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

Condition(s) targeted: Sarcoma; Neuroblastoma; Wilms Tumor; Osteosarcoma; Brain Tumor

Intervention: Pazopanib (GW786034) (Drug)

Phase: Phase 1

Status: Recruiting

Sponsored by: National Cancer Institute (NCI)

Overall contact:
NCI Referral Office, Phone: 1-888-NCI-1937, Email: ncicssc@mail.nih.gov

Background:

- Pazopanib, a drug that inhibits the growth of new blood vessels in tumors, was recently

approved by the Food and Drug Administration to treat advanced kidney cancer in adults. Pazopanib has been used in only a small number of adults, and more research is needed on whether it is safe and effective to use in children. Researchers are interested in determining safe and effective treatment doses of pazopanib in children, and in other studies will examine which form of pazopanib treatment (tablet or liquid) is most effective and well tolerated.

Objectives:

- To determine a safe and effective dose of pazopanib to treat solid tumors in children.

- To study the effects of pazopanib on blood cells, blood flow, and human development.

Eligibility:

- Children, adolescents, and young adults between 1 and 21 years of age who have been

diagnosed with solid tumors that have not responded to treatment.

Design:

- Eligible participants will be screened with a physical examination, blood and tumor

samples, and imaging studies.

- Participants will receive pazopanib tablets for 28-day cycles of treatment. Pazopanib

should be taken on an empty stomach, at least 1hour before or 2 hours after a meal. Participants may receive pazopanib for up to 24 cycles unless the tumor does not respond or participants develop serious side effects.

- Blood samples will be taken on days 1, 15, 22, and 27 of the first cycle of pazopanib,

with additional samples taken every 8 weeks during subsequent cycles.

- An optional part of the study will collect additional blood samples at regular

intervals for 24 hours after the first dose of pazopanib and at regular intervals after another dose during the second or third week of the first treatment cycle.

Official title: A Phase I Study of Pazopanib as a Single Agent for Children With Relapsed or Refractory Solid Tumors, Including CNS Tumors

Study design: Allocation: Non-Randomized, Control: Uncontrolled, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome: To estimate MTD and Phase II dose of oral pazopanib. To define the toxicities of oral pazopanib tablet or suspension. To characterize PKs.

Secondary outcome: To define antitumor and biologic activity and explore changes in tumor vascular permeability. To assess VEGF haplotype/phenotype relationships and explore concentration-effect with biomarkers and clinical outcomes.

Detailed description: Background:

- Pazopanib is a potent and selective multi-target receptor tyrosine kinase inhibitor of

vascular endothelial growth factor (VEGF) receptors (VEGFR)-1, - 2, and -3, c-kit and

platelet derived growth factor (PDGF) receptors-alpha and - beta.

- Preclinical experiments demonstrate that pazopanib causes significant and

dose-dependent inhibitory effects on cell proliferation and inhibition of VEGF-induced VEGFR-2 phosphorylation, growth inhibition of a variety of human tumor xenografts in mice, and inhibition of basic fibroblast growth factor-(bFGF) and VEGF-induced angiogenesis in murine models.

- Pazopanib has been evaluated in adult subjects with solid tumors in Phase I and II

studies, and objective anti-tumor activity has been observed in a variety of tumor types.

Objectives:

Primary Objectives:

- To estimate maximum tolerated dose (MTD) and/or recommended Phase II dose of oral

pazopanib administered on a once daily schedule to children with refractory solid tumors.

- To define the toxicities of oral pazopanib administered as either a tablet or

suspension.

- To characterize the pharmacokinetics of oral pazopanib in children with refractory

solid tumors.

Secondary Objectives:

- To preliminarily define the antitumor and biologic activity of oral pazopanib, and to

explore the changes in tumor vascular permeability following initiation of pazopanib.

- To preliminarily assess VEGF haplotype/phenotype relationships in children with cancer.

- To explore pazopanib concentration-effect relationships with biomarkers and with

clinical outcomes.

Eligibility:

- Patients > 2 years and less than or equal to 21 years of age with:

- Part 1 and 2a: Measureable or evaluable relapsed or refractory solid tumors

including CNS tumors with histologic verification except in patients with intrinsic brain stem tumors, optic pathway gliomas, or patients with pineal tumors and elevation of tumor markers.

- Part 2b: Histologically verified relapsed or refractory soft tissue sarcoma with

measurable disease (greater than or equal to 2 cm) in the head, neck, extremity or fixed within the abdomen or pelvis.

- Performance score: Karnofsky greater than or equal to 50% for patients 16 years of age;

Lansky greater than or equal to 50 for patients less than or equal to 16 years of age.

- Must have fully recovered from acute toxic effects from all prior therapy which have

been completed within the specified prior time frame. Have adequate organ function as determined by laboratory evaluation.

Design:

- This is a rolling six phase I trial design of pazopanib administered orally once daily

continuously on a 28 day cycle.

- Therapy may continue for up to 24 cycles in the absence of progressive disease or

unacceptable toxicity.

- Part 1 is the phase I dose escalation portion. Once the MTD or phase II recommended

dose is defined, up to 12 additional patients will enroll in Part 2a to obtain safety and pharmacokinetic data for the suspension formulation. In addition, up to 10 patients with recurrent/refractory soft tissue sarcoma and a measurable lesion will be enrolled in Part 2b at the MTD or recommended Phase II dose to further explore changes in tumor vascular permeability using dynamic contrast enhanced MRI.

- Participation in correlative biology studies or pharmacokinetic studies will be

optional in Part 1; pharmacokinetic studies will be required in Part 2a; and imaging and limited pharmacokinetic sampling will be required in Part 2b.

Minimum age: 1 Year. Maximum age: 21 Years. Gender(s): Both.

Criteria:

- Eligibility:

- Patients > 2 years and less than or equal to 21 years of age with:

- Part 1 and 2a: Measureable or evaluable relapsed or refractory solid tumors

including CNS tumors with histologic verification except in patients with intrinsic brain stem tumors, optic pathway gliomas, or patients with pineal tumors and elevation of tumor markers.

- Part 2b: Histologically verified relapsed or refractory soft tissue sarcoma with

measurable disease (greater than or equal to 2 cm) in the head, neck, extremity or fixed within the abdomen or pelvis.

- Performance score: Karnofsky greater than or equal to 50% for patients 16 years of

age; Lansky greater than or equal to 50 for patients less than or equal to 16 years of age.

- Must have fully recovered from acute toxic effects from all prior therapy which have

been completed within the specified prior time frame. Have adequate organ function as determined by laboratory evaluation.

NCI Referral Office, Phone: 1-888-NCI-1937, Email: ncicssc@mail.nih.gov

National Institutes of Health Clinical Center, 9000 Rockville Pike, Bethesda, Maryland 20892, United States; Recruiting

NIH Clinical Center Detailed Web Page

Related publications:

Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000 Jan 7;100(1):57-70. Review. No abstract available.

Bigler SA, Deering RE, Brawer MK. Comparison of microscopic vascularity in benign and malignant prostate tissue. Hum Pathol. 1993 Feb;24(2):220-6.

Bochner BH, Cote RJ, Weidner N, Groshen S, Chen SC, Skinner DG, Nichols PW. Angiogenesis in bladder cancer: relationship between microvessel density and tumor prognosis. J Natl Cancer Inst. 1995 Nov 1;87(21):1603-12.

Starting date: May 2010
Last updated: September 17, 2010