Sorafenib Tosylate Before and After Donor Bone Marrow Transplantation in Treating Patients With Acute Myeloid Leukemia
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Purpose
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/Efficacy 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 |
- 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.
- Cumulative incidence of NRM and relapse [ Time Frame: At day 100 ] [ Designated as safety issue: No ]Estimated by competing risks analysis using Grey's method.
- Cumulative incidence of NRM and relapse [ Time Frame: At 1 year ] [ Designated as safety issue: No ]Estimated by competing risks analysis using Grey's method.
- Cumulative incidence of NRM and relapse [ Time Frame: At 2 years ] [ Designated as safety issue: No ]Estimated by competing risks analysis using Grey's method.
- DFS [ Time Frame: At 1 year ] [ Designated as safety issue: No ]Reported with 90% confidence intervals overall and by cohort.
- 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 1 year ] [ 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)
Patients receive sorafenib tosylate PO 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.
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Drug: sorafenib tosylate
Other Names:
Procedure: bone marrow transplantation
Undergo BMT
Other Names:
Other: laboratory biomarker analysis
Correlative studies
|
Detailed Description:
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. Determine non-relapse mortality (NRM) overall and by cohort. II. Assess the disease-free (DFS) and overall survival (OS) for all patients and by cohort (DFS will be defined as time to death or relapse).
III. Determine correlative endpoints evaluating minimal-residual disease as measured by flow cytometry and fms-related tyrosine kinase 3 (FLT3) suppression by plasma inhibitory assay (PIA).
IV. Correlate sorafenib and the N-oxide metabolite (total and unbound) exposure 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.
Eligibility| Ages Eligible for Study: | 18 Years and older |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria:
Must meet both of the following criteria:
- Patients with acute myeloid leukemia with FLT3-internal tandem duplications (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 (BMT)
- Patients who have had count recovery (absolute neutrophil count [ANC] over 500/mm³, nontransfused platelet count over 50,000/mm³) and are at least 30 days after induction and/or transplantation but no more than 120 days post transplant
- 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 with active and/or untreated central nervous system (CNS) leukemia will not be eligible
- Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (Karnofsky ≥ 60%)
- Life expectancy of greater than four months
- Total bilirubin less than 2 times upper limit of normal (ULN)
- Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase(ALT)(serum glutamic pyruvate transaminase[SGPT]) ≤ 5 times institutional ULN
- Creatinine within normal institutional limits OR creatinine clearance ≥ 60 mL/min
- 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; 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
- No patients with uncontrolled hypertension (i.e., persistent grade 3 while undergoing treatment)
- No history of allergic reactions attributed to compounds of similar chemical or biologic composition to sorafenib
- 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
- No 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
- Human immunodeficiency virus (HIV)-positive patients are excluded
- Patients who are unable to swallow pills are not eligible
Patients may have received any prior therapy deemed necessary for induction of remission except for patients who have progressed while on sorafenib
- Patients who have responded to sorafenib previously are eligible for enrollment on the protocol
- No 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 active acute graft-vs-host disease (GVHD) who have been initiated on therapy or had therapy escalation within 21 days are not eligible
- Patients taking strong CYP3A4 inhibitors including enzyme-inducing anti-epileptic drugs (phenytoin, carbazepine, or phenobarbital), rifampin, grapefruit juice, or St. Johns wort) are not eligible
Contacts and Locations| United States, Maryland | |
| Johns Hopkins University | Recruiting |
| Baltimore, Maryland, United States, 21287-8936 | |
| Contact: Keith W. Pratz 410-502-7726 kpratz@jhmi.edu | |
| Principal Investigator: Keith W. Pratz | |
| Principal Investigator: | Keith Pratz | Johns Hopkins University |
More Information
No publications provided
| Responsible Party: | National Cancer Institute (NCI) |
| ClinicalTrials.gov Identifier: | NCT01578109 History of Changes |
| Other Study ID Numbers: | NCI-2012-00727, J11116, CDR0000730684, JHOC-J11116, U01CA070095 |
| Study First Received: | April 13, 2012 |
| Last Updated: | May 1, 2013 |
| Health Authority: | United States: Food and Drug Administration |
Additional relevant MeSH terms:
|
Leukemia, Myeloid, Acute Congenital Abnormalities Leukemia Leukemia, Myeloid Neoplasms by Histologic Type Neoplasms Sorafenib |
Antineoplastic Agents Therapeutic Uses Pharmacologic Actions Protein Kinase Inhibitors Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action |
ClinicalTrials.gov processed this record on May 23, 2013