A Pilot Study of Sorafenib in Patients With Acute Myeloid Leukemia as Peri-Transplant Remission Maintenance
I. Determine the toxicity and safety of incorporation of sorafenib tosylate (sorafenib) into
the pre- or post-transplant maintenance setting for three types of transplants.
I. Improvement of 2 year disease free survival after bone marrow transplant by 25% based on
a baseline relapse free survival at two years of 30%.
II. Secondary graft failure is defined as the decline in neutrophil count to < 500/cu mm
after achieving engraftment which is unrelated to infection or drug effect (sorafenib?) and
is unresponsive to stimulation by growth factors.
III. NRM is defined, as death in the absence of competing risks, relapse or progression of
disease. This secondary endpoint will be characterized and presented as a cumulative
incidence at day 100 and at 1 year after BMT.
IV. Survival without relapse or death (DFS) or without death (OS) will be determined and
presented as Kaplan-Meier estimates at 1 and 2 years post-transplant.
V. Patients will be evaluated for chronic GVHD both as described in the NIH consensus
project guidelines and by conventional criteria. The first day of chronic GVHD onset will be
used to calculate cumulative incidence curves using the competing risk method. Graft
failure, relapse or death without GVHD is considered competing risks for GVHD.
I. Patients will undergo serial examinations of bone marrow during the maintenance
treatments evaluating MRD by flow cytometry and FLT3 suppression by western blot analysis
and PIA. Samples will be collected to assess sorafenib and the N-oxide metabolite (total and
unbound) exposure to correlate with pharmacodynamic endpoints.
OUTLINE: Patients are stratified according to type of transplant (myeloablative, matched,
related donor vs nonmyeloablative, matched, haploidentical donor vs myeloablative,
haploidentical or partially mismatched, unrelated donor).
Patients receive sorafenib tosylate orally (PO) twice daily (BID) beginning at least 30 days
after completion of induction therapy and continuing until 4 days prior to bone marrow
transplant (BMT) preparative regimen. At time of engraftment but no later than 120 days
after BMT, patients receive sorafenib tosylate PO BID continuously for up to 2 years in the
absence of disease progression or unacceptable toxicity.
Patients undergo blood and bone marrow sample collection at baseline and periodically during
treatment to determine the effect of sorafenib tosylate and its metabolites on P-ERK and
P-FLT3 levels ex-vivo, presence of FLT3 target inhibition in-vivo, and MRD by PIA,
polymerase chain reaction assays, western blotting, and flow cytometry.
After completion of study treatment, patients are followed up for 24 months.
Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
All toxicities by type and grade will be reported with exact binomial proportions and 95% confidence intervals. The proportion of patients with graft failure in each cohort will also be reported with exact binomial proportions and 95% confidence intervals.
Up to 2 years
Johns Hopkins University
United States: Food and Drug Administration
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