Losartan + Sunitinib in Treatment of Osteosarcoma

Inclusion Criteria:

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

2. Stated willingness to comply with all study procedures and be available for theduration of the study.

3. Male or female aged ≥ 10 years old. 4. Histologically confirmed osteosarcoma (ateither original diagnosis or relapse) that has either recurred or progressed afterat 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 CNSmetastases which occurred 3 months or more prior, without evidence of activerecurrence, are acceptable.

5. Disease status

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

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

6. Performance status:

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

7. Prior Therapy:

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

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

2. Anti-cancer agents not known to be myelosuppressive (e.g., not associated withreduced 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 Gyare not eligible (see exclusion criteria).

8. Adequate bone marrow function, defined as:

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

• Platelet count ≥ 75,000/mm3 (transfusion independent, defined as not receivingplatelet 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 creatininebased on age/gender.

10. 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 atscreening will be allowed to enroll in the study at investigator discretion. Abaseline urine protein creatinine ratio (UPC) should be obtained for patients with ≥trace protein on urinalysis for consideration regarding Section 6.3.7 dosemodification requirements.

12. 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 astable dose of medication.

14. Ability to take and retain oral medications. NOTE: Medication can beadministered via nasogastric or gastrostomy tube.

Exclusion Criteria:

1. Patients who underwent major surgery within 14 days prior to start of treatment arenot eligible. NOTE: Core biopsy or central line placement are considered minor and are allowedwithin any time limitations.

2. Patients with uncontrolled coagulopathy or bleeding disorder, or any active bleeding (i.e., gastrointestinal or pulmonary) deemed to be clinically significant byinvestigator are not eligible.

3. Patients with history of pulmonary embolism or significant thromboembolic event withthe preceding 28 days. Patients with thromboembolic events > 28 days beforeenrollment who are stable on or completed an anticoagulation course are eligible.

4. Patients with history of cardiac irradiation with mean cardiac dose > 15 Gy are noteligible.

5. Patients with symptomatic cardiac disease (i.e. New York Heart Association orModified Ross Heart Failure Classification for Children > class 2) are not eligible.

6. Patients with any history of cardiac dysfunction including prior abnormalechocardiogram (ejection fraction < 50%), severe or unstable angina, peripheralvascular disease, congenital prolonged QTc syndrome, clinically significant cardiacarrhythmias, stroke, or myocardial infarction are not eligible.

7. Pregnancy

• Pregnant or breast-feeding women will not be entered on this study becausethere is not yet available information regarding human fetal or teratogenictoxicities. Pregnancy tests must be obtained in females who are post-menarchal.

• Males or females of reproductive potential may not participate unless they haveagreed to practice 1 highly effective and 1 additional effective (barrier)method of contraception at the same time during the entire study treatmentperiod and through 3 months after the last dose of study drug, or agree topractice true abstinence, when this is in line with the preferred and usuallifestyle of the subject. Patients who themselves or their partners haveundergone female or male sterilization do not require 2 methods ofcontraception. Highly effective methods are defined as those with <1% failurerate with perfect use and include: oral contraceptive pills (combined orprogesterone only), intrauterine devices (IUD), hormonal implant or injection,contraceptive patch, and vaginal ring.

8. Concomitant medications:

• Anti-hypertensives: Patients who cannot be controlled to goal blood pressurefor gender/age are not eligible.

• Corticosteroids: Patients receiving systemic corticosteroids are not eligible. > 14 days must have elapsed since last systemic corticosteroid. Note: patientsusing topical or inhaled corticosteroids are eligible.

• Investigational Drugs: Patients currently receiving another investigationaldrug are not eligible.

• Anti-cancer agents: Patients currently receiving other anti-cancer agents arenot eligible.

• Drug interactions: Patients who require treatment with medications that arestrong inhibitors or inducers of CYP3A4 or inhibitors of CYP2A9 or havereceived these medications in the 7 days prior to enrollment, are not eligible.Patients who require treatment with enzyme inducing anticonvulsants are noteligible.

• Medications that prolong QTc: Patients who require treatment with medicationsknown to prolong QTc are not eligible