Clinical trial NCT00098371: 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
Overall status: TERMINATED
Phase: PHASE2
Conditions: B-cell Chronic Lymphocytic Leukemia
Prolymphocytic Leukemia
Refractory Chronic Lymphocytic Leukemia
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2004-12-08
Enrollment: 64
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: 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.

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

Primary outcomes:
measure: Complete Response (CR) Rate
timeFrame: Up to 8 months
measure: Overall Response Rate (CR + PR)
timeFrame: Up to 8 months
measure: Response Duration
timeFrame: Up to 8 months
measure: Progression-free Survival (PFS) for Responding Patients as Assessed Using Standard Kaplan-Meier Methods
timeFrame: Up to 5 years
measure: Progression-free Survival for All Patients as Assessed Using Standard Kaplan-Meier Methods
timeFrame: Up to 5 years
measure: Overall Survival
timeFrame: Up to 5 years
measure: Toxicity
timeFrame: 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 outcomes:
measure: Pharmacokinetics (PK) (AUC) as Assessed by Plasma Levels of Both Flavopiridol and Metabolites of Flavopiridol
timeFrame: During treatment day 1 and day 8 of cycle 1
measure: PK (Cmax) as Assessed by Plasma Levels of Both Flavopiridol and Metabolites of Flavopiridol
timeFrame: During treatment day 1 and day 8 of course 1
measure: PK as Assessed by Levels of Both Flavopiridol and Metabolites of Flavopiridol in Urine Samples
timeFrame: Urine collected at 4 separate times in some patients during the first 24 hours after start of infusion on day 1 of course 1.
measure: Serial Levels of IL-6 as Assessed by Blood Plasma
timeFrame: 4.5 hours, 8 hours, 12 hours, and 24 hours following the initiation of therapy during day 1 of course 1
measure: Comparison of CLL Cell Samples Taken at Registration/Diagnosis to CLL Cell Samples Taken at Time of Relapse
timeFrame: At baseline and at time of relapse or when patient goes off therapy due to disease progression
measure: 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
timeFrame: up to 8 months
measure: 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)
timeFrame: At baseline, 4.5 hours (end of continuous infusion), 8 hours, and approximately 24 hours following initiation of therapy
measure: Comparison of Clinical Response and Tumor Lysis in Vivo With Drug-induced Apoptosis and Mitochondrial Perturbation in Vitro as Assessed by Flow Cytometry
timeFrame: At baseline
Other outcomes:
Locations:
city: Columbus
country: United States
facility: Ohio State University Medical Center
state: Ohio
Study officials:
affiliation: Ohio State University
name: John Byrd
role: PRINCIPAL_INVESTIGATOR
References:
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.
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.
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.
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.