Losartan and Sunitinib for the Treatment of Relapsed or Refractory Osteosarcoma
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.
- 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
- 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
- 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
- Eastern Cooperative Oncology Group (ECOG) performance status (>=18 years old) =< 2 or Karnofsky performance score (< 18 years old) >= 50
- 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 absolute neutrophil count [ANC] counts): >= 7 days after the last dose of agent
- 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
- Corticosteroids: >= 14 days must have elapsed since last dose of corticosteroid
- 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
- Interleukins, interferons and cytokines (other than hematopoietic growth factors): >= 21 days after the completion of interleukins, interferon or cytokines (other than hematopoietic growth factors)
- Stem cell Infusions: Autologous stem cell infusion, including boost infusion: >= 42 days
- Cellular therapy: >= 42 days after the completion of any type of cellular therapy (e.g., modified T cells, NK cells, dendritic cells, etc.)
- 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)
- Peripheral absolute neutrophil count (ANC) >= 750/mm^3
- Platelet count >= 75,000/mm^3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment)
- Hemoglobin >= 8 g/dL (with or without transfusion)
- 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)
- Total bilirubin =< 1.5 x upper limit of normal (ULN) for age
- 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
- Serum albumin >= 2.8 g/dL
- Current cardiac ejection fraction >= 50% by biplane Simpson method on echocardiogram
- Corrected QT (QTc) =< 480 ms
- 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
- Patients who underwent major surgery within 14 days prior to start of treatment are not eligible. NOTE: Core biopsy or central line placement are considered minor and are allowed within any time limitations
- Patients with uncontrolled coagulopathy or bleeding disorder, or any active bleeding (i.e. gastrointestinal or pulmonary) deemed to be clinically significant by investigator are not eligible
- Patients with history of pulmonary embolism or significant thromboembolic event with the preceding 28 days. Patients with thromboembolic events > 28 days before enrollment who are stable on or completed an anticoagulation course are eligible
- Patients with history of cardiac irradiation with mean cardiac dose > 15 Gy are not eligible
- Patients with symptomatic cardiac disease (i.e. New York Heart Association or Modified Ross Heart Failure Classification for Children >= class 2) are not eligible
- Patients with any history of cardiac dysfunction including prior abnormal echocardiogram (ejection fraction < 50%), severe or unstable angina, peripheral vascular disease, congenital prolonged QTc syndrome, clinically significant cardiac arrhythmias, stroke, or myocardial infarction are not eligible
- Pregnant or breast-feeding women will not be entered on this study because there is not yet available information regarding human fetal or teratogenic toxicities. Pregnancy tests must be obtained in females who are post-menarchal
- Males or females of reproductive potential may not participate unless they have agreed to practice 1 highly effective and 1 additional effective (barrier) method of contraception at the same time during the entire study treatment period and through 3 months after the last dose of study drug, or agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. Patients who themselves or their partners have undergone female or male sterilization do not require 2 methods of contraception. Highly effective methods are defined as those with < 1% failure rate with perfect use and include: oral contraceptive pills (combined or progesterone only), intrauterine devices (IUD), hormonal implant or injection, contraceptive patch, and vaginal ring
- Patients requiring more than one antihypertensive medication to control blood pressure, or have baseline blood pressure above the upper limit of normal (> 140/90 for patients >= 18 years old and > 95th percentile for age/gender for patients < 18 years old) are not eligible
- Patients receiving systemic corticosteroids are not eligible. >= 14 days must have elapsed since last systemic corticosteroid. Note: patients using topical or inhaled corticosteroids are eligible
- Patients currently receiving another investigational drug are not eligible
- Patients currently receiving other anti-cancer agents are not eligible
- Patients who require treatment with medications that are strong inhibitors or inducers of CYP3A4 or inhibitors of CYP2A9 or have received these medications in the 7 days prior to enrollment, are not eligible. Patients who require treatment with enzyme inducing anticonvulsants are not eligible
- Patients who require treatment with medications known to prolong QTc are not eligible
Locations & Contacts
Contact: Carrye Rudolph Cost
Trial Objectives and Outline
I. Evaluate the safety, tolerability, and define the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of losartan in combination with sunitinib in pediatric and adult patients with relapsed or refractory osteosarcoma.
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.
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) once daily (QD) on days 1-42 and sunitinib PO QD on days 1-28. Treatment repeats every 42 days for up to 17 cycles in the absence of disease progression or unacceptable toxicity.
After completion of treatment, patients are followed up at 30 days, and then periodically for up to 5 years.
Trial Phase & Type
University of Colorado
Carrye Rudolph Cost
Secondary IDs NCI-2019-06119, 18-2740.cc
Clinicaltrials.gov ID NCT03900793