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A Phase I Study of Pazopanib as a Single Agent for Children With Relapsed or Refractory Solid Tumors


Phase 1
2 Years
25 Years
Open (Enrolling)
Both
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, Metastatic Childhood Soft Tissue Sarcoma, Recurrent Childhood Brain Stem Glioma, Recurrent Childhood Central Nervous System Embryonal Tumor, Recurrent Childhood Soft Tissue Sarcoma, Recurrent Childhood Visual Pathway Glioma, Unspecified Childhood Solid Tumor, Protocol Specific

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Trial Information

A Phase I Study of Pazopanib as a Single Agent for Children With Relapsed or Refractory Solid Tumors


PRIMARY OBJECTIVES:

I. Estimate the maximum-tolerated dose and/or recommended phase II dose of pazopanib
hydrochloride in pediatric patients with relapsed or refractory solid tumors.

II. Define and describe the toxicities of this regimen in these patients. III. Characterize
the pharmacokinetics of pazopanib hydrochloride in these patients.

SECONDARY OBJECTIVES:

I. Preliminarily define the antitumor activity of pazopanib hydrochloride within the
confines of a phase I study.

II. Evaluate changes in tumor vascular permeability following initiation of pazopanib
hydrochloride and correlate these changes with clinical outcome by dynamic contrast-enhanced
MRI.

OUTLINE: This is a multicenter study dose-escalation study.

Patients receive oral pazopanib hydrochloride once daily on days 1-28. Courses repeat every
28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity.
Patients accrued after the maximum-tolerated dose (MTD) of pazopanib hydrochloride has been
determined receive pazopanib hydrochloride as an oral suspension.

Some patients undergo dynamic contrast-enhanced MRI at baseline and periodically during
study. Blood samples are collected at baseline and periodically during study for
pharmacokinetic studies.


Inclusion Criteria:



- Diagnosis of 1 of the following:

NOTE: Histologic confirmation not required for intrinsic brain stem cell tumor, optic
pathway gliomas, pineal tumors and elevations of cerebrospinal fluid, and serum tumor
markers including alpha-fetoprotein or beta-human chorionic gonadotropin.

- Histologically confirmed relapsed or refractory solid tumors at original diagnosis
including CNS tumors* (Part 1 and Part 2a)

- Neurologic deficits in patients with CNS tumors must have been relatively stable
for ≥ 1 week

- Histologically confirmed soft tissue sarcoma, desmoplastic small round cell tumor, or
extraosseus Ewing sarcoma at original diagnosis including the following (Part 2b):

- Tumor in the head, neck, or extremity or fixed within the abdomen or pelvis that
it is not sensitive to motion artifact

- No isolated pulmonary metastases

- Disease with no known curative therapy or no therapy proven to prolong
survival with acceptable quality of life

- Measurable or evaluable disease (Part 1 and Part 2a)

- Measurable tumor that is ≥ 2 cm in its longest diameter (Part 2b)

- Patients must be:

- > 2 years of age and ≤ 21 years of age (Part 1 and Part 2a)

- > 2 years of age and ≤ 25 years of age (Part 2b)

- Body surface area ≥ 0.48 m^2 (Part 1 and Part 2b)

- For patients with CNS tumors or CNS metastasis, there must be no evidence of new
CNS hemorrhage of more than punctate size and/or > 3 foci of punctate hemorrhage
on baseline MRI for primary CNS tumors ≥ 14 days prior to study entry

- Karnofsky performance status (PS) 50-100% (> 16 years of age)

- Lansky PS 50-100% (≤ 16 years of age)

- Platelet count ≥ 100,000/mm^3 (transfusion independent)

- ANC ≥ 1,000/mm^3

- Hemoglobin ≥ 8.0 g/dL (may receive RBC transfusions)

- Creatinine clearance or radioisotope GFR ≥ 70 mL/min OR serum creatinine based
on age/gender as follows:

- 0.6 mg/dL (1 to < 2 years of age)

- 0.8 mg/dL (2 to < 6 years of age)

- 1 mg/dL (6 to < 10 years of age)

- 1.2 mg/dL (10 to < 13 years of age)

- 1.5 mg/dL (male ) or 1.4 mg/dL (female) (13 to < 16 years of age)

- 1.7 mg/dL (male) or 1.4 mg/dL (female) ( ≥ 16 years of age)

- Urine protein:creatinine ratio < 1 OR urinalysis negative for protein OR 24-hour
urine protein level < 1 g

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

- ALT ≤ 110 U/L

- PT and PTT ≤ 1.2 times ULN

- INR ≤ 1.2

- Serum albumin ≥ 2 g/dL

- No grade > 1 abnormalities of potassium, calcium, magnesium, or phosphorous

- Supplementation allowed

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- Oral contraceptives are not considered effective

- Adequate cardiac function defined as any of the following:

- Shortening fraction of ≥ 27% by echocardiogram

- Ejection fraction of ≥ 50% by gated radionuclide study

- QTc < 450 msec

- No history of myocardial infarction, severe or unstable angina, or peripheral
vascular disease or familial QTc prolongation

- Adequate blood pressure defined as ≤ 95th percentile for age, height, and gender

- Known history of well-controlled seizures allowed

- Able to swallow whole tablets (Part 1 and Part 2b)

- No uncontrolled infection

- No evidence of active bleeding, intratumoral hemorrhage, or bleeding diathesis

- None of the following conditions within the past 6 months:

- Arterial thromboembolic events, including transient ischemic attack or
cerebrovascular accident

- Pulmonary embolism

- Deep vein thrombosis

- Other venous thromboembolic event

- No hemoptysis within the past 6 weeks

- No serious or non-healing wound, ulcer, or bone fracture

- No significant traumatic injury within the past 28 days

- No abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess
within the past 28 days

- No patients who, in the opinion of the investigator, may not be able to comply
with the safety monitoring requirements of the study

- No fine-needle aspiration within 48 hours before day 1 of therapy

- Fully recovered from all prior therapy (e.g., chemotherapy, immunotherapy, or
radiotherapy)

- At least 3 weeks since prior myelosuppressive chemotherapy (6 weeks for prior
nitrosourea)

- At least 7 days since prior hematopoietic growth factor

- At least 21 days since prior VEGF-Trap

- No prior pazopanib hydrochloride

- At least 7 days since prior VEGF-blocking tyrosine kinase inhibitor or other
biological agents

- At least 3 half-lives since prior monoclonal antibody, including bevacizumab

- At least 21 days since any other prior anticancer antibody therapy

- At least 2 weeks since prior local palliative radiotherapy (small port)

- At least 3 months since prior total-body irradiation, craniospinal radiotherapy,
or ≥ 50% radiotherapy to the pelvis

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

- At least 2 months since stem cell transplantation and no evidence of
graft-vs-host disease

- Thyroid replacement therapy allowed provided a stable dose has been received for
≥ 4 weeks

- No concurrent medication for cardiac function or hypertension

- Concurrent corticosteroids allowed provided dose is stable or decreasing for > 7
days (for patients enrolled in Part 1 and Part 2a of study)

- No concurrent corticosteroids for patients enrolled in Part 2b of the study

- No other concurrent anticancer agents or radiotherapy

- No other concurrent investigational drugs

- No concurrent enzyme-inducing anticonvulsants

- No concurrent anticoagulation therapy with coumadin and/or low molecular weight
heparin

- Prophylactic anticoagulation therapy (i.e., intraluminal heparin) of venous or
arterial access devices allowed

- No concurrent aspirin, ibuprofen, or other NSAIDs

- No concurrent drugs metabolized through several of the specific P450 cytochrome
isoform including inducers or inhibitors of CYP3A4

- No concurrent drugs with a known risk of torsades de pointes

- At least 28 days since prior major surgical procedure, laparoscopic procedure,
or open biopsy

- Port placement or central line placement 48 hours before day 1 of therapy allowed

- No core biopsy within the past 7 days

Type of Study:

Interventional

Study Design:

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

Outcome Measure:

Maximum-tolerated dose of pazopanib hydrochloride defined as the maximum dose at which fewer that one-third of patients experience DLT

Outcome Description:

Graded using the NCI CTCAE version 4.0.

Outcome Time Frame:

28 days

Safety Issue:

Yes

Principal Investigator

Julia Glade-Bender

Investigator Role:

Principal Investigator

Investigator Affiliation:

COG Phase I Consortium

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2011-01929

NCT ID:

NCT00929903

Start Date:

June 2009

Completion Date:

Related Keywords:

  • 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
  • Metastatic Childhood Soft Tissue Sarcoma
  • Recurrent Childhood Brain Stem Glioma
  • Recurrent Childhood Central Nervous System Embryonal Tumor
  • Recurrent Childhood Soft Tissue Sarcoma
  • Recurrent Childhood Visual Pathway Glioma
  • Unspecified Childhood Solid Tumor, Protocol Specific
  • Choriocarcinoma
  • Endodermal Sinus Tumor
  • Glioma
  • Carcinoma, Embryonal
  • Neoplasms, Germ Cell and Embryonal
  • Teratoma
  • Germinoma
  • Sarcoma
  • Optic Nerve Glioma
  • Neoplasms

Name

Location

Baylor College of MedicineHouston, Texas  77030
Children's Hospital of PhiladelphiaPhiladelphia, Pennsylvania  19104
Dana-Farber Cancer InstituteBoston, Massachusetts  02115
St. Jude Children's Research HospitalMemphis, Tennessee  38105-2794
Cincinnati Children's Hospital Medical CenterCincinnati, Ohio  45229-3039
Children's Hospital of Pittsburgh of UPMCPittsburgh, Pennsylvania  15213
University of Alabama at BirminghamBirmingham, Alabama  35294-3300
Indiana University Medical CenterIndianapolis, Indiana  46202
University of Texas Southwestern Medical CenterDallas, Texas  
Oregon Health and Science UniversityPortland, Oregon  97201
Seattle Children's HospitalSeattle, Washington  98105
Childrens Memorial HospitalChicago, Illinois  60614
Columbia University Medical CenterNew York, New York  10032
C S Mott Children's HospitalAnn Arbor, Michigan  48109