Efficacy Study of CYT997 in Combination With Carboplatin in Glioblastoma

Inclusion Criteria:

* Patients must have histologically-confirmed glioblastoma multiforme that has progressed after initial surgery, radiation therapy and temozolomide chemotherapy.
* Measurable tumour must be present on gadolinium-enhanced MRI
* At least 3 months must have elapsed from completing radiation to minimize the possibility of pseudo-progression.
* At least 4 weeks since prior chemotherapy (6 weeks if the last regimen included bischloroethylnitrosourea (BCNU) or Chloroethyl-Cyclohexyl-NitrosoUrea (CCNU)).
* Age ≥ 18 years.
* If patients are taking steroids, the dose must be stable for = 7 days.
* Eastern Cooperative Oncology Group (ECOG) performance status = 2.
* Life expectancy of greater than 2 months.
* Patients must have adequate organ and marrow function as defined below:

  * Absolute neutrophil count = 1.5 × 109/L
  * Platelet count = 100 × 109/L
  * Total bilirubin within normal limits
  * Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \< 5 × upper limit of normal (ULN)
  * Creatinine within normal limits OR creatinine clearance = 60 mL/min/1.73 m2 for patients with creatinine levels above normal
  * Normal left ventricular ejection fraction on a gated blood pool scan or echocardiogram
* Must agree to use adequate contraceptive measures if indicated
* Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

* Patients who have received any other investigational agent in the preceding four weeks prior to commencing therapy in this study.
* Patients who have been previously treated with carboplatin.
* Patients who have been previously treated with bevacizumab or other anti-angiogenesis or vascular-disrupting agents
* Patients who are receiving enzyme-inducing anticonvulsant drugs (EIACD) such as phenytoin or carbamazepine.
* Patients with a history of allergic reactions attributed to compounds of similar chemical composition to CYT997 or other agents used in the study.
* Patients with uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, cardiac arrhythmia or psychiatric illness/social situations that would limit compliance with study requirements.
* Pregnant or lactating women.
* Patients with immune deficiency, including HIV-positive patients.
* Patients with uncontrolled diarrhoea despite optimal medication and those with any history of acute gastrointestinal bleeding.
* Patients who are unable or unwilling to undergo MRI scanning
* Patients with the following conditions/treatments will be excluded:

  * Myocardial infarction (MI) or stroke within 6 months
  * History of stroke or transient ischemic attacks (TIAs)
  * Unstable angina pectoris or acute ischemic changes on ECG
  * History of diabetic retinopathy
  * Symptomatic peripheral arterial disease o Major surgery in the last 4 weeks
  * Evidence of intra-tumoural haemorrhage on imaging, except for stable grade-1 post-operative haemorrhage.
  * Current therapeutic anti-coagulation with warfarin or a heparin (excludes lowdose prophylactic heparin).
  * Uncontrolled hypertension
  * The need for any anti-arrhythmic drugs
* Presence of luminal stenosis of 50% or more in any of the extracranial or intracranial arteries supplying the brain, as measured by magnetic resonance angiography (MRA) at baseline.
* Patients with a baseline prolongation of the QTc interval of Common Terminology Criteria (CTC) grade 1 (QTc \> 0.45- 0.47 sec) or greater.
* Patients with impaired cardiac function or clinically significant cardiac diseases, including any one of the following:

  * Left ventricular ejection fraction (LVEF) \< 45% as determined by multigated acquisition (MUGA) scan or echocardiogram;
  * complete left bundle branch block;
  * obligate use of a cardiac pacemaker;
  * congenital long QT syndrome;
  * history or presence of ventricular tachyarrhythmia;
  * presence of unstable atrial fibrillation (ventricular response \> 100 bpm) Patients with stable atrial fibrillation are eligible, provided they do not meet any of the other cardiac exclusion criteria;
  * clinically significant resting bradycardia (\< 50 bpm);
  * right bundle branch block + left anterior hemiblock (bifascicular block);
  * angina pectoris = 3 months prior to starting study drug;
  * acute MI = 3 months prior to starting study drug; or
  * other clinically significant heart disease (e.g., congestive heart failure (CHF), uncontrolled hypertension, history of labile hypertension, or history of poor compliance with an antihypertensive regimen).
* Patients currently receiving treatment with medications known to prolong the QTc interval and/or to induce Torsades de Pointes arrhythmia.