Clinical trial NCT00445341: Flavopiridol to Treat Relapsed Mantle Cell Lymphoma or Diffuse Large B-Cell Lymphoma
Official title: A Phase I/II Study of Flavopiridol in Relapsed or Refractory Mantle Cell Lymphoma (MCL) and Diffuse Large B-Cell Lymphoma (DLBCL)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Lymphoma
Keywords: Microarray
Proteomics
Hybrid Schedule
Tumor Lysis Syndrome
Cyclin D1
Lymphoma
Mantle Cell Lymphoma
MCL
Diffuse Large B-Cell Lymphoma
DLBCL
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2007-03-09
Enrollment: 28
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Background:

Mantle cell lymphoma (MCL) and diffuse large B-cell lymphoma (DLBCL) are aggressive subtypes of non-Hodgkin lymphoma.

Flavopiridol is an investigational drug that works differently from standard chemotherapy and may target abnormalities in MCL and DLBCL cells, such as a protein excess that prevents tumor cells from dying.

A challenge in developing flavopiridol for treatment has been determining its optimal dosing schedule. The schedule used for this study is effective in a type of leukemia called chronic lymphocytic leukemia (CLL) and may benefit patients with MCL and DLBCL also.

Objectives:

To determine the highest dose of flavopiridol that can be given safely to patients with relapsed MCL and DLBCL at the dosing schedule detailed below

To assess the response of the tumor to flavopiridol given at the test dosing schedule

Eligibility:

Patients 18 years of age and older with relapsed MCL or DLBCL

Design:

Flavopiridol is given at four different dose levels, starting with the lowest dose for the first group of three to six patients and increasing with subsequent groups, depending on side effects at the preceding dose. The drug is given weekly for 4 weeks followed by a 2-week break (one cycle) for up to six cycles. It is given through a vein as a 30-minute infusion followed by a 4-hour infusion.

Patients undergo the following procedures for research studies and to evaluate the effect of treatment on the tumor:

* Blood tests
* Lymph node, bone marrow and tumor biopsies
* Lymphapheresis to collect blood cells for research
* Disease staging with imaging studies (computed tomography (CT), positron emission tomography (PET) and/or magnetic resonance imaging (MRI) after every 2 cycles

Detailed description: Background:

Flavopiridol is a synthetic N-methylpiperidinyl, chlorophenyl flavone compound that targets a number of different cellular pathways and processes.

It works through several different mechanisms that include inhibition of cyclin dependent kinases and the cyclin D-1 complex which is over-expressed in mantle cell lymphoma. Flavopiridol also has demonstrated activity in activated B-like diffuse large B-cell lymphoma cell lines.

One of the great challenges in developing flavopiridol and applying it clinically has been determining its optimal dosing schedule. Following several different dosing schedules, one strategy that has been very promising in chronic lymphocytic leukemia (CLL) is the application of so-called hybrid schedules of the drug (an infusion for an intermediate time following a bolus dose).

Objectives:

Assess the toxicity and safety of administration of this hybrid schedule.

Assess the response rate of the hybrid schedule of flavopiridol in relapsed mantle cell lymphoma (MCL) and diffuse large B-cell lymphoma (DLBCL).

Eligibility:

Relapsed MCL or DLBCL.

Eastern Cooperative Oncology Group (ECOG) performance status(P.S.) less than or equal to 2.

Age greater than or equal to 18 years.

Human immunodeficiency virus (HIV) serology negative

Design:

Phase I/II.

Phase I portion consists of 3-4 dose levels of 3-6 patients each.

Administer weekly times 4 and then 2 weeks off (1 cycle). Restage after every 2 cycles. Continue if complete response (CR), partial response (PR) or stable disease (SD) for up to 6 cycles. Dose reductions for toxicity will be addressed in the protocol.

Phase II portion of the study will be a Simon optimal two-stage design: designed to rule out 20% response rate (p0=0.20) in favor of a 45% response rate (p1=0.45).

The maximum sample size to be accrued for this study will be 71 patients.

Eligibility criteria: * ELIGIBILITY CRITERIA:

Previously treated mantle cell lymphoma or diffuse large B-cell lymphoma (to include mediastinal (thymic) large B-cell lymphoma; transformed large B-cell lymphoma; follicular grade IIIB large B-cell lymphoma; intravascular large B-cell lymphoma).

Confirmed pathological diagnosis at the National Cancer Institute, National Institutes of Health (NIH).

Recurrent measurable disease (measurable disease in 2 dimensions or leukemic disease which can be quantified and followed).

Prior anthracycline-based treatment for patients with diffuse large B-cell lymphoma (DLBCL).

Age greater than 18 years.

Eastern Cooperative Oncology Group (ECOG) performance 2 or better.

Major organ function: absolute neutrophil count (ANC) greater than 1000/mcL, Platelet greater than 50,000/mcL, Creatinine less than 1.5 mg/dL or creatinine clearance greater than 60 mL/min; serum glutamic pyruvic transaminase (SGPT) less than 5 x upper limit of normal; bilirubin less than 2 mg/dL (total) except less than 5 mg/dL in patients with Gilbert's syndrome as defined by greater than 80% unconjugated. ANC and platelet requirements must be met independent of transfusion.

Informed consent and willingness to use contraception by both men and women.

Both male and female patients must be willing to use adequate contraception (to include effective barrier methods of contraception) or to completely abstain from heterosexual intercourse while on protocol treatment.

EXCLUSION CRITERIA:

Pregnant or nursing because of an unknown potential for teratogenic or abortifacient effects.

Human immunodeficiency virus (HIV) serology negative. HIV positive patients receiving combination anti-retroviral therapy are excluded from the study because of possible pharmacokinetic interactions with flavopiridol. Additionally, the biology of HIV associated DLBCL's is often quite different from HIV negative disease due to involvement of Epstein Barr virus (EBV).

Hepatitis B surface antigen negative.

Active central nervous system (CNS) lymphoma. These patients have a poor prognosis and because they frequently develop progressive neurological dysfunction that would confound the evaluation of neurological and other adverse events.

History of inflammatory bowel disease unless this has been inactive for a period of 2 or more years.

Recovery from toxicity of prior therapy to a grade 1 or less.

Systemic cytotoxic or experimental treatments within 4 weeks of treatment.

White blood cell (WBC) greater than 100,000 cells/mcL.

Primary outcomes:
measure: Number of Participants With Adverse Events (e.g. Toxicity)
timeFrame: 47 months
measure: Response Rate (Complete Response (CR) and Partial Response (PR))
timeFrame: 2/16/2007 - 1/20/2011
Secondary outcomes:
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center, 9000 Rockville Pike
state: Maryland
Study officials:
affiliation: National Cancer Institute (NCI)
name: Mark Roschewski, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Worland PJ, Kaur G, Stetler-Stevenson M, Sebers S, Sartor O, Sausville EA. Alteration of the phosphorylation state of p34cdc2 kinase by the flavone L86-8275 in breast carcinoma cells. Correlation with decreased H1 kinase activity. Biochem Pharmacol. 1993 Nov 17;46(10):1831-40. doi: 10.1016/0006-2952(93)90590-s.
citation: Arguello F, Alexander M, Sterry JA, Tudor G, Smith EM, Kalavar NT, Greene JF Jr, Koss W, Morgan CD, Stinson SF, Siford TJ, Alvord WG, Klabansky RL, Sausville EA. Flavopiridol induces apoptosis of normal lymphoid cells, causes immunosuppression, and has potent antitumor activity In vivo against human leukemia and lymphoma xenografts. Blood. 1998 Apr 1;91(7):2482-90.
citation: Byrd JC, Peterson BL, Gabrilove J, Odenike OM, Grever MR, Rai K, Larson RA; Cancer and Leukemia Group B. Treatment of relapsed chronic lymphocytic leukemia by 72-hour continuous infusion or 1-hour bolus infusion of flavopiridol: results from Cancer and Leukemia Group B study 19805. Clin Cancer Res. 2005 Jun 1;11(11):4176-81. doi: 10.1158/1078-0432.CCR-04-2276.