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

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ClinicalTrials.gov Identifier: NCT01578109
Recruitment Status : Active, not recruiting
First Posted : April 16, 2012
Last Update Posted : May 25, 2018
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

April 13, 2012
April 16, 2012
May 25, 2018
January 13, 2012
December 31, 2018   (Final data collection date for primary outcome measure)
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.
  • Toxicity by type and grade reported with exact binomial proportions and 95% confidence intervals
  • Secondary graft failure reported with exact binomial proportions and 95% confidence intervals
Complete list of historical versions of study NCT01578109 on ClinicalTrials.gov Archive Site
  • 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.
  • Change in MRD by flow cytometry [ Time Frame: Baseline to day 365 ]
    Box plots will be used.
  • Change in FLT3 suppression by PIA and western blotting [ Time Frame: Baseline to day 365 ]
    Box plots will be used.
  • 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.
  • Event-free survival at 2 years after BMT
  • Cumulative incidences of NRM and relapse at 1 year after BMT by competing risks analyses using Grey's method
  • DFS and OS at 1 year using 90% confidence intervals overall and by cohort
  • Chronic GVHD by calculating cumulative incidence curves using the competing risk method
  • MRD on days 28, 180 and 365 by flow cytometry using boxplots
  • FLT3 suppression on days 28, 180 and 365 by PIA and western blotting using boxplots
  • Correlation between sorafenib tosylate, N-oxide metabolite exposure, and pharmacodynamic endpoints using non-parametric statistics
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.
Not Provided
 
Sorafenib Tosylate Before and After Donor Bone Marrow Transplant in Treating Patients With Acute Myeloid Leukemia
A Pilot Study of Sorafenib in Patients With Acute Myeloid Leukemia as Peri-transplant Remission Maintenance
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.

PRIMARY OBJECTIVES:

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.

SECONDARY OBJECTIVES:

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 Institutes of Health (NIH) consensus project guidelines and by conventional criteria.

TERTIARY OBJECTIVES:

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.

Interventional
Not Applicable
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
  • Acute Myeloid Leukemia in Remission
  • Acute Myeloid Leukemia With FLT3/ITD Mutation
  • 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
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.
Interventions:
  • Procedure: Bone Marrow Transplantation
  • Other: Laboratory Biomarker Analysis
  • Other: Pharmacological Study
  • Drug: Sorafenib Tosylate
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Active, not recruiting
45
36
Not Provided
December 31, 2018   (Final data collection date for primary outcome measure)

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
Sexes Eligible for Study: All
19 Years and older   (Adult, Older Adult)
No
Contact information is only displayed when the study is recruiting subjects
United States
 
 
NCT01578109
NCI-2012-00727
NCI-2012-00727 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
J11116
CDR0000730684
8992 ( Other Identifier: Johns Hopkins University/Sidney Kimmel Cancer Center )
8992 ( Other Identifier: CTEP )
P01CA015396 ( U.S. NIH Grant/Contract )
P30CA006973 ( U.S. NIH Grant/Contract )
P50CA100632 ( U.S. NIH Grant/Contract )
U01CA070095 ( U.S. NIH Grant/Contract )
UM1CA186691 ( U.S. NIH Grant/Contract )
No
Not Provided
Not Provided
National Cancer Institute (NCI)
National Cancer Institute (NCI)
Not Provided
Principal Investigator: Keith Pratz Johns Hopkins University/Sidney Kimmel Cancer Center
National Cancer Institute (NCI)
May 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP