Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outline
Published Results
Trial Contact Information
Related Information
Registry Information

Alternate Title

FR901228 in Treating Children with Refractory or Recurrent Solid Tumors or Leukemia

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase I	Treatment	Completed	Under 22	NCI	COG-ADVL0212 NCI-03-C-0307, NCT00053963, ADVL0212

Objectives

Primary

1. Determine the maximum tolerated dose (MTD) of FR901228 (depsipeptide) in pediatric patients with refractory or recurrent solid tumors.
2. Determine the dose-limiting toxic effects of this drug in these patients.
3. Determine the pharmacokinetics of this drug in these patients.
4. Assess tolerability of this drug at the solid tumor MTD in patients with refractory or recurrent leukemia.
5. Determine, preliminarily, the antitumor activity of this drug in these patients.

Entry Criteria

Disease Characteristics:

• Histologically confirmed malignancy
  • Extracranial solid tumors or brain tumors*
  • Diagnosis of leukemia allowed after maximum tolerated dose is determined, including any of the following:
    • Acute lymphoblastic leukemia
    • Acute myelogenous leukemia
    • Chronic myelogenous leukemia in blast crisis

   [Note: *Histology requirement waived for patients with brain stem or optic pathway tumors]

• Disease must be refractory to conventional therapy or no effective conventional therapy exists
• CNS tumors resulting in neurological deficits must be stable for 2 weeks before study entry

Prior/Concurrent Therapy:

Biologic therapy

• At least 1 week since prior growth factors
• At least 3 weeks since prior biologic therapy or immunotherapy and recovered
• At least 6 months since prior allogeneic stem cell transplantation
• No concurrent routine prophylactic growth factors

Chemotherapy

• At least 3 weeks since prior myelosuppressive chemotherapy (4 weeks for nitrosoureas) and recovered
• No prior FR901228 (depsipeptide)
• No other concurrent anticancer chemotherapy

Endocrine therapy

• Concurrent dexamethasone for CNS tumors allowed if on stable dose or decreasing dose for at least 1 week before study entry

Radiotherapy

• Recovered from prior radiotherapy
• At least 2 weeks since prior local palliative radiotherapy (small port)
• At least 6 months since prior craniospinal radiotherapy or radiotherapy to at least 50% of pelvis
• At least 6 weeks since other prior substantial bone marrow radiation

Surgery

• Not specified

Other

• More than a 5 half-life washout period since prior and no concurrent medications associated with prolongation of QTc interval
• No concurrent enzyme-inducing anticonvulsants
• No concurrent hydrochlorothiazide
• No other concurrent investigational drugs

Patient Characteristics:

Age

• Under 22

Performance status

• Karnofsky 60-100% (over 10 years old)
• Lansky 60-100% (10 years old and under)

Life expectancy

• At least 8 weeks

Hematopoietic

• Absolute neutrophil count at least 1,000/mm³ (for solid tumor patients without bone marrow involvement)
• Platelet count at least 100,000/mm³ (for solid tumor patients without bone marrow involvement; platelet transfusion independent) OR 20,000/mm³ (for leukemia patients; platelet transfusion allowed)
• Hemoglobin at least 8.0 g/dL (RBC transfusions allowed)

Hepatic

• Bilirubin no greater than 1.5 times upper limit of normal (ULN)
• ALT no greater than 5 times ULN
• Albumin at least 2 g/dL

Renal

• Glomerular filtration rate at least 70 mL/min

  OR

• Creatinine based on age as follows:
  • No greater than 0.8 mg/dL (for patients 5 years of age and under)
  • No greater than 1.0 mg/dL (for patients 6 to 10 years of age)
  • No greater than 1.2 mg/dL (for patients 11 to 15 years of age)
  • No greater than 1.5 mg/dL (for patients over 15 years of age)
• Calcium normal (with or without supplementation)

Cardiovascular

• Shortening fraction at least 27% by echocardiogram OR ejection fraction at least 50% by MUGA
• No symptomatic congestive heart failure
• No uncontrolled cardiac arrhythmia
• QTc less than 450 msec

Pulmonary

• No evidence of dyspnea at rest
• No exercise intolerance
• Pulse oximetry greater than 94%

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for 1 month after completion of study treatment
• Magnesium and potassium normal (with or without supplementation)
• No uncontrolled seizure disorder
• No uncontrolled infection
• No graft-vs-host disease
• No seizure disorder unless well controlled and not on enzyme-inducing anticonvulsants

Expected Enrollment

A total of 3-30 patients (3-24 with solid tumors and up to 6 with leukemia) will be accrued for this study within 2 years.

Outline

This is a dose-escalation, multicenter study. 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 with solid tumors 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 3 or 2 of 6 patients experience dose-limiting toxicity.

Cohorts of 3 patients (6 patients total) with leukemia receive FR901228 as above at the MTD.

Patients are followed for survival.

Fouladi M, Furman WL, Chin T, et al.: Phase I study of depsipeptide in pediatric patients with refractory solid tumors: a Children's Oncology Group report. J Clin Oncol 24 (22): 3678-85, 2006.[PUBMED Abstract]

Fouladi M, Furman WL, Chin T, et al.: A phase I trial of depsipeptide in children with refractory solid tumors: a Children's Oncology Group study. [Abstract] J Clin Oncol 23 (Suppl 16): A-8528, 807s, 2005.

Trial Contact Information

Trial Lead Organizations

Children's Oncology Group

Maryam Fouladi, MD, Protocol chair		Ph: 513-803-0721; 800-344-2462

Related Information

Web site for additional information

Registry Information
Official Title		A Phase I Study of Depsipeptide (NSC#630176, IND#51810) in Pediatric Patients with Refractory Solid Tumors and Leukemias
Trial Start Date		2002-12-16
Registered in ClinicalTrials.gov		NCT00053963
Date Submitted to PDQ		2002-12-11
Information Last Verified		2005-12-30
NCI Grant/Contract Number		CA97452

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