Flavopiridol in Treating Patients With Chronic Lymphocytic Leukemia or Prolymphocytic Leukemia

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Terminated
• CT.gov ID: NCT00098371
• Collaborator: (none)
• Enrollment: 64
• Location: 1
• Arm: 1
• Duration (Months): 91
• Patients Per Site Per Month: 0.7

Study Details

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

Condition or Disease	Intervention/Treatment	Phase
B-cell Chronic Lymphocytic Leukemia; Prolymphocytic Leukemia; Refractory Chronic Lymphocytic Leukemia	Drug: alvocidib	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. To determine the complete response (CR) and overall response rate (CR + Partial Response [PR]) of this regimen.

2. To assess the toxicity profile of this regimen. III. To examine response duration, progression-free survival and overall survival, following this treatment.

3. To assess the pharmacokinetics of this novel schedule of administration.

SECONDARY OBJECTIVES:

1. 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.

2. 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.

3. 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.

4. To examine cytokine levels (IL-6, IFN-gamma, TNF-alpha) during treatment with flavopiridol.

5. 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.

6. 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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 64 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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 Start Date: Apr 1, 2005
• Actual Primary Completion Date: Jun 1, 2009
• Actual Study Completion Date: Nov 1, 2012

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Treatment (alvocidib) 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.

Drug: alvocidib; Other Names: FLAVO flavopiridol HMR 1275 L-868275

Outcome Measures

Primary Outcome Measures

1. Complete Response (CR) Rate [Up to 8 months]

   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.

2. Overall Response Rate (CR + PR) [Up to 8 months]

   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.

3. Response Duration [Up to 8 months]

   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.

4. Progression-free Survival (PFS) for Responding Patients as Assessed Using Standard Kaplan-Meier Methods [Up to 5 years]

   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.

5. Progression-free Survival for All Patients as Assessed Using Standard Kaplan-Meier Methods [Up to 5 years]

   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.

6. Overall Survival [Up to 5 years]

   Overall survival data will be reported on a 3-month basis for 5 years

7. Toxicity [Measurement prior to each infusion, at end of therapy, 2 months post-completion and post-treatment follow-up every 3 months for two years.]

   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

1. Pharmacokinetics (PK) (AUC) as Assessed by Plasma Levels of Both Flavopiridol and Metabolites of Flavopiridol [During treatment day 1 and day 8 of cycle 1]

   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)

2. PK (Cmax) as Assessed by Plasma Levels of Both Flavopiridol and Metabolites of Flavopiridol [During treatment day 1 and day 8 of course 1]

   Pharmacokinetics were performed on day 1 and day 8 of cycle 1 by plasma levels of both flavopiridol and metabolites of flavopiridol

3. PK as Assessed by Levels of Both Flavopiridol and Metabolites of Flavopiridol in Urine Samples [Urine collected at 4 separate times in some patients during the first 24 hours after start of infusion on day 1 of course 1.]

   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.

4. Serial Levels of IL-6 as Assessed by Blood Plasma [4.5 hours, 8 hours, 12 hours, and 24 hours following the initiation of therapy during day 1 of course 1]

   IL-6 measures were adjusted for baseline values

5. Comparison of CLL Cell Samples Taken at Registration/Diagnosis to CLL Cell Samples Taken at Time of Relapse [At baseline and at time of relapse or when patient goes off therapy due to disease progression]

   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.

6. 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 [up to 8 months]

   overall response rates (CR+PR)

7. 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) [At baseline, 4.5 hours (end of continuous infusion), 8 hours, and approximately 24 hours following initiation of therapy]

   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)

8. Comparison of Clinical Response and Tumor Lysis in Vivo With Drug-induced Apoptosis and Mitochondrial Perturbation in Vitro as Assessed by Flow Cytometry [At baseline]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Ohio State University Medical Center	Columbus	Ohio	United States	43210

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: John Byrd, Ohio State University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT00098371
• Other Study ID Numbers: NCI-2009-00111; OSU 0491; N01CM62207
• First Posted: Dec 8, 2004
• Last Update Posted: Oct 24, 2016
• Last Verified: Aug 1, 2016

• Additional relevant MeSH terms: Leukemia; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Prolymphocytic; Alvocidib

Study Results

Participant Flow

Arm/Group Title	Treatment (Alvocidib)
Arm/Group 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.To improve tolerability of treatment regimen, an amendment to the protocol was done to reduce the cycle length from 42 days to 28 days, reducing the number of treatments per cycle from four (days 1, 8, 15 & 22) to three (days 1, 8, and 15).
Period Title: Overall Study
STARTED	64
COMPLETED	64
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Treatment (Alvocidib)
Arm/Group 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.
Overall Participants	64
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	44 68.8%
>=65 years	20 31.3%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	60
Sex: Female, Male (Count of Participants)
Female	22 34.4%
Male	42 65.6%
Region of Enrollment (participants) [Number]
United States	64 100%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

Patients were assessed for clinical response after two, four and six cycles.

Arm/Group Title	Treatment (Alvocidib)
Arm/Group 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.
Measure Participants	64
Number [percent of patients]	2

2. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

Schedule was amended (cycle length) from 42 to 28 days, reduction in the number of doses per cycle from 4 to 3 and administration of prophylactic dexamethasone 20 mg IV on each treatment day.

Arm/Group Title	Treatment (Alvocidib)
Arm/Group 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.
Measure Participants	64
Number (95% Confidence Interval) [percent of patients]	53

3. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

Duration of response was not collected for patients.

Arm/Group Title	Treatment (Alvocidib)
Arm/Group 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.
Measure Participants	0

4. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Alvocidib)
Arm/Group 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.
Measure Participants	34
Median (95% Confidence Interval) [months]	12

5. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Alvocidib)
Arm/Group 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.
Measure Participants	64
Median (95% Confidence Interval) [months]	8.6

6. Primary Outcome

Title	Overall Survival
Description	Overall survival data will be reported on a 3-month basis for 5 years
Time Frame	Up to 5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Alvocidib)
Arm/Group 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.
Measure Participants	64
Median (95% Confidence Interval) [months]	28.8

7. Primary Outcome

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.

Outcome Measure Data

Analysis Population Description

Grade 3 to 4 infections requiring IV antibiotics and were generally related to upper or lower respiratory infections or infections of indwelling central venous catheters.

Arm/Group Title	Treatment (Alvocidib)
Arm/Group 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. alvocidib
Measure Participants	64
Number [percentage of patients]	25

8. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

The values are overall averages for all patients on days 1 and 8 - therefore, there is only a single value for each parameter.

Arm/Group Title	Treatment (Alvocidib)
Arm/Group 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.
Measure Participants	63
Mean (Standard Deviation) [μM*hr]	9.42 (5.11)

9. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

The values are overall averages for all patients on days 1 and 8 - therefore, there is only a single value for each parameter.

Arm/Group Title	Treatment (Alvocidib)
Arm/Group 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.
Measure Participants	63
Mean (Standard Deviation) [μM]	2.04 (1.05)

10. Secondary Outcome

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.

Outcome Measure Data

Analysis Population Description

Data for this PK analysis was not collected and analyzed.

Arm/Group Title	Treatment (Alvocidib)
Arm/Group 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.
Measure Participants	0

11. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

IL-6 expression analysis was available for only day 1 and not day 8.

Arm/Group Title	Group 1	Group 2
Arm/Group Description	Patients without dexamethasone	Patients with dexamethasone
Measure Participants	26	31
4.5 hours	3.5	1.6
8 hours	13.4	2.2
12 hours	25.5	2.5
24 hours	13.2	3.9

12. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Data for this outcome as not collected and analyzed

Arm/Group Title	Treatment (Alvocidib)
Arm/Group 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. alvocidib
Measure Participants	0

13. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Data were not collected and analyzed for VH mutational status, ZAP-70 protein expression, CD38, and p53

Arm/Group Title	Patients With Del(17p13.1)	Patients Without Del(17p13.1)	Patients With Del(11q22.3)	Patients Without Del(11q22.3)	Patients With Complex Karyotype	Patients Without Complex Karyotype
Arm/Group Description	Complex Karyotype defined as three or more cytogenetic aberrations.	Complex Karyotype defined as fewer than three cytogenetic aberrations.
Measure Participants	21	43	28	36	27	37
Number [percentage of patients in each subgroup]	57	51	50	56	48	57

14. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Data was not collected and analyzed for this outcome

Arm/Group Title	Treatment (Alvocidib)
Arm/Group 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.
Measure Participants	0

15. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

A subset of patients who had sufficient material were analyzed according to response only.

Arm/Group Title	Responders	Non-Responders
Arm/Group Description	Patients who achieved a partial response (PR)	Patients who had stable disease (SD) or progressive disease (PD)
Measure Participants	9	4
Mean (Standard Deviation) [percentage of priming cells]	22.2 (16.5)	6.4 (4.3)

Adverse Events

Adverse Event Reporting Description	NCI Common Toxicity Criteria of Adverse Events (version 3) and modified NCI Common Toxicity Criteria guidelines for evaluating hematologic toxicity for leukemia was used to grade adverse events for patients. Adverse events are reported across all grades.
Arm/Group Title	Treatment (Alvocidib)
Arm/Group 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.
All Cause Mortality
	Treatment (Alvocidib)
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Treatment (Alvocidib)
	Affected / at Risk (%)	# Events
Total	4/64 (6.3%)
Infections and infestations
Infection	4/64 (6.3%)	4
Other (Not Including Serious) Adverse Events
	Treatment (Alvocidib)
	Affected / at Risk (%)	# Events
Total	64/64 (100%)
Blood and lymphatic system disorders
Anemia	38/64 (59.4%)	38
Gastrointestinal disorders
Diarrhea	60/64 (93.8%)	60
Nausea and Vomiting	48/64 (75%)	48
General disorders
Fatigue	60/64 (93.8%)	60
Immune system disorders
Cytokine Release Syndrome	27/64 (42.2%)	27
Infections and infestations
Infection	43/64 (67.2%)	43
Injury, poisoning and procedural complications
Thrombocytopenia	42/64 (65.6%)	42
Investigations
Neutropenia	62/64 (96.9%)	62
Transaminitis	59/64 (92.2%)	59
Hyperbilirubinemia	15/64 (23.4%)	15
Metabolism and nutrition disorders
Anorexia	20/64 (31.3%)	20
Tumor Lysis Syndrome	28/64 (43.8%)	28
Psychiatric disorders
Anxiety/Depression	11/64 (17.2%)	11

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.