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

Primary Purpose

Lymphoma

Status

Completed

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Flavopiridol

About this trial

This is an interventional treatment trial for Lymphoma focused on measuring Microarray, Proteomics, Hybrid Schedule, Tumor Lysis Syndrome, Cyclin D1, Lymphoma, Mantle Cell Lymphoma, MCL, Diffuse Large B-Cell Lymphoma, DLBCL

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

National Institutes of Health Clinical Center, 9000 Rockville Pike

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Flavopiridol in lymphoma patients

Arm Description

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.

Outcomes

Primary Outcome Measures

Number of Participants With Adverse Events (e.g. Toxicity)

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))

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.

Secondary Outcome Measures

Full Information

NCT ID

NCT00445341

First Posted

March 7, 2007

Last Updated

January 2, 2018

Sponsor

National Cancer Institute (NCI)

1. Study Identification

Unique Protocol Identification Number

NCT00445341

Brief Title

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

2. Study Status

Record Verification Date

January 2018

Overall Recruitment Status

Completed

Study Start Date

November 27, 2006 (Actual)

Primary Completion Date

April 30, 2012 (Actual)

Study Completion Date

October 18, 2012 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

National Cancer Institute (NCI)

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Lymphoma

Keywords

Microarray, Proteomics, Hybrid Schedule, Tumor Lysis Syndrome, Cyclin D1, Lymphoma, Mantle Cell Lymphoma, MCL, Diffuse Large B-Cell Lymphoma, DLBCL

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

28 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Flavopiridol in lymphoma patients

Arm Type

Experimental

Arm Description

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 Type

Drug

Intervention Name(s)

Flavopiridol

Other Intervention Name(s)

alvocidib

Intervention Description

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.

Primary Outcome Measure Information:

Title

Number of Participants With Adverse Events (e.g. Toxicity)

Description

Here is the number of participants with adverse events. For a detailed list of adverse events see the adverse event module.

Time Frame

47 months

Title

Response Rate (Complete Response (CR) and Partial Response (PR))

Description

Time Frame

2/16/2007 - 1/20/2011

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Mark Roschewski, M.D.

Organizational Affiliation

National Cancer Institute (NCI)

Official's Role

Principal Investigator

Facility Information:

Facility Name

National Institutes of Health Clinical Center, 9000 Rockville Pike

City

Bethesda

State/Province

Maryland

ZIP/Postal Code

20892

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

Citations:

PubMed Identifier

8250970

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.

Results Reference

background

PubMed Identifier

9516149

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.

Results Reference

background

PubMed Identifier

15930354

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.

Results Reference

background

Links:

URL

http://clinicalstudies.info.nih.gov/cgi/detail.cgi?B_2007-C-0081.html

Description

NIH Clinical Center Detailed Web Page

Learn more about this trial

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

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