FR901228 in Treating Patients With Recurrent High-Grade Gliomas

Study Overview
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Brief Summary
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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

Detailed Description
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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.

Official Title
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A Phase I-II Trial of Depsipeptide in Patients With Recurrent High-Grade Gliomas

Conditions
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Adult Anaplastic Astrocytoma, Adult Anaplastic Oligodendroglioma, Adult Giant Cell Glioblastoma, Adult Gliosarcoma, Recurrent Adult Brain Tumor

Intervention / Treatment
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* Drug: depsipeptide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Phase I and phase II: Histologically confirmed recurrent intracranial malignant glioma, including any of the following: Glioblastoma multiforme Gliosarcoma Anaplastic astrocytoma Anaplastic oligodendroglioma Anaplastic mixed oligoastrocytoma Malignant astrocytoma not otherwise specified 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)* Surgical resection for relapsed disease with no anticancer therapy for up to 12 weeks, followed by a second surgical resection, is considered 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 Fertile male patients must continue barrier contraception for 3 months 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1 Dose Escalation - Romidepsin<br>Patients receive FR901228 (romidepsin) IV over 4 hours on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Dose escalation two dose levels: Romidepsin (depsipeptide): 13.3mg/m2 and 17.7mg/m2 Pharmacokinetics | Drug: depsipeptide<br>* Given IV<br>* Other names: romidepsin;|
| Experimental: Phase 2 Dose from Phase 1 - Romidepsin<br>Patients receive FR901228 (romidepsin) as in phase I at dose level 1. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity Romidepsin (depsipeptide): 13.3mg/m2 | Drug: depsipeptide<br>* Given IV<br>* Other names: romidepsin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Dose-limiting Toxicities Due to Romidepsin Graded According to the NCI Common Toxicity Criteria (CTCAE Version 3.0) (Phase I) | dose limiting toxicity defined as: ANC </=1000 or Platelets <100K; SGOT >/= 3X ULN and T. Bili >/= 1.5 ULN grade 3 Nausea, vomiting, fatigue and asymptomatic hypocalcemia (treatment may continue after discuss with PI) | First 4 weeks of treatment | 
| 6 Months Progression-free Survival (Phase II) | evaluated patients with glioblastoma (GBM (35 patients) | At 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rate Associated With Depsipeptide Therapy (Phase II) | RECIST Complete Response (CR): Complete disappearance of all measurable and evaluable disease. No new lesions. No evidence of non-evaluable disease. Patients must be on no steroids. Partial Response (PR): Greater than or equal to 50% decrease under baseline in the sum of products of perpendicular diameters of all measurable lesions. No progression of evaluable disease. No new lesions. Stable/No Response: Does not qualify for CR, PR, or progression. The designation of Stable/No Response requires a minimum of 8 weeks duration. Progression: 25% increase in the sum of products of all measurable lesions over smallest sum observed (over baseline if no decrease) OR clear worsening of any evaluable disease, OR appearance of any new lesion/site, OR clear clinical worsening or failure to return for evaluation due to death or deteriorating condition | Up to 2 years |