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A Phase I Study of Sunitinib (SU11248), an Oral Multi-Targeted Tyrosine Kinase Inhibitor, in Children With Refractory Solid Tumors


Phase 1
2 Years
21 Years
Not Enrolling
Both
Central Nervous System Metastases, Childhood Central Nervous System Choriocarcinoma, Childhood Central Nervous System Embryonal Tumor, Childhood Central Nervous System Germ Cell Tumor, Childhood Central Nervous System Germinoma, Childhood Central Nervous System Mixed Germ Cell Tumor, Childhood Central Nervous System Teratoma, Childhood Central Nervous System Yolk Sac Tumor, Recurrent Childhood Central Nervous System Embryonal Tumor, Unspecified Childhood Solid Tumor, Protocol Specific

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Trial Information

A Phase I Study of Sunitinib (SU11248), an Oral Multi-Targeted Tyrosine Kinase Inhibitor, in Children With Refractory Solid Tumors


PRIMARY OBJECTIVES:

I. Determine the maximum tolerated dose (MTD) and recommended phase II dose of sunitinib
malate in pediatric patients with refractory solid tumors.

II. Determine the toxicity of this regimen in these patients. III. Characterize the
pharmacokinetics of this regimen in these patients. IV. Evaluate the tolerability and
pharmacokinetic profile of sunitinib malate capsule contents sprinkled over applesauce or
yogurt using the recommended phase II dose.

SECONDARY OBJECTIVES:

I. Determine, preliminarily, the antitumor effects of this regimen in these patients.

II. Describe changes in peripheral blood monocyte counts, circulating endothelial cells, and
plasma angiogenic factors during treatment with sunitinib malate.

III. Explore changes in tumor vascular permeability using dynamic contrast-enhanced
(DCE)-magnetic resonance imaging (MRI) in patients receiving sunitinib malate.

OUTLINE: This is a multicenter, dose-escalation study (part A) followed by a
pediatric-friendly formulation study (part B).

PART A: Patients receive oral sunitinib malate once daily on days 1-28 days. Treatment
repeats every 42 days for up to 18 courses in the absence of disease progression or
unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of sunitinib malate until the MTD is
determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients
experience dose-limiting toxicity.

PART B: Patients receive sunitinib malate capsule contents sprinkled over applesauce or
yogurt once daily on days 1-28. Treatment repeats every 42 days for up to 18 courses in the
absence of disease progression or unacceptable toxicity. After the first course, patients
may switch to capsule formulation for convenience.

NOTE: Patients will not receive sunitinib malate on day 2 of the first course to allow for
pharmacokinetic testing.

Blood is collected on days 1, 7, 14, 21, and 28 of course 1 for pharmacokinetic studies
using liquid chromatography/mass spectrometry.

After completion of study treatment, patients are followed up for 30 days.


Inclusion Criteria:



- Histologically confirmed solid tumor (not required for patients with intrinsic brain
stem tumors or optic pathway gliomas)

- Recurrent or refractory disease

- Measurable or evaluable disease

- No known curative therapy or therapy proven to prolong survival with an acceptable
quality of life exists

- Patients with metastatic bone marrow disease are eligible but are not evaluable for
hematologic toxicity

- Must not be refractory to red blood cell or platelet transfusions

- Primary CNS tumors or known CNS metastases allowed

- Neurological deficits must have been relatively stable for ≥ 1 week before study
enrollment

- No imaging evidence of prior intracranial hemorrhage

- No evidence of new CNS hemorrhage on baseline MRI obtained within 14 days before
study enrollment (ECHO gradient MRI sequences per institutional guidelines
required for evaluation of CNS hemorrhage)

- The presence of small punctuate CNS hemorrhage on these scans will exclude
a patient from participation

- No known bone marrow metastatic disease

- No tumors involving the pleural surface

- Karnofsky performance status (PS) 50-100% (> 10 years of age) OR Lansky PS 50-100% (≤
10 years of age)

- Absolute neutrophil count ≥ 1,000/mm³*

- Platelet count ≥ 100,000/mm³ (transfusion independent)*

- Hemoglobin ≥ 8.0 g/dL (transfusions allowed)*

- Creatinine clearance or radioisotope glomerular filtration rate ≥ 70 mL/min OR
creatinine based on age/gender as follows:

- No greater than 0.8 mg/dL (2 to 5 years of age)

- No greater than 1 mg/dL (6 to 9 years of age)

- No greater than 1.2 mg/dL (10 to 12 years of age)

- No greater than 1.5 mg/dL (male) OR 1.4 mg/dL (female) (13 to 15 years of age)

- No greater than 1.7 mg/dL (male) OR 1.4 mg/dL (female) (≥ 16 years of age)

- Bilirubin ≤ 1.5 times upper limit of normal (ULN)

- ALT and AST ≤ 2.5 times ULN (≤ 5 times ULN for liver metastases)

- Albumin ≥ 2 g/dL

- LVEF or shortening fraction normal

- Corrected QT interval ≤ 450 msec

- Amylase ≤ 1.5 times ULN

- Lipase ≤ 1.5 times ULN

- Body surface area ≥ 0.5 m² (≥ 0.4 m² for part B)

- Blood pressure within ULN

- Not pregnant or nursing

- Fertile patients must use effective contraception

- No uncontrolled infection

- Able to swallow sunitinib malate capsules (part A only)

- No pre-existing thyroid abnormality (hyper- or hypothyroidism) with unstable thyroid
function

- No prior CNS hemorrhage

- No history of allergic reaction attributed to sunitinib malate or component of
sunitinib malate capsules

- No allergy to both applesauce and yogurt (part B only)

- Recovered from prior therapy

- No prior sunitinib malate

- No prior anthracycline (any dose)

- No prior radiotherapy to a radiation field that included the heart(including total
body or craniospinal irradiation)

- At least 3 months since prior stem cell transplantation or rescue (without total-body
irradiation) and no evidence of graft-vs-host disease

- At least 2 weeks since prior local, palliative, small-port radiotherapy (at least 6
months for radiation to ≥ 50% of pelvis)

- At least 6 weeks since other prior substantial bone marrow radiotherapy

- At least 3 weeks since prior myelosuppressive therapy (6 weeks for nitrosoureas)

- At least 1 week since prior antineoplastic biologic agents

- At least 1 week since prior and no concurrent hematopoietic growth factors

- At least 12 days since prior and no concurrent CYP3A4 inducers, including any of the
following:

- Rifampin

- Rifabutin

- Carbamazepine

- Phenobarbital

- Phenytoin

- Hypericum perforatum (St. John's wort)

- Efavirenz

- Tipranavir

- At least 7 days since prior and no concurrent CYP3A4 inhibitors, including any of the
following:

- Azole antifungals (e.g., itraconazole or ketoconazole)

- Clarithromycin

- Erythromycin

- Diltiazem

- Verapamil

- HIV protease inhibitors (e.g., indinavir, saquinavir, ritonavir, atazanavir, or
nelfinavir)

- Delavirdine

- No more than 1 concurrent antihypertensive agent

- No concurrent major surgery

- No concurrent antithrombotic or antiplatelet agents, including any of the following:

- Warfarin

- Heparin

- Low molecular weight heparin

- Acetylsalicylic acid (aspirin)

- Ibuprofen

- Other nonsteroidal anti-inflammatory drugs

- No concurrent medication for the treatment of hypertension

- No other concurrent investigational drugs

- No other concurrent anticancer agents, including chemotherapy, radiotherapy,
immunotherapy, or biologic therapy

Type of Study:

Interventional

Study Design:

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

MTD and recommended phase II dose

Outcome Description:

MTD will be the maximum dose at which fewer than one-third of patients experience dose-limiting toxicity (DLT).

Outcome Time Frame:

During course 1 of therapy

Safety Issue:

Yes

Principal Investigator

Steven DuBois

Investigator Role:

Principal Investigator

Investigator Affiliation:

Children's Oncology Group

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2009-00361

NCT ID:

NCT00387920

Start Date:

October 2006

Completion Date:

Related Keywords:

  • Central Nervous System Metastases
  • Childhood Central Nervous System Choriocarcinoma
  • Childhood Central Nervous System Embryonal Tumor
  • Childhood Central Nervous System Germ Cell Tumor
  • Childhood Central Nervous System Germinoma
  • Childhood Central Nervous System Mixed Germ Cell Tumor
  • Childhood Central Nervous System Teratoma
  • Childhood Central Nervous System Yolk Sac Tumor
  • Recurrent Childhood Central Nervous System Embryonal Tumor
  • Unspecified Childhood Solid Tumor, Protocol Specific
  • Choriocarcinoma
  • Endodermal Sinus Tumor
  • Neoplasm Metastasis
  • Carcinoma, Embryonal
  • Neoplasms, Germ Cell and Embryonal
  • Teratoma
  • Germinoma
  • Neoplasms

Name

Location

Baylor College of Medicine Houston, Texas  77030
Dana-Farber Cancer Institute Boston, Massachusetts  02115
University of Alabama at Birmingham Birmingham, Alabama  35294-3300
University of Texas Southwestern Medical Center Dallas, Texas  
Seattle Children's Hospital Seattle, Washington  98105
University of California San Francisco Medical Center-Mount Zion San Francisco, California  94115
Columbia University Medical Center New York, New York  10032
University of California San Francisco Medical Center San Francisco, California  94143
C S Mott Children's Hospital Ann Arbor, Michigan  48109