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

This study is ongoing, but not recruiting participants.
Information provided by (Responsible Party):
National Cancer Institute (NCI) Identifier:
First received: April 13, 2012
Last updated: January 31, 2017
Last verified: January 2017
This pilot clinical trial studies the side effects of sorafenib tosylate 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
Procedure: Bone Marrow Transplantation
Other: Laboratory Biomarker Analysis
Other: Pharmacological Study
Drug: Sorafenib Tosylate

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: No masking
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:
  • Proportion of patients removed from the study in each cohort due to toxicity [ Time Frame: Up to 24 months ]
    Will be reported with exact binomial proportions and 95% confidence intervals. All toxicities by type and grade will be reported. 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:
  • Change in FLT3 suppression by PIA and western blotting [ Time Frame: Baseline to day 365 ]
    Box plots will be used.

  • Change in MRD by flow cytometry [ Time Frame: Baseline to day 365 ]
    Box plots will be used.

  • Cumulative incidence of NRM and relapse [ Time Frame: Up to 2 years ]
    Estimated by competing risks analysis using Grey's method.

  • DFS [ Time Frame: Up to 2 years ]
    Standard life table methods with Kaplan-Meier (KM) plots will be used to analyze DFS. Reported with 90% confidence intervals overall and by cohort.

  • OS [ Time Frame: Up to 2 years ]
    Standard life table methods with KM plots will be used to analyze OS. Reported with 90% confidence intervals overall and by cohort.

  • Pharmacodynamic parameters of sorafenib tosylate [ Time Frame: Up to 2 years post-transplant ]
    Samples will be collected to assess sorafenib tosylate and the N-oxide metabolite (total and unbound) exposure to correlate with pharmacodynamic endpoints using non-parametric statistics.

Other Outcome Measures:
  • Changes in T-regulatory cell population [ Time Frame: Baseline to 2 years post-transplant ]
    Regression modeling of subdistribution functions in competing risks by Gray's method will be conducted to examine how changes in immunologic parameters are associated with subsequent development of GVHD. An appropriate transformation will be used to normalize the data. Differences between pre- and post-transplantation will be explored using methods appropriate for paired data. Patterns of change in marker values over time may also be explored using appropriate modeling.

Estimated Enrollment: 45
Study Start Date: January 2012
Estimated Primary Completion Date: December 2018 (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/or transplant and no more than 120 days after transplant continuing for up to 2 years after transplant in the absence of disease progression or unacceptable toxicity.
Procedure: Bone Marrow Transplantation
Undergo BMT
Other Names:
  • BMT
  • Bone Marrow Grafting
  • Bone Marrow Transplant
  • Marrow Transplantation
Other: Laboratory Biomarker Analysis
Correlative studies
Other: Pharmacological Study
Correlative studies
Drug: Sorafenib Tosylate
Given PO
Other Names:
  • BAY 43-9006 Tosylate
  • BAY 54-9085
  • Nexavar
  • sorafenib

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. Non-relapse mortality (NRM) is defined, as death in the absence of competing risks, relapse or progression of disease.

IV. Survival without relapse or death (disease-free survival [DFS]) or without death (overall survival [OS]) will be determined and presented as Kaplan-Meier estimates at 1 and 2 years post-transplant.

V. Patients will be evaluated for chronic graft versus host disease (GVHD) both as described in the National Institute of Health (NIH) consensus project guidelines and by conventional criteria.


I. Patients will undergo serial examinations of bone marrow during the maintenance treatments evaluating minimal residual disease (MRD) by flow cytometry and fms-related tyrosine kinase 3 (FLT3) suppression by western blot analysis and plasma inhibitory assay (PIA).

OUTLINE: This is a dose-escalation study.

Patients receive sorafenib tosylate orally (PO) twice daily (BID) beginning at least 30 days after completion of induction therapy and/or transplant but no more than 120 days after transplant continuing for up to 2 years after transplant in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 24 months.


Ages Eligible for Study:   19 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Acute myeloid leukemia with a fms-like tyrosine kinase 3 (FLT3)-internal tandem duplication (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] > 500,000/mm^3 non transfused platelet count over 30,000/mm^3) 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 2 x upper limit of normal
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate 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 (i.e., methotrexate, cytarabine, or thiotepa)
  • Patients may not be receiving any other investigational agents
  • Patients with uncontrolled hypertension (i.e., persistent grade 3 while undergoing treatment)
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to sorafenib
  • 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; breastfeeding should be discontinued if the mother is treated sorafenib
  • Human immunodeficiency virus (HIV)-positive patients are excluded
  • 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 family 3, subfamily A, polypeptide 4 (CYP3A4) inhibitors including enzyme-inducing anti-epileptic drugs (phenytoin, carbazepine, or phenobarbitol), rifampin, grape fruit juice, or St. John's wort are not eligible
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its identifier: NCT01578109

United States, Maryland
University of Maryland/Greenebaum Cancer Center
Baltimore, Maryland, United States, 21201
Johns Hopkins University/Sidney Kimmel Cancer Center
Baltimore, Maryland, United States, 21287
Sponsors and Collaborators
National Cancer Institute (NCI)
Principal Investigator: Keith Pratz Johns Hopkins University/Sidney Kimmel Cancer Center
  More Information

Responsible Party: National Cancer Institute (NCI) Identifier: NCT01578109     History of Changes
Other Study ID Numbers: NCI-2012-00727  NCI-2012-00727  J11116  CDR0000730684  J11116  8992  P30CA006973  P50CA100632  U01CA070095  UM1CA186691 
Study First Received: April 13, 2012
Last Updated: January 31, 2017

Additional relevant MeSH terms:
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Vitamin B Complex
Growth Substances
Physiological Effects of Drugs processed this record on February 23, 2017