Chronic Lymphocytic Leukemia Clinical Trial
Official title:
Phase I-II Study of Low Dose CdA Combined With Valproic Acid (VPA) in Previously Treated B-cell Chronic Lymphocytic Leukemia (CLL) Patients
Rationale New chemotherapeutic agents are needed in relapsing B-Cell Chronic Lymphocytic
Leukemia (B-CLL) to overcome resistance of CLL cells. Valproic acid (VPA) is an inhibitor of
histone deacetylase (HDAC) used as an anticonvulsant and mood-stabilizing drug for decades.
VPA mediates apoptosis in CLL cells through caspase activation. VPA shows toxicity toward
CLL cells displaying alterations in the p53 pathway. The combination of VPA with fludarabine
or 2-Chlorodeoxyadenosine (CdA, Cladribine) results in synergistic loss of B-CLL cell
viability, and significant increase in apoptosis. The highest index of synergism is observed
between VPA and CdA, a purine nucleoside analog active in B-CLL.
Study design Overall, the study will be proposed to previously treated patients with
advanced B-CLL, who are not eligible for aggressive approaches, and who exhibit progressive
disease. A total of 33 patients will be included. Estimated enrolment time is 2 years.
- First part: It is planned to start therapy with single VPA during 2 months, targeting
plasma levels that have been reported to be active in vitro toward CLL cells (but that
do not exceed therapeutic levels in seizure prevention), and in parallel, to verify
whether cellular targets of VPA have been actually inhibited in leukemic B-lymphocytes.
- Second part: After the VPA preloading period (2 months), patients will be evaluated to
receive CdA. CdA will be given at 5.6 mg/m²/day intravenously during 3 days, a
reduced-dose schedule which is less toxic - at no obvious cost of loss of efficacy - as
compared to the standard dosage of 5 days. CdA was chosen because it displays the
highest level of in vitro synergism with VPA. Four monthly courses of CdA will be
given. Patients will then be evaluated. VPA will be stopped at the time of response
evaluation (scheduled 28 days after the last course of CdA).
n/a
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
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