Sunitinib in Treating Young Patients With Refractory Solid Tumors

Unspecified Childhood Solid Tumor, Protocol Specific Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00387920
• Other study ID #: NCI-2009-00361
• Secondary ID: NCI-2009-00361CD
• Status: Completed
• Phase: Phase 1
• First received: October 12, 2006
• Last updated: January 27, 2014
• Start date: October 2006

Study information

• Verified date: January 2014
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 35
• Est. primary completion date: September 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 2 Years to 21 Years

Eligibility

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

Study Design

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

Related Conditions & MeSH terms

• 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
• Choriocarcinoma
• Neoplasms
• Neoplasms, Germ Cell and Embryonal
• Recurrent Childhood Central Nervous System Embryonal Tumor
• Unspecified Childhood Solid Tumor, Protocol Specific

Intervention

Drug:
• sunitinib malate
Given orally

Other:
• pharmacological study
Correlative studies

Procedure:
• dynamic contrast-enhanced magnetic resonance imaging
Undergo DCE-MRI

Other:
• laboratory biomarker analysis
Correlative studies

Locations

Country	Name	City	State
Canada	Centre Hospitalier Universitaire Sainte-Justine	Montreal	Quebec
Canada	Hospital for Sick Children	Toronto	Ontario
United States	C S Mott Children's Hospital	Ann Arbor	Michigan
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio
United States	University of Texas Southwestern Medical Center	Dallas	Texas
United States	Baylor College of Medicine	Houston	Texas
United States	Columbia University Medical Center	New York	New York
United States	Childrens Hospital of Orange County	Orange	California
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Children's Hospital of Pittsburgh of UPMC	Pittsburgh	Pennsylvania
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	UCSF-Mount Zion	San Francisco	California
United States	University of California San Francisco Medical Center-Parnassus	San Francisco	California
United States	Seattle Children's Hospital	Seattle	Washington
United States	Children's National Medical Center	Washington	District of Columbia

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Countries where clinical trial is conducted

United States,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	MTD and recommended phase II dose	MTD will be the maximum dose at which fewer than one-third of patients experience dose-limiting toxicity (DLT).	During course 1 of therapy	Yes
Primary	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	Yes
Primary	Pharmacokinetics of sunitinib malate using liquid spectrometry/mass spectroscopy methods		At baseline and days 1, 7, 14, 21, and 28 of course 1	No
Primary	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	No
Secondary	Correlative studies	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.	Days 1 and 28 of course 1	No