Pazopanib Hydrochloride in Treating Young Patients With Solid Tumors That Have Relapsed or Not Responded to Treatment

Official Title: “A Phase I Study of Pazopanib as a Single Agent for Children With Relapsed or Refractory Solid Tumors”

RATIONALE: Pazopanib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor.

PURPOSE: This phase I trial is studying the side effects and best dose of pazopanib hydrochloride in treating young patients with solid tumors that have relapsed or not responded to treatment.

OBJECTIVES:

Primary - Estimate the maximum-tolerated dose and/or recommended phase II dose of pazopanib hydrochloride in pediatric patients with relapsed or refractory solid tumors. - Define and describe the toxicities of this regimen in these patients. - Characterize the pharmacokinetics of pazopanib hydrochloride in these patients.

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

Intervention(s) in this Clinical Trial

• Drug: pazopanib hydrochloride
• Other: pharmacological study

Primary Measures

• Maximum-tolerated dose and/or recommended phase II dose of pazopanib hydrochloride
  • Safety Issue?: No
• Adverse events according to NCI CTCAE v. 3.0
  • Safety Issue?: Yes
• Pharmacokinetics
  • Safety Issue?: No

Secondary Measures

• Overall response to pazopanib hydrochloride according to RECIST criteria
  • Safety Issue?: No

DISEASE CHARACTERISTICS:

• Diagnosis of 1 of the following:
• 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
• Slides or tissue blocks from either initial diagnosis or relapse must be available for central review
• 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.
• 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

PATIENT CHARACTERISTICS:

• 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

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• 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
• No fine-needle aspiration within 48 hours before day 1 of therapy

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 2 Years

Maximum Age for this Clinical Trial: 25 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Investigator: Children's Oncology Group Other

Overall Clinical Trial Officials and Contacts

Julia L. Glade-Bender, MD Study Chair Herbert Irving Comprehensive Cancer Center  

Information obtained from ClinicalTrials.gov on February 12, 2012

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00929903

Study ID Number: CDR0000646720

ClinicalTrials.gov Identifier: NCT00929903

Health Authority: Unspecified

Clinical trial summary from the National Cancer Institute's PDQ® database