A Phase I-II Trial of Depsipeptide in Patients With Recurrent High-Grade Gliomas
A Phase I-II Trial of Depsipeptide in Patients With Recurrent High-Grade Gliomas
This phase I/II trial is studying the side effects and best dose of FR901228 and to see how well it works in treating patients with recurrent high-grade gliomas. FR901228 may stop the growth of tumor cells by blocking the enzymes necessary for their growth
PRIMARY OBJECTIVES:
I. Determine the maximum tolerated dose (MTD) of FR901228 (depsipeptide) in patients with recurrent malignant gliomas who are taking enzyme-inducing antiepileptic drugs (EIAEDs). (Phase I) II. Determine the safety profile of this drug in these patients. (Phase I) III. Determine the pharmacokinetics and pharmacodynamics of this drug in these patients. (Phase I) IV. Determine the clinical efficacy of this drug, as measured by 6-month progression-free survival and objective tumor response, in these patients. (Phase II) V. Determine the safety profile of this drug when administered at the phase I MTD concurrently with or without EIAEDs in these patients. (Phase II)
OUTLINE: This is a multicenter, phase I, dose-escalation study followed by a phase II study. Patients are stratified according to study phase (I vs II), concurrent use of enzyme-inducing anti-epileptic drugs (EIAEDs) (yes vs no), histology (recurrent glioblastoma multiforme/gliosarcoma vs recurrent anaplastic glioma), pre-operative candidacy (yes vs no), and measurable/evaluable disease (yes vs no). Patients are assigned to 1 of 2 treatment groups (group A: no EIAEDs or group B: concurrent use of EIAEDs).
Phase I (group B only): Patients receive FR901228 (depsipeptide) IV over 4 hours on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of FR901228 until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of up to 6 patients experience dose-limiting toxicity.
Phase II (groups A and B):
Group A (phase II): Patients receive FR901228 as in phase I at dose level 1. Group B (phase II): Patients receive FR901228 as in phase I at the MTD.
Inclusion Criteria:
Phase I and phase II:
Histologically confirmed recurrent intracranial malignant glioma, including any of the following:
Unequivocal evidence of tumor progression by MRI or CT scan while on a steroid dosage that has been stable for at least 5 days
Patients previously treated with interstitial brachytherapy or stereotactic radiosurgerymust have confirmation of true progressive disease (rather than radiation necrosis) by positron-emission tomography, thallium scan, magnetic resonance spectroscopy, or surgical documentation
Must have failed prior radiotherapy that was completed at least 6 weeks ago
No more than 2 prior therapies (initial treatment and treatment for 1 relapse)*
Patients in group B must have been receiving enzyme-inducing antiepileptic drugs (EIAEDs) for at least the past 2 weeks
Performance status - Karnofsky 60-100%
More than 8 weeks
WBC ≥ 3,000/mm^3
Absolute neutrophil count ≥ 1,500/mm^3
Platelet count ≥ 100,000/mm^3
Hemoglobin ≥ 10 g/dL (transfusions allowed)
SGOT < 2 times upper limit of normal (ULN)
Bilirubin < 2 times ULN
Creatinine < 1.5 mg/dL
No congestive heart failure (i.e., New York Heart Association class II-IV, ejection fraction < 40% by MUGA scan or < 50% by echocardiogram and/or MRI)
No myocardial infarction within the past year
No uncontrolled dysrhythmias
No poorly controlled angina
No significant left ventricular hypertrophy by EKG
No cardiac ischemia (ST depression of 2 mm) by EKG
No hypertrophic or restrictive cardiomyopathy from prior treatment or other causes
No uncontrolled hypertension (i.e., blood pressure ≥ 160/95 mm Hg)
No cardiac arrhythmia requiring antiarrhythmic medication
No known cardiac abnormalities (e.g., congenital long QT syndrome and QTc interval > 480 milliseconds)
No history of sustained ventricular tachycardia, ventricular fibrillation, Torsade de Pointes, or cardiac arrest unless controlled with concurrent automatic implantable cardioverter defibrillator
No known history of coronary artery disease (e.g., Canadian class II-IV angina)
No other significant cardiac disease
No other malignancy within the past 3 years except nonmelanoma skin cancer or carcinoma in situ of the cervix
No active infection
No significant uncontrolled medical illness that would preclude study participation
No disease that would obscure toxicity or dangerously alter drug metabolism
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective barrier contraception during and for at least 2 weeks after study participation
At least 1 week since prior interferon or thalidomide
No concurrent prophylactic filgrastim (G-CSF)
No concurrent anticancer immunotherapy
At least 2 weeks since prior vincristine
At least 6 weeks since prior nitrosoureas
At least 3 weeks since prior procarbazine
No prior FR901228 (depsipeptide)
No other concurrent anticancer chemotherapy
See Disease Characteristics
At least 1 week since prior tamoxifen
No concurrent anticancer hormonal therapy
See Disease Characteristics
No concurrent anticancer radiotherapy
See Disease Characteristics
Prior recent resection of recurrent or progressive tumor allowed if patient has recovered
Recovered from all prior therapy
At least 2 weeks since prior EIAEDs (patients in Group A only)
At least 4 weeks since prior cytotoxic therapy
At least 4 weeks since prior investigational agents
At least 1 week since prior isotretinoin
At least 1 week since other prior non-cytotoxic therapy (except radiosensitizers)
No concurrent valproic acid
No concurrent hydrochlorothiazide
No concurrent medication that causes QTc prolongation
No other concurrent anticancer therapy
No other concurrent investigational drugs