Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Trial Contact Information
Registry Information

Alternate Title

FR901228 Alone or Combined With Rituximab and Fludarabine in Treating Patients With Relapsed or Refractory Low-Grade B-Cell Non-Hodgkin's Lymphoma

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase II, Phase I	Treatment	Completed	18 and over	NCI	MSGCC-0307 NCI-6015, 6015, NCT00079443

Objectives

Primary

1. Determine the clinical efficacy of single-agent FR901228 (depsipeptide), in terms of complete and partial response rates, in patients with relapsed or refractory low-grade B-cell non-Hodgkin's lymphoma. (Phase II)
2. Determine the feasibility of adding FR901228 to a rituximab and fludarabine combination regimen in these patients. (Phase I)
3. Determine the maximum tolerated dose of FR901228 when administered with this combination regimen in these patients. (Phase I)

Secondary

1. Correlate changes in histone acetylation assays with disease response (clinical outcome) in patients treated with this regimen.
2. Determine the minimal residual disease by immunohistochemistry in patients treated with this regimen.

Entry Criteria

Disease Characteristics:

• Histologically and clinically confirmed low-grade follicular B-cell non-Hodgkin's lymphoma (NHL), including the following subtypes:
  • Follicular small cleaved cell
  • Follicular mixed small and large cell
  • Small lymphocytic lymphoma



• CD20-positive by immunohistochemistry or flow cytometry



• Relapsed and/or refractory disease
  • Received at least 1, but no more than 4, prior chemotherapy regimens for low-grade follicular NHL
    • For phase II, prior therapies may have included rituximab or fludarabine as a single agent only
    • For phase I, prior rituximab and fludarabine must not have been administered in combination or sequentially
      • Prior rituximab and/or fludarabine as single agents are allowed provided patient achieved a 50% response (i.e., partial response to prior therapy)



• Measurable disease 4 weeks after the last chemotherapy regimen, meeting at least 1 of the following criteria:
  • At least 1 unidimensional lesion > 1.5 cm by CT scan
  • Positive bone marrow biopsy



• No bulky disease (single mass ≥ 10 cm)



• No known CNS involvement by MRI and/or cerebrospinal fluid examination

 [Note: A new classification scheme for adult non-Hodgkin's lymphoma has been adopted by PDQ. The terminology of "indolent" or "aggressive" lymphoma will replace the former terminology of "low", "intermediate", or "high" grade lymphoma. However, this protocol uses the former terminology.]

Prior/Concurrent Therapy:

Biologic therapy

• See Disease Characteristics
• More than 6 weeks since prior rituximab and recovered
• Concurrent growth factors (e.g., filgrastim [G-CSF] or epoetin alfa) allowed
• No prior allogeneic stem cell transplantation

Chemotherapy

• See Disease Characteristics
• More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas and mitomycin) and recovered
• More than 6 weeks since prior fludarabine and recovered (phase II)
• No prior FR901228 or any other histone deacetylase inhibitor

Endocrine therapy

• No concurrent pharmacological doses of corticosteroids for concurrent medical conditions

Radiotherapy

• More than 4 weeks since prior radiotherapy and recovered

Surgery

• Not specified

Other

• More than 8 weeks since prior UCN-01 and recovered
• No concurrent drugs that would cause prolongation of QTc
• No concurrent hydrochlorothiazide
• No other concurrent investigational agents
• No other concurrent anticancer therapy

Patient Characteristics:

Age

• 18 and over

Performance status

• ECOG 0-2

Life expectancy

• At least 4 months

Hematopoietic

• Absolute neutrophil count ≥ 1,000/mm³ (500/mm³ for bone marrow involvement by lymphoma)
• Platelet count ≥ 100,000/mm³ (50,000/mm³ for bone marrow involvement by lymphoma)

Hepatic

• Bilirubin ≤ 1.5 times upper limit of normal (ULN)
• AST/ALT ≤ 3 times ULN

Renal

• Creatinine ≤ 1.5 times ULN

Cardiovascular

• No left ventricular hypertrophy on EKG
• No prior life-threatening arrhythmias
• No myocardial infarction within the past 6 months
• No severe coronary artery disease
• No cardiomyopathy
• No New York Heart Association class II-IV congestive heart failure
• Ejection fraction > 40%
• No EKG abnormality (i.e., ischemic ST-T abnormalities, QT prolongation, pathologic q waves, or arrhythmias)
  • Benign premature atrial or ventricular contractions or first- or second-degree atrioventricular block allowed

Other

• No prior life-threatening allergic reaction to study agents
• No other prior malignancies except basal cell carcinoma or cervical intra-epithelial neoplasia
• No prior uncontrolled seizures
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use 2 (1 highly active and 1 additional effective) methods of contraception

Expected Enrollment

A total of 19-36 patients will be accrued for the phase II portion of this study within 9 months. A total of 3-24 patients will be accrued for the phase I portion of this study.

Outcomes

Maximum tolerated dose (MTD) of depsipeptide (phase I)
Feasibility (phase I)
Complete and partial response rates (phase II)

Correlation of changes in histone deacetylation assays with disease response
Minimal residual disease as measured by immunohistochemistry

Outline

This is a multicenter, phase II study of single-agent FR901228 followed by a phase I, dose-escalation study of FR901228.

• Phase II: Patients receive FR901228 IV over 4 hours on days 1, 8, and 15. Treatment repeats every 28 days for 4 courses in the absence of disease progression or unacceptable toxicity.

  Patients who achieve a complete or partial remission receive 2 additional courses (for a total of 6 courses). Patients with stable disease after 4 courses or progressive disease at any time after 2 courses proceed to the phase I portion of the study.




• Phase I: Patients receive rituximab IV over approximately 4-8 hours on day 1; fludarabine IV over 10-30 minutes on days 2-4; and FR901228 IV over 4 hours on days 2, 9, and 16. Treatment repeats every 28 days for up to 6 courses 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 6 patients experience dose-limiting toxicity.

Patients are followed for up to 3 years from study entry.

Trial Contact Information

Trial Lead Organizations

Greenebaum Cancer Center at University of Maryland Medical Center

Ashraf Badros, MD, Protocol chair		Ph: 410-328-2565; 800-888-8823

Registry Information
Official Title		A Phase II Study of Single Agent Depsipeptide (NSC 63017) Followed by a Phase I Study of Rituximab/Fludarabine Combination With an Escalating Dose of Depsipeptide in Relapsed or Refractory Low Grade B- Cell Lymphomas
Trial Start Date		2004-02-25
Registered in ClinicalTrials.gov		NCT00079443
Date Submitted to PDQ		2004-02-05
Information Last Verified		2007-03-28
NCI Grant/Contract Number		CA69854

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