Summary

This phase I/Ib trial studies the side effects, best dose, and anti-tumor activity of losartan and sunitinib in treating patients with osteosarcoma that has come back (relapsed) or does not respond to treatment (refractory). Losartan and sunitinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Objectives

PRIMARY OBJECTIVE:
I. Evaluate the safety, tolerability, and define the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of the losartan and sunitinib combination in pediatric and adult patients with relapsed or refractory osteosarcoma.

SECONDARY OBJECTIVES:
I. Describe the pharmacokinetics (PK) of losartan when given in combination with sunitinib in pediatric and young adult patients with relapsed or refractory osteosarcoma.
II. Describe the pharmacodynamic (PD) effects of losartan and sunitinib, specifically effects on monocyte migration, plasma CCL2 levels, and changes to the peripheral CCR2+ monocyte population, when given in combination in pediatric and adult patients with relapsed or refractory osteosarcoma.
III. Describe the preliminary antitumor activity of losartan in combination with sunitinib in pediatric and adult patients with relapsed or refractory osteosarcoma.

EXPLORATORY OBJECTIVES:
I. Describe changes to peripheral T cell populations including CD4+, CD8+, and regulatory T cells, which occurs with treatment of losartan and sunitinib.
II. Describe changes to peripheral immune-related cytokines/chemokines such as TGF-beta, IFN-gamma and VEGF with treatment of losartan and sunitinib.
III. Characterize tumor-infiltrating leukocytes, micro-vessel density, and immune-related gene expression in resected pulmonary metastases of patients treated with losartan and sunitinib.

OUTLINE: This is a dose-escalation and dose expansion study of losartan in combination with sunitinib.

Patients receive losartan orally (PO) twice daily (BID) on days 1-42 and sunitinib PO once daily (QD) on days 1-28. Treatment repeats every 42 days for up to 17 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo echocardiography, x-ray imaging, computed tomography (CT) scan, magnetic resonance imaging (MRI), blood sample collection and may undergo positron emission tomography (PET) scan throughout the study.

After completion of treatment, patients are followed up at 30 days, and then periodically for up to 5 years.

Eligibility

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)
2. Stated willingness to comply with all study procedures and be available for the duration of the study
3. 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 central nervous system (CNS) metastasis are not eligible. Previously treated CNS metastases which occurred 3 months or more prior, without evidence of active recurrence, are acceptable
5. DOSE ESCALATION (PART A): Patients must have measurable or evaluable disease
6. COHORT EXPANSION (PART B): Patients with measurable or evaluable disease and those with completely resected disease are eligible
7. Eastern Cooperative Oncology Group (ECOG) performance status (>=18 years old) =< 2 or Karnofsky performance score (< 18 years old) >= 50
8. 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
9. 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)
10. Anti-cancer agents not known to be myelosuppressive (e.g. not associated with reduced platelet or absolute neutrophil count [ANC] counts): >= 7 days after the last dose of agent
11. 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
12. Corticosteroids: >= 14 days must have elapsed since last dose of corticosteroid
13. 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
14. Interleukins, interferons and cytokines (other than hematopoietic growth factors): >= 21 days after the completion of interleukins, interferon or cytokines (other than hematopoietic growth factors)
15. Stem cell Infusions: Autologous stem cell infusion, including boost infusion: >= 42 days
16. Cellular therapy: >= 42 days after the completion of any type of cellular therapy (e.g., modified T cells, NK cells, dendritic cells, etc.)
17. Radiation therapy (XRT)/External beam irradiation including protons: >= 14 days after local XRT; >= 150 days after total body irradiation (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)
18. Peripheral absolute neutrophil count (ANC) >= 750/mm^3
19. Platelet count >= 75,000/mm^3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment)
20. Hemoglobin >= 8 g/dL (with or without transfusion)
21. Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 OR a serum creatinine based on age/gender as follows: * Age 2 to < 6 years, maximum serum creatinine (mg/dL): 0.8 (male); 0.8 (female) * Age 6 to < 10 years, maximum serum creatinine (mg/dL): 1 (male); 1 (female) * Age 10 to < 13 years, maximum serum creatinine (mg/dL): 1.2 (male); 1.2 (female) * Age 13 to < 16 years, maximum serum creatinine (mg/dL): 1.5 (male); 1.4 (female) * Age >= 16 years, maximum serum creatinine (mg/dL): 1.7 (male); 1.4 (female)
22. Total bilirubin =< 1.5 x upper limit of normal (ULN) for age
23. Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 135 U/L. For the purpose of this study, the ULN for SGPT is 45 U/L
24. Serum albumin >= 2.8 g/dL
25. 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 dose modification requirements
26. Current cardiac ejection fraction >= 50% by biplane Simpson method on echocardiogram
27. Corrected QT (QTc) =< 480 ms
28. Patients with preexisting hyper- or hypothyroidism must be on a stable dose of medication
29. Ability to take and retain oral medications. NOTE: Medication can be administered via nasogastric or gastrostomy tube