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Flavopiridol to Treat Relapsed Mantle Cell Lymphoma or Diffuse Large B-Cell Lymphoma

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00445341
Recruitment Status : Completed
First Posted : March 9, 2007
Results First Posted : October 5, 2012
Last Update Posted : January 30, 2018
Sponsor:
Information provided by (Responsible Party):
Mark Roschewski, M.D., National Institutes of Health Clinical Center (CC)

Tracking Information
First Submitted Date  ICMJE March 7, 2007
First Posted Date  ICMJE March 9, 2007
Results First Submitted Date  ICMJE September 5, 2012
Results First Posted Date  ICMJE October 5, 2012
Last Update Posted Date January 30, 2018
Actual Study Start Date  ICMJE November 27, 2006
Actual Primary Completion Date April 30, 2012   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 5, 2012)
  • Number of Participants With Adverse Events (e.g. Toxicity) [ Time Frame: 47 months ]
    Here is the number of participants with adverse events. For a detailed list of adverse events see the adverse event module.
  • Response Rate (Complete Response (CR) and Partial Response (PR)) [ Time Frame: 2/16/2007 - 1/20/2011 ]
    Response was assessed by the Cheson criteria. Complete response is complete disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease related symptoms if present before therapy, and normalization of those biochemical abnormalities (e.g.(LDH) definitely assignable to the lymphoma. All lymph nodes must have regressed to normal size (</= 1.5 cm in greatest diameter if > 1.5 cm before therapy). Previously involved nodes that were 1.1 to 1.5 cm in greatest diameter must have decreased to </= 1 cm or by more than 75% in the sum of the products of the greatest diameters (SPD). Spleen, if considered to be enlarged before therapy, must have regressed in size. Partial response is a >/= 50% decrease in the SPD of 6 largest dominant nodes or nodal masses. No increase in size of nodes, liver or spleen and no new sites of disease. Splenic and hepatic nodules must regress by >/= 50% in the SPD. Bone marrow is irrelevant for determination of a PR.
Original Primary Outcome Measures  ICMJE
 (submitted: March 7, 2007)
  • Maximum tolerated dose (Phase I)
  • Toxicity (Phase I)
  • Response rate (complete response and partial response)
Change History
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE
 (submitted: March 7, 2007)
  • Pharmacokinetics
  • Incidence of tumor lysis syndrome
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Flavopiridol to Treat Relapsed Mantle Cell Lymphoma or Diffuse Large B-Cell Lymphoma
Official Title  ICMJE A Phase I/II Study of Flavopiridol in Relapsed or Refractory Mantle Cell Lymphoma (MCL) and Diffuse Large B-Cell Lymphoma (DLBCL)
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Lymphoma
Intervention  ICMJE Drug: Flavopiridol
Flavopiridol 30 mg/m^2 is given weekly for 4 weeks followed by a 2 week break for up to 6 cycles. It is given through a vein as a 30 minute infusion followed by a 4 hour infusion.
Other Name: alvocidib
Study Arms  ICMJE Experimental: Flavopiridol in lymphoma patients
Flavopiridol 30 mg/m^2 is given weekly for 4 weeks followed by a 2 week break for up to 6 cycles. It is given through a vein as a 30 minute infusion followed by a 4 hour infusion.
Intervention: Drug: Flavopiridol
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: July 13, 2011)
28
Original Enrollment  ICMJE
 (submitted: March 7, 2007)
71
Actual Study Completion Date  ICMJE October 18, 2012
Actual Primary Completion Date April 30, 2012   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE
  • 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.

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00445341
Other Study ID Numbers  ICMJE 070081
07-C-0081
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Mark Roschewski, M.D., National Institutes of Health Clinical Center (CC)
Study Sponsor  ICMJE National Cancer Institute (NCI)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Mark Roschewski, M.D. National Cancer Institute (NCI)
PRS Account National Institutes of Health Clinical Center (CC)
Verification Date January 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP