Clinical trial NCT00387920: Sunitinib in Treating Young Patients With Refractory Solid Tumors
Official title: A Phase I Study of Sunitinib (SU11248), an Oral Multi-Targeted Tyrosine Kinase Inhibitor, in Children With Refractory Solid Tumors
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: 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
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2006-10-13
Enrollment: 35
Sex: ALL
Minimum age (years): 2
Maximum age (years): 21
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: MTD and recommended phase II dose
timeFrame: During course 1 of therapy
measure: Adverse events as assessed by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0
timeFrame: Weekly during course 1, assessed up to 35 days
measure: Pharmacokinetics of sunitinib malate using liquid spectrometry/mass spectroscopy methods
timeFrame: At baseline and days 1, 7, 14, 21, and 28 of course 1
measure: Tolerability and pharmacokinetic profile of capsule contents sprinkled over applesauce or yogurt
timeFrame: At baseline and days 1, 7, 14, 21, and 28 of course 1
Secondary outcomes:
measure: Correlative studies
timeFrame: Days 1 and 28 of course 1
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Orange
country: United States
facility: Childrens Hospital of Orange County
state: California
city: San Francisco
country: United States
facility: UCSF-Mount Zion
state: California
city: San Francisco
country: United States
facility: University of California San Francisco Medical Center-Parnassus
state: California
city: Washington
country: United States
facility: Children's National Medical Center
state: District of Columbia
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Ann Arbor
country: United States
facility: C S Mott Children's Hospital
state: Michigan
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Children's Hospital of Pittsburgh of UPMC
state: Pennsylvania
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: Seattle
country: United States
facility: Seattle Children's Hospital
state: Washington
city: Toronto
country: Canada
facility: Hospital for Sick Children
state: Ontario
city: Montreal
country: Canada
facility: Centre Hospitalier Universitaire Sainte-Justine
state: Quebec
Study officials:
affiliation: COG Phase I Consortium
name: Steven DuBois
role: PRINCIPAL_INVESTIGATOR
References:
citation: Wang E, DuBois SG, Wetmore C, Verschuur AC, Khosravan R. Population Pharmacokinetics of Sunitinib and its Active Metabolite SU012662 in Pediatric Patients with Gastrointestinal Stromal Tumors or Other Solid Tumors. Eur J Drug Metab Pharmacokinet. 2021 May;46(3):343-352. doi: 10.1007/s13318-021-00671-7. Epub 2021 Apr 14.
citation: Wang E, DuBois SG, Wetmore C, Khosravan R. Population pharmacokinetics-pharmacodynamics of sunitinib in pediatric patients with solid tumors. Cancer Chemother Pharmacol. 2020 Aug;86(2):181-192. doi: 10.1007/s00280-020-04106-z. Epub 2020 Jul 4.