Sunitinib in Treating Young Patients With Refractory Solid Tumors

Sponsor

National Cancer Institute (NCI) (NIH)

Overall Status

Completed

CT.gov ID

NCT00387920

Collaborator

(none)

Enrollment

Locations

Arm

2.1

Patients Per Site

Study Details

Study Description

Brief Summary

This phase I trial is studying the side effects and best dose of sunitinib in treating young patients with refractory solid tumors. Sunitinib may stop the growth of tumor cells by blocking some of the enzymes needed for their growth and by blocking blood flow to the tumor.

Condition or Disease	Intervention/Treatment	Phase
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	Drug: sunitinib malate Other: pharmacological study Procedure: dynamic contrast-enhanced magnetic resonance imaging Other: laboratory biomarker analysis	Phase 1

Detailed Description

PRIMARY OBJECTIVES:

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

Determine, preliminarily, the antitumor effects of this regimen in these patients.
Describe changes in peripheral blood monocyte counts, circulating endothelial cells, and plasma angiogenic factors during treatment with sunitinib malate.
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.

Study Design

Study Type:

Interventional

Actual Enrollment :

35 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

Oct 1, 2006

Actual Primary Completion Date :

Sep 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (enzyme inhibitor therapy) 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. 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.	Drug: sunitinib malate Given orally Other Names: SU11248 sunitinib Sutent Other: pharmacological study Correlative studies Other Names: pharmacological studies Procedure: dynamic contrast-enhanced magnetic resonance imaging Undergo DCE-MRI Other Names: DCE-MRI Other: laboratory biomarker analysis Correlative studies

Arm

Intervention/Treatment

Experimental: Treatment (enzyme inhibitor therapy)

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. 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.

Drug: sunitinib malate

Given orally

Other Names:

SU11248

sunitinib

Sutent

Other: pharmacological study

Correlative studies

Other Names:

pharmacological studies

Procedure: dynamic contrast-enhanced magnetic resonance imaging

Undergo DCE-MRI

Other Names:

DCE-MRI

Other: laboratory biomarker analysis

Correlative studies

Outcome Measures

Primary Outcome Measures

MTD and recommended phase II dose [During course 1 of therapy]
MTD will be the maximum dose at which fewer than one-third of patients experience dose-limiting toxicity (DLT).
Adverse events as assessed by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 [Weekly during course 1, assessed up to 35 days]
Pharmacokinetics of sunitinib malate using liquid spectrometry/mass spectroscopy methods [At baseline and days 1, 7, 14, 21, and 28 of course 1]
Tolerability and pharmacokinetic profile of capsule contents sprinkled over applesauce or yogurt [At baseline and days 1, 7, 14, 21, and 28 of course 1]

Secondary Outcome Measures

Correlative studies [Days 1 and 28 of course 1]
The laboratory, radiology, and pathology correlative studies are largely expected to be exploratory. Mean and median values will be reported at each time point for circulating endothelial cells, monocyte count, plasma angiogenic markers, and DCE-MRI vascular permeability. Depending on the distribution of data, either the paired t-test or Wilcoxon signed rank test will be used to evaluate for statistically significant changes in these markers from pre-treatment to post-treatment.

Eligibility Criteria

Criteria

Ages Eligible for Study:

2 Years to 21 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham	Birmingham	Alabama	United States	35294
2	Childrens Hospital of Orange County	Orange	California	United States	92868-3874
3	UCSF-Mount Zion	San Francisco	California	United States	94115
4	University of California San Francisco Medical Center-Parnassus	San Francisco	California	United States	94143
5	Children's National Medical Center	Washington	District of Columbia	United States	20010
6	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02115
7	C S Mott Children's Hospital	Ann Arbor	Michigan	United States	48109
8	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
9	Columbia University Medical Center	New York	New York	United States	10032
10	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio	United States	45229
11	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19104
12	Children's Hospital of Pittsburgh of UPMC	Pittsburgh	Pennsylvania	United States	15224
13	University of Texas Southwestern Medical Center	Dallas	Texas	United States	75390
14	Baylor College of Medicine	Houston	Texas	United States	77030
15	Seattle Children's Hospital	Seattle	Washington	United States	98105
16	Hospital for Sick Children	Toronto	Ontario	Canada	M5G 1X8
17	Centre Hospitalier Universitaire Sainte-Justine	Montreal	Quebec	Canada	H3T 1C5