per million. While advancements in treatment occurred in the 1970s and 1980s, the 5-year overall survival rate remains at approximately 70% for localized disease and 30% for metastatic disease. Mycophenolate mofetil, a prodrug of mycophenolic acid (MPA), inhibits inosine monophosphate dehydrogenase (IMPDH), an enzyme upregulated in some cancers. Preclinical studies have demonstrated MPA's anticancer activity against osteosarcoma cell lines, with IC50 values ranging from 0.46 to 7.30 μM, and in vivo experiments have shown tumor growth inhibition and reduced lung metastasis in mice treated with mycophenolate mofetil.
Trial Design and Objectives
The Phase II trial will enroll 27 adolescent and adult patients with high-grade locally advanced or metastatic osteosarcoma. Participants will receive mycophenolate mofetil orally at a dose of 5 g/day (or lower) for 4 cycles (28 days/cycle) or until disease progression or unacceptable toxicity. The study employs a two-stage design: in Stage 1, 19 patients will be enrolled, and the trial will proceed to Stage 2 with an additional 8 patients only if at least 3 patients in Stage 1 achieve the primary endpoint. Secondary endpoints include overall survival (OS), overall response rate (ORR), safety parameters, pharmacokinetic parameters, biomarkers, pain score, and quality of life.
Inclusion and Exclusion Criteria
Eligible patients must have a histologically confirmed diagnosis of high-grade locally advanced or metastatic osteosarcoma not amenable to surgery, radiation, or combined modality therapy with curative intent. They must also have measurable disease, evidence of disease progression after at least one standard chemotherapy regimen, or patient refusal for further standard chemotherapy. Key exclusion criteria include a history of another malignancy within 5 years, current treatment with another investigational agent, and impaired renal function.
Treatment and Monitoring
Patients will be closely monitored for toxicity, and the dose of mycophenolate mofetil may be adjusted based on individual tolerance. Allopurinol will be co-administered to block the guanine salvage pathway. Prophylactic medications, including ivermectin, trimethoprim-sulfamethoxazole, and acyclovir, will be administered to prevent potential infections during the study. If mycophenolate mofetil demonstrates benefit (stable disease or partial response) at Week 16, treatment will continue in an extension period.
Statistical Analysis
The primary endpoint, PFS at 16 weeks, will be analyzed as a binary variable (disease control success or failure). PFS and OS will be summarized using the Kaplan-Meier method. The trial will be stopped prematurely if fewer than 3 patients among the first 19 achieve disease control success, based on the Simon minimax criterion.
