A Phase Ib/II Study of CYT997 in Combination With Carboplatin in Relapsed Glioblastoma Multiforme
- 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
- Must agree to use adequate contraceptive measures if indicated
- Ability to understand and the willingness to sign a written informed consent document
- 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
- 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
- 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.