Flavopiridol in Treating Patients With Chronic Lymphocytic Leukemia or Prolymphocytic Leukemia

NCT00098371 | Terminated Phase 2 Results

• 3 other identifiers: NCI-2009-00111OSU 0491N01CM62207
• Study Type: interventional
• Target: 64
• Locations: 1 country
• Sites: 1

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

Conditions

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

Outcome Measures

Primary Outcomes (7)

• 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.

  Up to 8 months

• 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.

  Up to 8 months

• 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.

  Up to 8 months

• 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.

  Up to 5 years

• 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.

  Up to 5 years

• Overall Survival

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

  Up to 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.

  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 (8)

• 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

• PK (Cmax) as Assessed by Plasma Levels of Both Flavopiridol and Metabolites of Flavopiridol

  During treatment day 1 and day 8 of course 1

• 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.

• 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

• 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

Study Arms (1)

Treatment (alvocidib)

EXPERIMENTAL

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

Interventions

alvocidib DRUG

Also known as: FLAVO, flavopiridol, HMR 1275, L-868275

Treatment (alvocidib)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

Ohio State University Medical Center

Columbus, Ohio, 43210, United States

Location

Related Publications (4)

• 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.

  PMID: 19826119 RESULT

• 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.

  PMID: 24990615 RESULT

• 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.

  PMID: 22289993 RESULT

• 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.

  PMID: 25596730 DERIVED

MeSH Terms

Conditions

Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Prolymphocytic

Interventions

alvocidib

Condition Hierarchy (Ancestors)

Leukemia, B-Cell; Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Results Point of Contact

• Title: John Byrd, MD
• Organization: The Ohio State University Comprehensive Cancer Center

John.Byrd@osumc.edu

614-293-9869

Study Officials

• John Byrd

  Ohio State University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 7, 2004
• First Posted: December 8, 2004
• Study Start: April 1, 2005
• Primary Completion: June 1, 2009
• Study Completion: November 1, 2012
• Last Updated: October 24, 2016
• Results First Posted: October 24, 2016

Record last verified: 2016-08

Locations

US (1)