A Phase I/Ib Study of Losartan in Combination With Sunitinib in the Treatment of Pediatric and Adult Patients With Relapsed or Refractory Osteosarcoma

• 1. Provision to sign and date the consent form (if individual is a minor, provision of a parent or legal guardian to sign and date the consent form and provision of individual to provide assent for study).

‣ Stated willingness to comply with all study procedures and be available for the duration of the study.

‣ Male or female aged ≥ 10 years old. 4. Histologically confirmed osteosarcoma (at either original diagnosis or relapse) that has either recurred or progressed after at least one prior systemic therapy and for which no curative therapy exists.

• Patients with surface or periosteal osteosarcoma are not eligible.

• Patients with active CNS metastasis are not eligible. Previously treated CNS metastases which occurred 3 months or more prior, without evidence of active recurrence, are acceptable.

‣ Disease status

• Dose Escalation (Part A): Patients must have measurable or evaluable disease.

• Cohort Expansion (Part B): Patients with measurable or evaluable disease and those with completely resected disease are eligible.

‣ Performance status:

• ECOG performance status (≥18 years old) ≤ 2 or Karnofsky performance score (\<18 years old)≥ 50.

‣ Prior Therapy:

• Patients must have fully recovered from the acute toxic effects of all prior anti-cancer therapy and must meet the following minimum duration from prior anti-cancer directed therapy prior to enrollment. If after the required timeframe, the numerical eligibility criteria are met (e.g., blood count criteria) the patient is considered to have recovered adequately.

‣ Cytotoxic chemotherapy or other anti-cancer agents known to be myelosuppressive. At least 21 days after the last dose of cytotoxic or myelosuppressive chemotherapy (42 days if prior nitrosourea).

⁃ Anti-cancer agents not known to be myelosuppressive (e.g., not associated with reduced platelet or ANC counts): ≥ 7 days after the last dose of agent.

• i. Antibodies: ≥ 21 days must have elapsed from infusion of last dose of antibody, and toxicity related to prior antibody therapy must be recovered to Grade ≤ 1.

• ii. Corticosteroids: ≥ 14 days must have elapsed since last dose of corticosteroid.

• iii. Hematopoietic growth factors: ≥ 14 days after the last dose of a long- acting growth factor (e.g., pegfilgrastim) or 7 days for short-acting growth factor.

• iv. Interleukins, Interferons and Cytokines (other than hematopoietic growth factors): ≥ 21 days after the completion of interleukins, interferon or cytokines (other than Hematopoietic Growth Factors).

• v. Stem cell Infusions: Autologous stem cell infusion, including boost infusion: ≥ 42 days.

• vi. Cellular Therapy: ≥ 42 days after the completion of any type of cellular therapy (e.g., modified T cells, NK cells, dendritic cells, etc.) vii. XRT/External Beam Irradiation including protons: ≥ 14 days after local XRT; ≥ 150 days after TBI, craniospinal XRT or if radiation to ≥ 50% of the pelvis; ≥ 42 days if other substantial bone marrow radiation.

• NOTE: Patients with history of cardiac irradiation with mean cardiac dose \> 15 Gy are not eligible (see exclusion criteria).

‣ Adequate bone marrow function, defined as:

• Peripheral absolute neutrophil count (ANC) ≥ 750/mm3

• Platelet count ≥ 75,000/mm3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment).

• Hemoglobin ≥ 8 g/dL (with or without transfusion) 9. Adequate renal function, defined as:

• Creatinine clearance or radioisotope GFR \> 70 mL/min/1.73 m2 OR a serum creatinine based on age/gender.

∙ Adequate hepatic function, defined as:

• Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age

• SGPT (ALT) ≤ 135 U/L. For the purpose of this study, the ULN for SGPT is 45 U/L.

• Serum albumin ≥ 2.8 g/dL 11. Patients with ≥ trace protein on urinalysis at screening will be allowed to enroll in the study at investigator discretion. A baseline urine protein creatinine ratio (UPC) should be obtained for patients with ≥ trace protein on urinalysis for consideration regarding Section 6.3.7 dose modification requirements.

∙ Adequate cardiac function, defined as:

• Current cardiac ejection fraction \> 50% by biplane Simpson method on echocardiogram

• QTc ≤ 480 ms 13. Patients with preexisting hyper- or hypothyroidism must be on a stable dose of medication.

∙ Ability to take and retain oral medications. NOTE: Medication can be administered via nasogastric or gastrostomy tube.