Those studies demonstrate strong rationale to combine a multikinase inhibitor targeting VEGFR, PDGFR with mTOR inhibitor. Moreover, another multi-targeted TKI, lenvatinib monotherapy showed promising activity in osteosarcoma. Therefore, clinical trial with Lenvatinib in combined with everolimus is ongoing for solid tumors (NCT03245151). Considering lenvatinib and everolimus (18 mg/day and 5 mg/day) already approved as standard treatment for renal cell carcinoma based on the powerful ORR, PFS, and OS14, these noteworthy findings advance the treatment paradigm for bone sarcoma patients.

Because all those trials for sarcoma were done in the absence of a control group, based on such clinical studies, a confirmatory trial comparing mTOR inhibitor and a multi-targeted tyrosine kinase inhibitor (multi-TKI) combination versus monotherapy is essential. Therefore, we planned to conduct the randomized phase II trial of everolimus in combination with lenvatinib for advanced/metastatic bone sarcomas. In addition, we will explore predictive biomarkers by repeated biopsies and blood samplings during the treatment.

Inclusion Criteria:

1. Histologically confirmed advanced Osteosarcoma, Ewing sarcoma, Chondrosarcoma with 1-2 prior chemotherapy

   : neoadjuvnat or adjuvant chemotherapy is counted as one regimen

2. Age ≥19 years, <80 years

3. ECOG performance status of 0-1

4. Has at least 1 measurable lesion (as defined by Response Evaluation Criteria in Solid Tumors Version 1.1).

5. Has adequate organ function defined by the following criteria:

   • Hb ≥ 9.0 g/dL
   • Absolute neutrophil count (ANC) ≥ 1000 /µL
   • Platelet ≥ 75,000/ µL
   • Serum Creatinine: ≥ 50 mL/min
   • Total Bilirubin: ≤ 1.5 × UNL (upper normal limit)
   • AST(SGOT)): ≤ 3.0 × UNL or ≤ 5.0 × UNL (in patients with liver metastasis)
   • ALT(SGPT): ≤ 3.0 × UNL or ≤ 5.0 × UNL (in patients with liver metastasis)

6. Female patient of childbearing potential has a negative serum or urine pregnancy test for β-hCG

7. Able to provide written informed consent and comply with the protocol requirements

   Exclusion Criteria:

   • Any concurrent chemotherapy, biologic, or hormonal therapy for cancer treatment within 2 weeks prior to entering the study. Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone replacement therapy) is acceptable

     • Any previous treatment to lenvatinib or mTOR inhibitor

       • Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria

         • Major surgical procedure (as defined by the Investigator) within 14 days prior to the first dose of IP ⑤Active or prior documented autoimmune or inflammatory disorders

           -including inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc.

           • History of the following conditions within the past 6 months.

             • coronary angioplasty or stent placement, myocardial infarction, unstable angina, coronary artery bypass grafting, peripheral arterial disease (Grade III) or congestive heart failure (Grade IV) according to the New York Heart Association classification, thromboembolism (patients on stable anticoagulation for ≥6 weeks are eligible), hemoptysis, intracranial hemorrhage, or clinically significant gastrointestinal bleeding ⑦Has an active infection requiring parenteral treatment

               • History of another primary malignancy.

   However, enrollment is permitted in the following cases:

   • Basal cell or squamous cell carcinoma of the skin after curative resection

   • Cervical carcinoma in situ after at least 1 year following successful treatment

   • Patients who have been disease-free for at least 3 years after completion of treatment

     ⑨Known or active CNS metastasis and/or carcinomatous meningitis

   • Participants with previously treated brain metastases are eligible if radiologically stable.

     • female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to emply effective birth control from screening to 90 days after the last dose](streamdown:incomplete-link)