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A Pilot Study of Sorafenib in Patients With Acute Myeloid Leukemia as Peri-Transplant Remission Maintenance

18 Years
Open (Enrolling)
Adult Acute Myeloid Leukemia in Remission, Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities, Adult Acute Myeloid Leukemia With Del(5q), Adult Acute Myeloid Leukemia With Inv(16)(p13;q22), Adult Acute Myeloid Leukemia With t(15;17)(q22;q12), Adult Acute Myeloid Leukemia With t(16;16)(p13;q22), Adult Acute Myeloid Leukemia With t(8;21)(q22;q22)

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Trial Information

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.

Inclusion Criteria:

- Acute Myeloid leukemia with a FLT3-ITD who are in a complete remission or partial
remission(less than 10% blasts in marrow) as documented by bone marrow biopsy and who
plan to undergo a bone marrow transplantation

- Patients who have had count recovery (ANC over 500, non transfused platelet count
over 50) and are at least 30 days after induction and/or transplantation but no more
than 120 days post transplant

- Patients may have received any prior therapy deemed necessary for induction of
remission except for patients whom have progressed while on sorafenib; patients who
have responded to sorafenib previously are eligible for enrollment on the protocol

- ECOG performance status =< 2 (Karnofsky >= 60%)

- Life expectancy of greater than four months

- Total bilirubin less than 2x upper limit of normal

- AST(SGOT)/ALT(SGPT) =< 5 X institutional upper limit of normal

- Creatinine within normal institutional limits OR creatinine clearance >= 60
mL/min/1.73 m^2 for patients with creatinine levels above institutional normal

- Women of child-bearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) prior to study entry and
for the duration of study participation; should a woman become pregnant or suspect
she is pregnant while participating in this study, she should inform her treating
physician immediately; contraception should continue for at least 30 days after the
last dose of sorafenib

- Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

- Patients who have had chemotherapy or radiotherapy within 2 weeks except for
intrathecal chemotherapy(ie Methotrexate, Cytarabine, or Thiotepa)

- Patients may not be receiving any other investigational agents

- Patients with uncontrolled hypertension(ie, persistent grade 3 while undergoing

- Patients with active and/or untreated CNS leukemia will not be eligible

- Patients must not have any evidence of bleeding diathesis or be on any therapeutic
anticoagulation such as LMW heparin or warfarin for DVT treatment

- Uncontrolled intercurrent illness including, but not limited to ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements

- Pregnant women are excluded from this study because sorafenib is chemotherapeutic
agent with the potential for teratogenic or abortifacient effects; because there is
an unknown but potential risk for adverse events in nursing infants secondary to
treatment of the mother with sorafenib, breastfeeding should be discontinued if the
mother is treated sorafenib

- HIV-positive patients are excluded because management of these patients in the
hematopoietic cell transplant setting has not yet been well defined and is currently
the subject of investigation in other studies addressing this issue

- Patients with active acute GVHD who have been initiated on therapy or had therapy
escalation within 21 days are not eligible

- Patients with lack of engraftment(less than 90% donor DNA in bone marrow or
peripheral blood) after bone marrow transplant as evidence by RFLP(restriction
fragment length polymorphism) are not eligible

- Patients who are unable to swallow pills are not eligible

- Patients taking strong CYP3A4 inhibitors including enzyme-inducing anti-epileptic
drugs (phenytoin, carbazepine, or phenobarbitol), rifampin, grape fruit juice, or St.
Johns Wort are not eligible

Type of Study:


Study Design:

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:


Outcome Description:

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.

Outcome Time Frame:

Up to 2 years

Safety Issue:


Principal Investigator

Keith Pratz

Investigator Role:

Principal Investigator

Investigator Affiliation:

Johns Hopkins University


United States: Food and Drug Administration

Study ID:




Start Date:

January 2012

Completion Date:

Related Keywords:

  • Adult Acute Myeloid Leukemia in Remission
  • Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities
  • Adult Acute Myeloid Leukemia With Del(5q)
  • Adult Acute Myeloid Leukemia With Inv(16)(p13;q22)
  • Adult Acute Myeloid Leukemia With t(15;17)(q22;q12)
  • Adult Acute Myeloid Leukemia With t(16;16)(p13;q22)
  • Adult Acute Myeloid Leukemia With t(8;21)(q22;q22)
  • Congenital Abnormalities
  • Leukemia
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid



Johns Hopkins UniversityBaltimore, Maryland  21205