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About
This phase I/II trial is studying the side effects and best dose of tandutinib and to see how well it works in treating patients with recurrent or progressive glioblastoma.Tandutinib 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.
Full description
PRIMARY OBJECTIVES:
I. Assess the ability of tandutinib to achieve a target tumor/plasma ratio ≥ 0.33 in patients with recurrent glioblastoma undergoing resection. (Feasibility study) II. Detect potential biological effects of tandutinib by measuring platelet-derived growth factor receptor phosphorylation status and downstream activation of Akt and Erk. (Feasibility study) III. Determine the maximum tolerated dose of tandutinib in patients with recurrent or progressive glioblastoma. (Phase I) IV. Estimate the frequency of toxicities associated with tandutinib in patients with recurrent or progressive glioblastoma. (Phase I) V. Describe the pharmacokinetics of this route of administration in patients with recurrent or progressive glioblastoma. (Phase I) VI. Assess tumor response rate in patients with recurrent or progressive glioblastoma. (Phase II)
SECONDARY OBJECTIVES:
I. Estimate overall survival of patients with recurrent or progressive glioblastoma. (Phase II) II. Estimate the 6-month progression-free survival rate in these patients. (Phase II) III. Assess the toxicities associated with tandutinib in these patients. (Phase II) IV. Assess the pharmacokinetic profile of this route of administration in these patients. (Phase II) V. 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.
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Inclusion and exclusion criteria
Criteria:
Histologically confirmed glioblastoma:
Measurable disease, defined as contrast-enhancing progressive or recurrent glioblastoma by MRI or CT imaging within the past 2 weeks
Must be maintained on a stable corticosteroid regimen from the time of baseline scan to the start of study treatment
Feasibility study only:
Karnofsky performance status 60-100%
Absolute neutrophil count >= 1,500/mm^3
Hemoglobin >= 10 mg/dL
Bilirubin =< 1.5 mg/dL
AST and ALT =< 4 times upper limit of normal
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective barrier method contraception during and for 3 months after completion of study treatment
Mini Mental State Exam score >= 15
Mean QTc =< 500 msec (with Bazett's correction) by screening electrocardiogram
LVEF >= 40%
No history of familial long QT syndrome
No myocardial infarction within the past 6 months
No severe uncontrolled ventricular arrhythmias
No uncontrolled angina
No electrocardiographic evidence of acute ischemia or active conduction system abnormalities
No ongoing vomiting or nausea >= grade 2
No gastrointestinal tract disease resulting in an inability to take oral medication or a requirement for intravenous alimentation
No active peptic ulcer disease
No other condition that would impair ability to swallow pills or absorb oral medications
No muscular dystrophy
No myasthenia gravis
No other known or suspected primary muscular or neuromuscular disease
No history of allergic reactions attributed to compounds of similar chemical or biologic composition to tandutinib (e.g., erlotinib hydrochloride, gefetinib, or doxazosin mesylate)
Patients who developed an acneiform/maculopustular rash while receiving either gefitinib or erlotinib hydrochloride are eligible unless the rash is considered an allergic reaction (angioedema/urticaria) or Stevens-Johnson syndrome
No ongoing or active infections
No psychiatric illness or social situations that would preclude study compliance
No other serious infection or medical illness
At least 3 weeks since prior chemotherapy (6 weeks for nitrosoureas)
No other uncontrolled illness
No other malignancy within the past 5 years except for basal cell or squamous cell skin cancer or carcinoma in situ of the cervix or breast
Recovered from prior therapy
At least 3 months since prior radiotherapy
No prior surgical procedures affecting absorption
No concurrent combination antiretroviral therapy for HIV-positive patients
No other concurrent investigational agents
No concurrent agent that would cause QTc prolongation
No concurrent prophylactic growth factors (e.g., filgrastim [G-CSF] or sargramostim [GM-CSF])
At least 10 days since prior and no concurrent anticonvulsant drugs that induce hepatic metabolic enzymes (e.g., primidone, oxcarbazepine, phenytoin, carbamazepine, or phenobarbital)
No prior treatment with small molecule inhibitors of platelet-derived growth factor receptor (e.g., sunitinib malate, sorafenib, or imatinib mesylate)
Platelet count >= 100,000/mm^3
No New York Heart Association class III or IV heart failure
Creatinine =< 1.5 mg/dL OR creatinine clearance >= 60mL/min
Primary purpose
Allocation
Interventional model
Masking
60 participants in 3 patient groups
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Data sourced from clinicaltrials.gov
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