FR901228 in Treating Patients With Recurrent High-Grade Gliomas

Phase 1

Completed

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

Interventions: Drug: depsipeptide

Registration Number: NCT00085540

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 50

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

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Phase 1 Dose Escalation - Romidepsin	depsipeptide	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
Phase 2 Dose from Phase 1 - Romidepsin	depsipeptide	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

Primary Outcome Measures

Name	Time	Method
Number of Participants With Dose-limiting Toxicities Due to Romidepsin Graded According to the NCI Common Toxicity Criteria (CTCAE Version 3.0) (Phase I)	First 4 weeks of treatment	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)
6 Months Progression-free Survival (Phase II)	At 6 months	evaluated patients with glioblastoma (GBM (35 patients)

Secondary Outcome Measures

Name	Time	Method
Response Rate Associated With Depsipeptide Therapy (Phase II)	Up to 2 years	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

Trial Locations

Locations (8): University of California Los Angeles
🇺🇸
Los Angeles, California, United States
MD Anderson Cancer Center
🇺🇸
Houston, Texas, United States
National Cancer Institute Neuro-Oncology Branch
🇺🇸
Bethesda, Maryland, United States
University of California San Francisco
🇺🇸
San Francisco, California, United States
Memorial Sloan-Kettering Cancer Center
🇺🇸
New York, New York, United States
Dana Farber Cancer Institute
🇺🇸
Boston, Massachusetts, United States
University of Pittsburgh
🇺🇸
Pittsburgh, Pennsylvania, United States
University of Wisconsin
🇺🇸
Madison, Wisconsin, United States