HDAC Inhibitor Valproic Acid as an Effective Therapy for Chronic Lymphocytic Leukemia
18 Years
N/A
Both
Chronic Lymphocytic Leukemia
Trial Information
HDAC Inhibitor Valproic Acid as an Effective Therapy for Chronic Lymphocytic Leukemia
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.
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
Type of Study:
Interventional
Study Design:
Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Outcome Measure:
Best clinical response as defined by NCIWG criteria for CLL
Outcome Time Frame:
6 months after commencing therapy
Safety Issue:
No
Principal Investigator
David Szwajcer, MD
Investigator Role:
Principal Investigator
Investigator Affiliation:
CancerCare Manitoba / University of Manitoba
Authority:
Canada: Health Canada
Study ID:
CCM-001
NCT ID:
NCT00524667
Start Date:
January 2008
Completion Date:
July 2011
Related Keywords:
- Chronic Lymphocytic Leukemia
- Active CLL
- Leukemia
- Leukemia, Lymphocytic, Chronic, B-Cell
- Leukemia, Lymphoid
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