This study is a Phase 1/1b clinical trial that aims to determine the Maximally Tolerated Dose
of Losartan and Sunitinib Combination Therapy. Patients will first be accrued to the Dose
Escalation phase of the study, using a 3+3 design. Medication dosages will increase until a
maximally tolerated dose is found. Patients will then be accrued to the Dose Expansion phase
of the trial, where efficacy of pre-determined dose will be preliminarily assessed.
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 10-40 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.
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
those with completely resected disease are eligible.
6. Performance status:
• ECOG performance status (>18 years old) ≤ 2 or Karnofsky performance score (<18
years old) > 50.
7. 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.
- 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
- 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
- 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.)
- 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).
8. 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 as follows:
Age 2 to <6: Male=0.8, Female=0.8; Age 6 to <10: Male=1, Female=1; Age 10 to <13:
Male=1.2, Female=1.2; Age 13 to <16: Male=1.5, Female=1.4; Age >/= to 16: Male=1.7,
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. Adequate cardiac function, defined as:
- Current cardiac ejection fraction ≥ 50% by biplane Simpson method on
- QTc ≤ 480 ms
12. Patients with preexisting hyper- or hypothyroidism must be on a stable dose of
13. Ability to take and retain oral medications. NOTE: Medication can be administered via
nasogastric or gastrostomy tube.
1. 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.
2. 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.
3. 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.
4. Patients with history of cardiac irradiation with mean cardiac dose > 15 Gy are not
5. Patients with symptomatic cardiac disease (i.e. New York Heart Association or Modified
Ross Heart Failure Classification for Children > class 2) are not eligible.
6. 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.
8. Concomitant medications:
- Anti-hypertensives: Patients requiring more than one antihypertensive medication
to control blood pressure, or have baseline blood pressure > 95th percentile for
age are not eligible (see Appendix VIII).
- Corticosteroids: 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.
- Investigational Drugs: Patients currently receiving another investigational drug
are not eligible.
- Anti-cancer agents: Patients currently receiving other anti-cancer agents are not
- Drug interactions: 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 (see
- Medications that prolong QTc: Patients who require treatment with medications
known to prolong QTc are not eligible