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Flavopiridol in Treating Patients With Chronic Lymphocytic Leukemia or Prolymphocytic Leukemia

Primary Purpose

B-cell Chronic Lymphocytic Leukemia, Prolymphocytic Leukemia, Refractory Chronic Lymphocytic Leukemia

Status
Terminated
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
alvocidib
Sponsored by
National Cancer Institute (NCI)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for B-cell Chronic Lymphocytic Leukemia

Eligibility Criteria

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

Inclusion Criteria: Histologically confirmed B-cell chronic lymphocytic leukemia (CLL) or prolymphocytic leukemia (PLL) arising from CLL No de novo PLL Lymphocyte count > 5,000/mm^3 at some point since initial diagnosis of CLL B-cells co-expressing CD5 AND CD19 or CD20 If no dim serum immunoglobulin or CD23 expression on leukemia cells, must be examined for cyclin D1 overexpression OR t(11;14) to rule out mantle cell lymphoma Requiring therapy, defined by any of the following: Massive or progressive splenomegaly and/or lymphadenopathy Anemia (hemoglobin < 11 g/dL) OR thrombocytopenia (platelet count < 100,000/mm^3) Weight loss > 10% within the past 6 months Grade 2 or 3 fatigue Fevers > 100.5°C or night sweats for > 2 weeks with no evidence of infection Progressive lymphocytosis with an increase of > 50% over a 2-month period OR an anticipated doubling time < 6 months Received ≥ 1 prior chemotherapy regimen that included fludarabine or nucleoside equivalent OR alternative therapy if contraindication to fludarabine exists (i.e., autoimmune hemolytic anemia) Performance status - ECOG 0-2 More than 2 years See Disease Characteristics Baseline cytopenias allowed WBC ≤ 200,000/mm^3 Bilirubin ≤ 1.5 times upper limit of normal (ULN) (unless due to Gilbert's disease, hemolysis, or disease infiltration of the liver) AST ≤ 2 times ULN (unless due to hemolysis or disease infiltration of the liver) Creatinine ≤ 2.0 mg/dL Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No other malignancy that would limit life expectancy See Disease Characteristics No other concurrent chemotherapy No concurrent chronic corticosteroids or corticosteroids as antiemetics No concurrent hormonal therapy except steroids for new adrenal failure or hormones for nondisease-related conditions (e.g., insulin for diabetes) No concurrent radiotherapy

Sites / Locations

  • Ohio State University Medical Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (alvocidib)

Arm Description

Patients receive flavopiridol IV over 30 minutes followed by a 4-hour infusion on days 1, 8, 15, and 22. Treatment repeats every 42 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients achieving at least a partial remission (PR) and whose PR lasts for > 6 months after completion of treatment may receive 6 additional courses of flavopiridol.

Outcomes

Primary Outcome Measures

Complete Response (CR) Rate
CR requires all of the following for at least two months from completion of therapy: Absence of lymphadenopathy in excess of 1 cm on physical exam; No hepatomegaly or splenomegaly on physical exam; Absence of constitutional symptoms; Normal CBC (complete blood count) as exhibited by polymorphonuclear leukocytes > 1500/µL, platelets > 100,000/µL, hemoglobin > 11.0 g/dl (untransfused); lymphocyte count < 5,000/µL; Bone marrow aspirate and biopsy must be normocellular for age with < 30% of nucleated cells being lymphocytes. Lymphoid nodules must be absent.
Overall Response Rate (CR + PR)
CR requires all of the following: Absence of lymphadenopathy in excess of 1 cm on physical exam; No hepatomegaly or splenomegaly on physical exam; Absence of constitutional symptoms; Normal CBC as exhibited by polymorphonuclear leukocytes > 1500/µL, platelets > 100,000/µL, hemoglobin > 11.0 g/dl (untransfused); lymphocyte count < 5,000/µL; Bone marrow aspirate and biopsy must be normocellular for age with < 30% of nucleated cells being lymphocytes. Lymphoid nodules must be absent. Patients with CR after induction but wih treatment-related persistent cytopenia is a PR. PR requires a > 50% decrease in peripheral lymphocyte count from pretreatment value, > 50% reduction in lymphadenopathy, and/or > 50% reduction in splenomegaly/hepatomegaly. These patients must have one of the following: polymorphonuclear leukocytes > 1,500/μL , platelets > 100,000/μL, hemoglobin > 11.0 g/dl (untransfused) or any with 50% improvement from pretreatment value.
Response Duration
Response evaluation criteria based on the Revised National Cancer Institute-sponsored Working Group Guidelines for response. Descriptive statistics will be computed (median, range, mean, standard deviation, minimum, and maximum) on response duration.
Progression-free Survival (PFS) for Responding Patients as Assessed Using Standard Kaplan-Meier Methods
PFS was calculated from the date of study entry until time of disease progression or death, whichever came first, censoring patients alive and relapse free at last follow up. Patients who withdrew from study to undergo an allogeneic SCT (Stem cell transplantation) were censored at the time of transplantation.
Progression-free Survival for All Patients as Assessed Using Standard Kaplan-Meier Methods
PFS was calculated from the date of study entry until time of disease progression or death, whichever came first, censoring patients alive and relapse free at last follow up. Patients who withdrew from study to undergo an allogeneic SCT were censored at the time of transplantation.
Overall Survival
Overall survival data will be reported on a 3-month basis for 5 years
Toxicity
Toxicity determination based on NCI Common Toxicity Criteria version 3 and modified NCI Common toxicity guidelines for evaluating hematologic toxicity in leukemia.

Secondary Outcome Measures

Pharmacokinetics (PK) (AUC) as Assessed by Plasma Levels of Both Flavopiridol and Metabolites of Flavopiridol
Pharmacokinetics were performed on day 1 and day 8 of cycle 1 by plasma levels of both flavopiridol and metabolites of flavopiridol using Area Under the Curve (AUC)
PK (Cmax) as Assessed by Plasma Levels of Both Flavopiridol and Metabolites of Flavopiridol
Pharmacokinetics were performed on day 1 and day 8 of cycle 1 by plasma levels of both flavopiridol and metabolites of flavopiridol
PK as Assessed by Levels of Both Flavopiridol and Metabolites of Flavopiridol in Urine Samples
urine samples were collected in some patients during the first 24 hours after the start of the infusion on cycle 1, day 1 to isolate metabolites of flavopiridol to be used as internal standard for plasma metabolite quantification experiments.
Serial Levels of IL-6 as Assessed by Blood Plasma
IL-6 measures were adjusted for baseline values
Comparison of CLL Cell Samples Taken at Registration/Diagnosis to CLL Cell Samples Taken at Time of Relapse
Samples will be examined for ex vivo sensitivity to flavopiridol, expression of select anti-apoptosis proteins, BCRP mRNA and protein expression, difference in gene expression by cDNA microarray and potentially by epigenetic arrays. Comparisons will be used to evaluate mechanisms of acquired flavopiridol resistance.
Correlation of Adverse Prognostic Factors With Response to Flavopiridol Treatment as Assessed by Interphase Cytogenetics, VH Mutational Status, ZAP-70 Protein Expression, CD38, and p53
overall response rates (CR+PR)
Levels of Mcl-1 mRNA, Mcl-1 Protein, HIF-1alpha Protein, HIF-1alpha mRNA, NF-kappaB Activation, Total IkB, IkB Phosphorylation, GSK-beta Activity, and IL-6 Target Genes (i.e., STAT3)
Assessed by real time RT-PCR (mcl-1, HIF-1alpha), immunoblot analysis (mcl-1, HIF-1alpha, I-kappaB, I-kappaB phosphorylation, targets of IL-6), and electrophoretic mobility shift analysis (NF-kappaB activation)
Comparison of Clinical Response and Tumor Lysis in Vivo With Drug-induced Apoptosis and Mitochondrial Perturbation in Vitro as Assessed by Flow Cytometry
CLL cells will be incubated with control or flavopiridol (1 or 2.8 microMolar) for 4-hours followed by a 20 hours in media with 10% heat-inactivated human serum. Assessment of apoptosis following exposure of human CLL cells will be performed using annexin/PI flow cytometry. Patient samples with greater than 50% live cells (annexin-/PI-) following exposure to 2.8 microMolar flavopiridol will be considered to have insensitive disease. Patients whose CLL cells have less than 50% live cells at 1 microMolar will be considered to have highly sensitive disease.

Full Information

First Posted
December 7, 2004
Last Updated
August 31, 2016
Sponsor
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT00098371
Brief Title
Flavopiridol in Treating Patients With Chronic Lymphocytic Leukemia or Prolymphocytic Leukemia
Official Title
A Phase II Study of Flavopiridol Administered as a 30 Minute Loading Dose Followed by a 4-Hour Continuous Infusion in Patients With Previously Treated B-Cell Chronic Lymphocytic Leukemia or Prolymphocytic Leukemia Arising From CLL
Study Type
Interventional

2. Study Status

Record Verification Date
August 2016
Overall Recruitment Status
Terminated
Why Stopped
CTEP Initiated Action.
Study Start Date
April 2005 (undefined)
Primary Completion Date
June 2009 (Actual)
Study Completion Date
November 2012 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Cancer Institute (NCI)

4. Oversight

5. Study Description

Brief Summary
This phase II trial is studying how well flavopiridol works in treating patients with chronic lymphocytic leukemia or prolymphocytic leukemia. Drugs used in chemotherapy, such as flavopiridol, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing
Detailed Description
PRIMARY OBJECTIVES: I. To determine the complete response (CR) and overall response rate (CR + Partial Response [PR]) of this regimen. II. To assess the toxicity profile of this regimen. III. To examine response duration, progression-free survival and overall survival, following this treatment. IV. To assess the pharmacokinetics of this novel schedule of administration. SECONDARY OBJECTIVES: I. To determine the influence of adverse prognostic factors including interphase cytogenetics, VH mutational status, ZAP-70 expression, CD38, and p53 mutational status with response to flavopiridol treatment. II. To determine the influence of flavopiridol treatment on serial measurements of mcl-1 (mRNA and protein), HIF-1 (mRNA and protein), NF-kappaB activity, IkappaB, IkappaB phosphorylation, GSK-beta, and IL-6 down-stream targets. III. To assess the relationship of drug induced apoptosis and mitochondrial perturbation of Chronic Lymphocytic Leukemia (CLL) cells in vitro and subsequent relationship to clinical response and tumor lysis in vivo. IV. To examine cytokine levels (IL-6, IFN-gamma, TNF-alpha) during treatment with flavopiridol. V. To assess pharmacokinetics (PK) to determine the variability of PK and PD analyses between treatment administrations and correlation with specific Single Nucleotide Polymorphisms (SNPs) potentially involved in flavopiridol disposition. VI. To assess differences in diagnosis and relapse samples to investigate mechanisms of acquired flavopiridol resistance in primary CLL cells. OUTLINE: This is an open-label study. Patients receive flavopiridol IV over 30 minutes followed by a 4-hour infusion on days 1, 8, 15, and 22. Treatment repeats every 42 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients achieving at least a partial remission (PR) and whose PR lasts for > 6 months after completion of treatment may receive 6 additional courses of flavopiridol.Patients are followed at 2 months and then every 3 months for 5 years.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
B-cell Chronic Lymphocytic Leukemia, Prolymphocytic Leukemia, Refractory Chronic Lymphocytic Leukemia

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
64 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Treatment (alvocidib)
Arm Type
Experimental
Arm Description
Patients receive flavopiridol IV over 30 minutes followed by a 4-hour infusion on days 1, 8, 15, and 22. Treatment repeats every 42 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients achieving at least a partial remission (PR) and whose PR lasts for > 6 months after completion of treatment may receive 6 additional courses of flavopiridol.
Intervention Type
Drug
Intervention Name(s)
alvocidib
Other Intervention Name(s)
FLAVO, flavopiridol, HMR 1275, L-868275
Primary Outcome Measure Information:
Title
Complete Response (CR) Rate
Description
CR requires all of the following for at least two months from completion of therapy: Absence of lymphadenopathy in excess of 1 cm on physical exam; No hepatomegaly or splenomegaly on physical exam; Absence of constitutional symptoms; Normal CBC (complete blood count) as exhibited by polymorphonuclear leukocytes > 1500/µL, platelets > 100,000/µL, hemoglobin > 11.0 g/dl (untransfused); lymphocyte count < 5,000/µL; Bone marrow aspirate and biopsy must be normocellular for age with < 30% of nucleated cells being lymphocytes. Lymphoid nodules must be absent.
Time Frame
Up to 8 months
Title
Overall Response Rate (CR + PR)
Description
CR requires all of the following: Absence of lymphadenopathy in excess of 1 cm on physical exam; No hepatomegaly or splenomegaly on physical exam; Absence of constitutional symptoms; Normal CBC as exhibited by polymorphonuclear leukocytes > 1500/µL, platelets > 100,000/µL, hemoglobin > 11.0 g/dl (untransfused); lymphocyte count < 5,000/µL; Bone marrow aspirate and biopsy must be normocellular for age with < 30% of nucleated cells being lymphocytes. Lymphoid nodules must be absent. Patients with CR after induction but wih treatment-related persistent cytopenia is a PR. PR requires a > 50% decrease in peripheral lymphocyte count from pretreatment value, > 50% reduction in lymphadenopathy, and/or > 50% reduction in splenomegaly/hepatomegaly. These patients must have one of the following: polymorphonuclear leukocytes > 1,500/μL , platelets > 100,000/μL, hemoglobin > 11.0 g/dl (untransfused) or any with 50% improvement from pretreatment value.
Time Frame
Up to 8 months
Title
Response Duration
Description
Response evaluation criteria based on the Revised National Cancer Institute-sponsored Working Group Guidelines for response. Descriptive statistics will be computed (median, range, mean, standard deviation, minimum, and maximum) on response duration.
Time Frame
Up to 8 months
Title
Progression-free Survival (PFS) for Responding Patients as Assessed Using Standard Kaplan-Meier Methods
Description
PFS was calculated from the date of study entry until time of disease progression or death, whichever came first, censoring patients alive and relapse free at last follow up. Patients who withdrew from study to undergo an allogeneic SCT (Stem cell transplantation) were censored at the time of transplantation.
Time Frame
Up to 5 years
Title
Progression-free Survival for All Patients as Assessed Using Standard Kaplan-Meier Methods
Description
PFS was calculated from the date of study entry until time of disease progression or death, whichever came first, censoring patients alive and relapse free at last follow up. Patients who withdrew from study to undergo an allogeneic SCT were censored at the time of transplantation.
Time Frame
Up to 5 years
Title
Overall Survival
Description
Overall survival data will be reported on a 3-month basis for 5 years
Time Frame
Up to 5 years
Title
Toxicity
Description
Toxicity determination based on NCI Common Toxicity Criteria version 3 and modified NCI Common toxicity guidelines for evaluating hematologic toxicity in leukemia.
Time Frame
Measurement prior to each infusion, at end of therapy, 2 months post-completion and post-treatment follow-up every 3 months for two years.
Secondary Outcome Measure Information:
Title
Pharmacokinetics (PK) (AUC) as Assessed by Plasma Levels of Both Flavopiridol and Metabolites of Flavopiridol
Description
Pharmacokinetics were performed on day 1 and day 8 of cycle 1 by plasma levels of both flavopiridol and metabolites of flavopiridol using Area Under the Curve (AUC)
Time Frame
During treatment day 1 and day 8 of cycle 1
Title
PK (Cmax) as Assessed by Plasma Levels of Both Flavopiridol and Metabolites of Flavopiridol
Description
Pharmacokinetics were performed on day 1 and day 8 of cycle 1 by plasma levels of both flavopiridol and metabolites of flavopiridol
Time Frame
During treatment day 1 and day 8 of course 1
Title
PK as Assessed by Levels of Both Flavopiridol and Metabolites of Flavopiridol in Urine Samples
Description
urine samples were collected in some patients during the first 24 hours after the start of the infusion on cycle 1, day 1 to isolate metabolites of flavopiridol to be used as internal standard for plasma metabolite quantification experiments.
Time Frame
Urine collected at 4 separate times in some patients during the first 24 hours after start of infusion on day 1 of course 1.
Title
Serial Levels of IL-6 as Assessed by Blood Plasma
Description
IL-6 measures were adjusted for baseline values
Time Frame
4.5 hours, 8 hours, 12 hours, and 24 hours following the initiation of therapy during day 1 of course 1
Title
Comparison of CLL Cell Samples Taken at Registration/Diagnosis to CLL Cell Samples Taken at Time of Relapse
Description
Samples will be examined for ex vivo sensitivity to flavopiridol, expression of select anti-apoptosis proteins, BCRP mRNA and protein expression, difference in gene expression by cDNA microarray and potentially by epigenetic arrays. Comparisons will be used to evaluate mechanisms of acquired flavopiridol resistance.
Time Frame
At baseline and at time of relapse or when patient goes off therapy due to disease progression
Title
Correlation of Adverse Prognostic Factors With Response to Flavopiridol Treatment as Assessed by Interphase Cytogenetics, VH Mutational Status, ZAP-70 Protein Expression, CD38, and p53
Description
overall response rates (CR+PR)
Time Frame
up to 8 months
Title
Levels of Mcl-1 mRNA, Mcl-1 Protein, HIF-1alpha Protein, HIF-1alpha mRNA, NF-kappaB Activation, Total IkB, IkB Phosphorylation, GSK-beta Activity, and IL-6 Target Genes (i.e., STAT3)
Description
Assessed by real time RT-PCR (mcl-1, HIF-1alpha), immunoblot analysis (mcl-1, HIF-1alpha, I-kappaB, I-kappaB phosphorylation, targets of IL-6), and electrophoretic mobility shift analysis (NF-kappaB activation)
Time Frame
At baseline, 4.5 hours (end of continuous infusion), 8 hours, and approximately 24 hours following initiation of therapy
Title
Comparison of Clinical Response and Tumor Lysis in Vivo With Drug-induced Apoptosis and Mitochondrial Perturbation in Vitro as Assessed by Flow Cytometry
Description
CLL cells will be incubated with control or flavopiridol (1 or 2.8 microMolar) for 4-hours followed by a 20 hours in media with 10% heat-inactivated human serum. Assessment of apoptosis following exposure of human CLL cells will be performed using annexin/PI flow cytometry. Patient samples with greater than 50% live cells (annexin-/PI-) following exposure to 2.8 microMolar flavopiridol will be considered to have insensitive disease. Patients whose CLL cells have less than 50% live cells at 1 microMolar will be considered to have highly sensitive disease.
Time Frame
At baseline

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Histologically confirmed B-cell chronic lymphocytic leukemia (CLL) or prolymphocytic leukemia (PLL) arising from CLL No de novo PLL Lymphocyte count > 5,000/mm^3 at some point since initial diagnosis of CLL B-cells co-expressing CD5 AND CD19 or CD20 If no dim serum immunoglobulin or CD23 expression on leukemia cells, must be examined for cyclin D1 overexpression OR t(11;14) to rule out mantle cell lymphoma Requiring therapy, defined by any of the following: Massive or progressive splenomegaly and/or lymphadenopathy Anemia (hemoglobin < 11 g/dL) OR thrombocytopenia (platelet count < 100,000/mm^3) Weight loss > 10% within the past 6 months Grade 2 or 3 fatigue Fevers > 100.5°C or night sweats for > 2 weeks with no evidence of infection Progressive lymphocytosis with an increase of > 50% over a 2-month period OR an anticipated doubling time < 6 months Received ≥ 1 prior chemotherapy regimen that included fludarabine or nucleoside equivalent OR alternative therapy if contraindication to fludarabine exists (i.e., autoimmune hemolytic anemia) Performance status - ECOG 0-2 More than 2 years See Disease Characteristics Baseline cytopenias allowed WBC ≤ 200,000/mm^3 Bilirubin ≤ 1.5 times upper limit of normal (ULN) (unless due to Gilbert's disease, hemolysis, or disease infiltration of the liver) AST ≤ 2 times ULN (unless due to hemolysis or disease infiltration of the liver) Creatinine ≤ 2.0 mg/dL Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No other malignancy that would limit life expectancy See Disease Characteristics No other concurrent chemotherapy No concurrent chronic corticosteroids or corticosteroids as antiemetics No concurrent hormonal therapy except steroids for new adrenal failure or hormones for nondisease-related conditions (e.g., insulin for diabetes) No concurrent radiotherapy
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
John Byrd
Organizational Affiliation
Ohio State University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Ohio State University Medical Center
City
Columbus
State/Province
Ohio
ZIP/Postal Code
43210
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
19826119
Citation
Lin TS, Ruppert AS, Johnson AJ, Fischer B, Heerema NA, Andritsos LA, Blum KA, Flynn JM, Jones JA, Hu W, Moran ME, Mitchell SM, Smith LL, Wagner AJ, Raymond CA, Schaaf LJ, Phelps MA, Villalona-Calero MA, Grever MR, Byrd JC. Phase II study of flavopiridol in relapsed chronic lymphocytic leukemia demonstrating high response rates in genetically high-risk disease. J Clin Oncol. 2009 Dec 10;27(35):6012-8. doi: 10.1200/JCO.2009.22.6944. Epub 2009 Oct 13.
Results Reference
result
PubMed Identifier
24990615
Citation
Pierceall WE, Warner SL, Lena RJ, Doykan C, Blake N, Elashoff M, Hoff DV, Bearss DJ, Cardone MH, Andritsos L, Byrd JC, Lanasa MC, Grever MR, Johnson AJ. Mitochondrial priming of chronic lymphocytic leukemia patients associates Bcl-xL dependence with alvocidib response. Leukemia. 2014 Nov;28(11):2251-4. doi: 10.1038/leu.2014.206. Epub 2014 Jul 3. No abstract available.
Results Reference
result
PubMed Identifier
22289993
Citation
Woyach JA, Lozanski G, Ruppert AS, Lozanski A, Blum KA, Jones JA, Flynn JM, Johnson AJ, Grever MR, Heerema NA, Byrd JC. Outcome of patients with relapsed or refractory chronic lymphocytic leukemia treated with flavopiridol: impact of genetic features. Leukemia. 2012 Jun;26(6):1442-4. doi: 10.1038/leu.2011.375. Epub 2012 Jan 13. No abstract available.
Results Reference
result
PubMed Identifier
25596730
Citation
Yeh YY, Chen R, Hessler J, Mahoney E, Lehman AM, Heerema NA, Grever MR, Plunkett W, Byrd JC, Johnson AJ. Up-regulation of CDK9 kinase activity and Mcl-1 stability contributes to the acquired resistance to cyclin-dependent kinase inhibitors in leukemia. Oncotarget. 2015 Feb 20;6(5):2667-79. doi: 10.18632/oncotarget.2096.
Results Reference
derived

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Flavopiridol in Treating Patients With Chronic Lymphocytic Leukemia or Prolymphocytic Leukemia

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