A Phase I Trial of Cabozantinib (XL184) in Combination With High-dose Ifosfamide in Adults and Children With Relapsed/Refractory Ewing Sarcoma and Osteosarcoma
The purpose of this study is to better understand how safe and effective the drug cabozantinib in combination with high-dose ifosfamide is in the treatment of children and adults with relapsed/refractory Ewing sarcoma and osteosarcoma.
• Histologic diagnosis of Ewing sarcoma (including Ewing-like sarcoma) or osteosarcoma. Biopsy from current relapse/progression is highly preferred, though will accept tissue from prior relapse/progression or initial diagnosis with approval from the study Principal Investigator or designee.
• Disease that has progressed on or relapsed after upfront initial therapy, which must have included traditional chemotherapy. A maximum of 2 prior lines of traditional cytotoxic myelosuppressive systemic therapy is allowed.
• Measurable disease, according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1), within 21 days of enrollment.
• Age, within the following parameters by cohort:
∙ Phase I dose-finding cohort: age 12 to 40 years at the time of enrollment.
‣ Phase I dose-confirmation cohort: age 5 to \< 12 years at the time of enrollment.
• Body surface area (BSA): \> 0.35 m2.
• Performance status: Lansky play (\< 16 years of age) or Karnofsky (\> 16 years of age) of ≥ 50, corresponding to Eastern Cooperative Oncology Group (ECOG) categories \< 2.
• Prior toxicity: recovery to baseline or grade \< 1, as per the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 (v5.0), from all acute toxicities, unless adverse events (AE) are clinically non-significant (i.e. alopecia) or controlled on supportive care (i.e. nausea/vomiting, hypothyroidism).
• Able to swallow tablets whole.
• Hematopoietic function:
∙ Absolute neutrophil count \> 1,000/uL (without hematopoietic growth factor within the time frame noted below).
‣ Hemoglobin \> 8 g/dL (without transfusion in the last 7 days).
‣ Platelets \> 100,000/uL (without transfusion in the last 7 days).
⁃ Renal function:
• Normal renal function determined by one of the following means (even if others are outside of normal range): 1) serum creatinine \< 1.5 x upper limit of normal (ULN) for age; 2) cystatin C within normal limits; 3) nuclear medicine glomerular filtration rate (GFR) within normal limits, or 4) calculated creatinine clearance of \> 70 mL/min/1.73 m2 (≥ 1.17mL/sec)
∙ Urine protein/creatinine ratio (UPCR) ≤ 1 mg/mg (≤ 113.2 mg/mmol), or 24-hour urine protein ≤ 1 g.
⁃ Hepatic function:
• Total bilirubin \< 1.5 x ULN (for subjects with Gilbert's disease \< 3.0 x ULN).
∙ Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) ≤ 3 x ULN (ALP ≤ 5 x ULN is allowed with documented bone metastases). For the purpose of this study, the ULN for ALT is defined as 45 IU/L.
∙ Serum albumin \> 2.8 g/dL.
∙ Prothrombin time (PT) and partial thromboplastin time (PTT) \< 1.3 x ULN.
⁃ Sexually active fertile subjects and their partners must agree to use medically accepted methods of contraception (i.e. barrier methods, including male condom, female condom, or diaphragm with spermicidal gel) during the course of the study and for 4 months after the last dose of study treatment.
⁃ Female subjects of childbearing potential must not be pregnant at screening. Female subjects are considered to be of childbearing potential unless one of the following criteria are met:
• Pre-pubertal by tanner staging, defined as Tanner stage 1 or 2.
∙ Documented permanent sterilization (i.e. hysterectomy, bilateral salpingectomy, or bilateral oophorectomy). Documentation of permanent sterilization or postmenopausal status may include review of medical records, medical examinations, or medical history interview by study site.