HDAC Inhibitor Valproic Acid as an Effective Therapy for Chronic Lymphocytic Leukemia

July 18, 2011 updated by: CancerCare Manitoba

OBJECTIVES

To investigate:

  • the mechanism of Valproic Acid (VPA)-induced apoptosis in B-CLL
  • the ability of VPA in combination with standard chemotherapy or new antitumor agents to induce a synergistic antitumor effect in chronic lymphocytic leukemia (CLL) cells
  • the clinical efficacy of VPA in previously treated CLL patients.

This will be an example of a translational research study where the results of our laboratory studies will be applied to a clinical trial in the CLL clinic at CancerCare Manitoba.

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

Detailed Description

All participants will be treated with valproic acid (VPA) at a starting dose of 15 mg/kg/day orally in divided doses. This dose produces a VPA plasma level of 346-693 μM and is the recommended starting dose for patients with seizure disorder. Each week a pre-dose serum VPA level will be determined by immunoassay and the daily dose increased by 5 mg/kg/d to ensure a predose level > 1mM. Once the target dose has been achieved serum VPA levels will be determined on a monthly basis to ensure a pre dose level >1mM.

After completing 28 days of therapy participants will be examined and have lab work drawn (CBC with differential, electrolytes, BUN, creatinine, total protein, albumin, calcium, LDH, total and direct bilirubin, ALT/AST, and β2-microglobulin. Females of child bearing age will undergo a pregnancy test prior to each 28 day cycle). For participants identified as having stable or progressive disease (National Cancer Institute Criteria), Fludarabine (Flu) therapy will be added to VPA on a 28 day cycle. Oral Flu will be administered at a dose of 40 mg/m2/day on days 1-3 of a 28 day cycle in addition to VPA as described above. Dose adjustments for Flu will be based on creatinine clearance. All participants receiving fludarabine will receive irradiated blood products and pneumocystis carnii prophylaxis.

Treatment will be continued with VPA ± Flu to a maximum of six 28 day cycles. Therapy will be discontinued prior to six 28 day cycles if: a) the participant requests discontinuation, b) if the participant is unable to comply with the protocol, c) the medical care team thinks a change of therapy would be in the best interest of the participant, d) there is evidence of progressive disease after two cycles of VPA + Flu, e) if the participant experiences unacceptable toxicity attributable to the study drugs such as ≥3 non-hematological toxicity or prolonged grade 4 hematological toxicity (NCI common toxicity criteria, Table 5 of the protocol), f) if the AST/ALT increase to > 6x the upper limit of normal or g) the participant becomes pregnant.

Study Type

Interventional

Enrollment (Actual)

6

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Canada
    • Manitoba
      • Winnipeg, Manitoba, Canada, R3E 0V9
        • CancerCare Manitoba

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Active CLL (as defined by the National Cancer Institute Working Group)
  • Patients must have received at least one prior therapy for CLL and have been treated with a nucleoside analogue.
  • Recruitment will be limited to those with an ECOG performance status of 2 or less.

Exclusion Criteria:

  • Patients who are pregnant or breastfeeding
  • Patients with a history of autoimmune cytopenias
  • Patients with platelets < 50 x 109/L or an absolute neutrophil count < 1.5X109/L
  • Patients with hepatic disease or an AST/ALT 6x above the upper limit of normal
  • Patients with a calculated creatinine clearance < 30 ml/min using the Cockroft and Gault formula
  • Patients with a history of pancreatitis
  • Patients who are receiving drugs that affect VPA protein binding or metabolism
  • Patients with active infection, HIV or active viral hepatitis
  • Patients with active secondary malignancy or who have central nervous system involvement with CLL
  • Patients diagnosed with more an aggressive lymphoproliferative disorder such as Richter's transformation

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: 1
Drug: Valproic acid & fludarabine
valproic acid (VPA) starting dose of 15 mg/day p.o. in divided doses, increased weekly by 5 mg/kg/day until >1mM Fludarabine 40 mg/m2/day orally will be added after completing 28 days of VPA if participant has been identified as having stable or progressive disease.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Best clinical response as defined by NCIWG criteria for CLL
Time Frame: 6 months after commencing therapy
6 months after commencing therapy

Secondary Outcome Measures

Outcome Measure
Time Frame
Effect of treatment on histone acetylation status; hematological toxicity (graded according to NCIWG criteria for CLL) and nonhematological toxicity (graded according to NCI common toxicity criteria)
Time Frame: throughout therapy
throughout therapy

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

CancerCare Manitoba

Collaborators

The Leukemia and Lymphoma Society

Investigators

  • Principal Investigator: David Szwajcer, MD, CancerCare Manitoba / University of Manitoba

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

January 1, 2008

Primary Completion (Actual)

July 1, 2011

Study Completion (Actual)

July 1, 2011

Study Registration Dates

First Submitted

August 31, 2007

First Submitted That Met QC Criteria

August 31, 2007

First Posted (Estimate)

September 3, 2007

Study Record Updates

Last Update Posted (Estimate)

July 20, 2011

Last Update Submitted That Met QC Criteria

July 18, 2011

Last Verified

July 1, 2011

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • CCM-001

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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