Tandutinib in Treating Patients With Recurrent or Progressive Glioblastoma

OBJECTIVES:

Primary

- Assess the ability of tandutinib to achieve a target tumor/plasma ratio ≥ 0.33 in
patients with recurrent glioblastoma undergoing resection. (Feasibility study)

- Detect potential biological effects of tandutinib by measuring platelet-derived growth
factor receptor phosphorylation status and downstream activation of Akt and Erk.
(Feasibility study)

- Determine the maximum tolerated dose of tandutinib in patients with recurrent or
progressive glioblastoma. (Phase I)

- Estimate the frequency of toxicities associated with tandutinib in patients with
recurrent or progressive glioblastoma. (Phase I)

- Describe the pharmacokinetics of this route of administration in patients with
recurrent or progressive glioblastoma. (Phase I)

- Assess tumor response rate in patients with recurrent or progressive glioblastoma.
(Phase II)

Secondary

- Estimate overall survival of patients with recurrent or progressive glioblastoma.
(Phase II)

- Estimate the 6-month progression-free survival rate in these patients. (Phase II)

- Assess the toxicities associated with tandutinib in these patients. (Phase II)

- Assess the pharmacokinetic profile of this route of administration in these patients.
(Phase II)

- Explore protein-expression patterns that distinguish patients who respond to therapy
from those who do not. (Phase II)

OUTLINE: This is a multicenter, prospective, nonrandomized, feasibility study and phase I
study (in parallel) followed by an open label phase II study.

- Feasibility study: Patients receive oral tandutinib twice daily for 7 days. Patients
then undergo biopsy or surgery to remove the tumor. Within 2 weeks after biopsy or
surgery, patients receive oral tandutinib twice daily* on days 1-28. Courses repeat
every 28 days in the absence of disease progression or unacceptable toxicity.

- Phase I: Patients receive oral tandutinib twice daily* on days 1-28. Courses repeat
every 28 days in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of tandutinib until the maximum tolerated
dose (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. At least 6 patients are treated at the MTD.

NOTE: *On day 1 of course 1, patients receive only 1 dose of tandutinib.

- Phase II: Patients receive tandutinib as in phase I at the MTD determined in phase I.

Patients undergo blood sample collection for pharmacokinetic studies. Patients in the
feasibility portion of the study also undergo blood and tissue sample collection for
correlative studies by mass spectrometry for tandutinib concentration. Samples are also
examined for circulating endothelial cells and plasma proteins (vascular endothelial growth
factor [VEGF]-A, -B, -C, and -D, soluble VEGF receptors [sVEGFR's], placental growth factor
[P1GF], platelet-derived growth factor [PDGF]-AA, PDGF-AB, PDGF-BB, angiopoietin-1 and -2,
tumstatin, thrombospondin-1, and IL-8) as potential markers of the antiangiogenic effect of
tandutinib.

After completion of study treatment, patients are followed every 2 months.

PROJECTED ACCRUAL: Approximately 85 patients will be accrued for this study.