A Feasibility Assessment and a Phase I/II Trial of MLN518 for Treatment of Patients With Recurrent Glioblastoma

Inclusion Criteria

Criteria:

- Histologically confirmed glioblastoma:

- Progressive or recurrent disease after prior radiotherapy (with or without
chemotherapy)

- Patients with a previous low-grade glioma that progressed after prior
radiotherapy (with or without chemotherapy) and are found to have glioblastoma
by biopsy are eligible

- 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:

- Planning to undergo surgical resection or biopsy

- Stereotactic biopsy for confirmation of tumor progression or differentiation of
tumor progression from treatment-induced effects allowed

- Corticosteroids must be tapered to the lowest required steroid dose and patient
must be maintained on a stable dose after surgery or biopsy

- 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