Sorafenib Tosylate Before and After Donor Bone Marrow Transplantation in Treating Patients With Acute Myeloid Leukemia

This study is currently recruiting participants.
Verified February 2014 by National Cancer Institute (NCI)
Information provided by (Responsible Party):
National Cancer Institute (NCI) Identifier:
First received: April 13, 2012
Last updated: February 7, 2014
Last verified: February 2014

This pilot trial studies how well sorafenib tosylate works before and after donor bone marrow transplantation in treating patients with acute myeloid leukemia. Sorafenib tosylate may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Condition Intervention
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)
Drug: sorafenib tosylate
Procedure: bone marrow transplantation
Other: laboratory biomarker analysis

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Pilot Study of Sorafenib in Patients With Acute Myeloid Leukemia as Peri-Transplant Remission Maintenance

Resource links provided by NLM:

Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Toxicity [ Time Frame: Up to 2 years ] [ Designated as safety issue: Yes ]
    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.

Secondary Outcome Measures:
  • Cumulative incidence of NRM and relapse [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
    Estimated by competing risks analysis using Grey's method.

  • DFS [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
    Reported with 90% confidence intervals overall and by cohort.

  • OS [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
    Reported with 90% confidence intervals overall and by cohort.

  • Change in MRD by flow cytometry [ Time Frame: From baseline to days 28, 180, and 365 ] [ Designated as safety issue: No ]
    Box plots will be used.

  • Change in FLT3 suppression by PIA and western blotting [ Time Frame: From baseline to on days 28, 180 and 365 ] [ Designated as safety issue: No ]
    Box plots will be used.

Estimated Enrollment: 36
Study Start Date: January 2012
Estimated Primary Completion Date: December 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (sorafenib tosylate and transplant)
Patients receive sorafenib tosylate PO BID beginning at least 30 days after completion of induction therapy and continuing until 4 days prior to 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.
Drug: sorafenib tosylate
Given PO
Other Names:
  • BAY 43-9006
  • BAY 43-9006 Tosylate Salt
  • BAY 54-9085
  • Nexavar
  • SFN
Procedure: bone marrow transplantation
Undergo BMT
Other Names:
  • BMT
  • transplantation, bone marrow
Other: laboratory biomarker analysis
Correlative studies

Detailed Description:


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.


Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Acute Myeloid leukemia with a fms-like tyrosine kinase (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 (absolute neutrophil count [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
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
  • Life expectancy of greater than four months
  • Total bilirubin less than 2x upper limit of normal
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvate transaminase [SGPT]) =< 5 X institutional upper limit of normal
  • Creatinine =< 1.5 x upper limit of normal OR creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels > 1.5 x upper limit of 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 treatment)
  • Patients with active and/or untreated central nervous system (CNS) leukemia will not be eligible
  • Patients must not have any evidence of bleeding diathesis or be on any therapeutic anticoagulation such as low molecular weight (LMW) heparin or warfarin for deep vein thrombosis (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
  • Human immunodeficiency virus (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 deoxyribonucleic acid [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 cytochrome P450 3A4 (CYP3A4) inhibitors including enzyme-inducing anti-epileptic drugs (phenytoin, carbazepine, or phenobarbitol), rifampin, grape fruit juice, or St. Johns wort are not eligible
  Contacts and Locations
Please refer to this study by its identifier: NCT01578109

United States, Maryland
Johns Hopkins University Recruiting
Baltimore, Maryland, United States, 21287
Contact: Keith W. Pratz    410-502-7726   
Principal Investigator: Keith W. Pratz         
University of Maryland Greenebaum Cancer Center Recruiting
Baltimore, Maryland, United States, 21201-1595
Contact: Ashkan Emadi    410-328-2596   
Principal Investigator: Ashkan Emadi         
Sponsors and Collaborators
Principal Investigator: Keith Pratz Johns Hopkins University
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI) Identifier: NCT01578109     History of Changes
Other Study ID Numbers: NCI-2012-00727, NCI-2012-00727, CDR0000730684, NA_00066136, JHOC-J11116, J11116, 8992, P30CA006973, U01CA070095
Study First Received: April 13, 2012
Last Updated: February 7, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Leukemia, Myeloid, Acute
Congenital Abnormalities
Leukemia, Myeloid
Neoplasms by Histologic Type
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action processed this record on April 15, 2014