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Sorafenib Plus 5-Azacitidine Initial Therapy of Patients With Acute Myeloid Leukemia (AML) and High Risk Myelodysplastic Syndrome (MS) With FLT3-ITD Mutation

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT02196857
Recruitment Status : Completed
First Posted : July 22, 2014
Last Update Posted : May 13, 2019
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

Brief Summary:
The goal of this clinical research study is to learn if 5-azacitidine and sorafenib can help to control the disease in patients with AML and high risk MDS with FLT3-ITD mutation. The safety of this drug combination will also be studied.

Condition or disease Intervention/treatment Phase
Leukemia Drug: Azacytidine Drug: Sorafenib Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 17 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase II Study of Sorafenib Plus 5-Azacitidine for the Initial Therapy of Patients With Acute Myeloid Leukemia and High Risk Myelodysplastic Syndrome With FLT3-ITD Mutation
Actual Study Start Date : February 6, 2015
Actual Primary Completion Date : November 27, 2018
Actual Study Completion Date : November 27, 2018

Arm Intervention/treatment
Experimental: Azacytidine + Sorafenib
Azacitidine 75 mg/m2 administered subcutaneously (SQ) or intravenously (IV) daily for 7 days per 28 day cycle. Sorafenib administered orally at a dose of 400 mg twice daily every day continuously.
Drug: Azacytidine
75 mg/m2 administered subcutaneously (SQ) or intravenously (IV) on Days 1 - 7 for a 28 day cycle.
Other Names:
  • 5-Azacytidine
  • 5-AZA
  • Vidaza
  • 5-AZC
  • AZA-CR
  • Ladakamycin
  • NSC-102816

Drug: Sorafenib
400 mg by mouth twice daily about 12 hours apart, every day for a 28 day cycle.
Other Names:
  • Nexavar
  • BAY 43-9006

Primary Outcome Measures :
  1. Overall Response of Azacytidine and Sorafenib [ Time Frame: After 3, 28 day cycles ]
    Criteria for response per the International Working Group for myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Data analysis performed using SAS or S-plus, as appropriate. All patients who received at least 1 dose of the combined agents will be included in the intent-to-treat analysis for efficacy. . Overall response rates presented with 95% confidence intervals. Association between response and patient and disease characteristics examined by two-sample t-test or Chi-square test.

Secondary Outcome Measures :
  1. Toxicity Profile of Azacytidine and Sorafenib [ Time Frame: After 3, 28 day cycles ]
    Severity of toxicities graded according to the NCI Common Toxicity Criteria for Adverse Effects (CTCAE) v4.0. Standard reporting guidelines followed for adverse events. Safety data summarized by category, severity and frequency. Proportion of patients with adverse events (AEs) estimated, along with the Bayesian 95% credible interval. Descriptive summaries provided for all patients for each safety parameter by cycle, grade, and relationship to treatment.

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. Patients with untreated AML (> or equal to 20% blasts in bone marrow and/or peripheral blood) or high risk MDS (> or equal to 10% blasts in bone marrow). A. Patients with AML and history of MDS who have received prior therapy with a hypomethylating agent (including azacytidine) and/or with lenalidomide for prior MDS are eligible if the treating physician feels that participation in the study is in the patients' best interest. B. Patients should have molecular evidence of the presence of FLT3-ITD mutation with a molecular burden of at least 10%.
  2. Age > or equal to 60 years; patients younger than 60 who are unsuitable for or unwilling to receive standard cytotoxic chemotherapy are also eligible to be enrolled.
  3. ECOG Performance Status < or equal 2.
  4. Adequate liver (bilirubin < or equal to 1.5 x ULN, ALT or AST < or equal to 2.5 x ULN and Alkaline phosphatase < or equal to 4 x ULN if not related to leukemic disease) and renal (creatinine < or equal to 1.5 x ULN) function.
  5. Patients must provide written informed consent.
  6. Patients must have been off therapy for MDS for 2 weeks prior to entering this study, and must have recovered from the toxic effects of that therapy to at least grade 1, unless there is evidence of rapidly progressive disease. Use of hydroxyurea (any dose) or ara-C (up to 1 g/m^2 X 2 doses) for patients with rapidly proliferative disease is allowed before the start of study therapy; these should be stopped for 24 hours prior to the initiation of azacitidine and sorafenib.
  7. Women of childbearing potential should be advised to avoid becoming pregnant with an adequate method of contraception (barrier or hormonal methods) and men should be advised to not father a child while receiving treatment with azacitidine. All men and women of childbearing potential must use acceptable methods of birth control throughout the study as described below: Women of childbearing potential must have a negative serum pregnancy test performed within 7 days prior to the start of treatment. Men should use adequate birth control for at least 30 days after the last administration of sorafenib. Post-menopausal women (defined as no menses for at least one year) and surgically sterilized women are not required to undergo a pregnancy test. Females of childbearing potential: Recommendation is for 2 effective contraceptive methods during the study.
  8. 7. Continued: Adequate forms of contraception are double-barrier methods (condoms with spermicidal jelly or foam and diaphragm with spermicidal jelly or foam), oral, depo provera, or injectable contraceptives, intrauterine devices, and tubal ligation. Male patients with female partners who are of childbearing potential: Recommendation is for male and partner to use at least 2 effective contraceptive methods, as described above, during the study.
  9. Ability to understand and the willingness to sign a written informed consent. A signed informed consent must be obtained prior to any study specific procedures.
  10. INR < or equal to 1.5. Patients receiving anti-coagulation treatment with an agent such as warfarin or heparin MAY be allowed to participate. For patients on warfarin, the INR should be measured prior to initiation of sorafenib and monitored weekly, or as defined by the local standard of care, until INR is stable.

Exclusion Criteria:

  1. Nursing and pregnant females.
  2. Patients with acute promyelocytic leukemia are excluded.
  3. Patients with known allergy to sorafenib or azacitidine, mannitol or any of their components.
  4. Patients with known severe impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of sorafenib.
  5. Patients with any other known disease (except carcinoma in-situ) or concurrent severe and/or uncontrolled medical condition (e.g. uncontrolled diabetes, cardiovascular disease including congestive heart failure, myocardial infarction within 6 months and uncontrolled hypertension, chronic renal disease (creatinine clearance < 20 ml/min using the Cockcroft and Gault formula), or active uncontrolled infection) which could compromise participation in the study.
  6. Patients with a known confirmed diagnosis of HIV infection or active viral hepatitis (B or C).
  7. Patients who have had any major surgical procedure within 28 days prior to Day 1.
  8. Patients unwilling or unable to comply with the protocol.
  9. Cardiac disease: Congestive heart failure > class II NYHA. Patients must not have unstable angina (anginal symptoms at rest) or new onset angina (began within the last 3 months) or myocardial infarction within the past 6 months.
  10. Uncontrolled hypertension defined as systolic blood pressure > 150? mmHg or diastolic pressure > 90 mmHg, despite optimal medical management.
  11. Active clinically serious infection > CTCAE v4, Grade 2 not controlled with antibiotics.
  12. Thrombolic or embolic events such as a cerebrovascular accident including transient ischemic attacks within the past 6 months.
  13. Pulmonary hemorrhage/bleeding event > or equal to CTCAE v4. Grade 2 within 4 weeks of first dose of study drug.
  14. Any other hemorrhage/bleeding event > or equal to CTCAE v4. Grade 3 within 4 weeks of first dose of study drug.
  15. Serious non-healing wound, ulcer, or bone fracture.
  16. Evidence of bleeding diathesis or coagulopathy within the past 6 months.
  17. Known or suspected allergy to sorafenib or any agent given in the course of this trial.
  18. Substance abuse, medical, psychological or social conditions that may interfere with the patient's participation in the study or evaluation of the study results including known non-compliance issues on study trials.
  19. Use of strong CYP3A4 inducer.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT02196857

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United States, Texas
University of Texas MD Anderson Cancer Center
Houston, Texas, United States, 77030
Sponsors and Collaborators
M.D. Anderson Cancer Center
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Principal Investigator: Farhad Ravandi-Kashani, MD M.D. Anderson Cancer Center

Additional Information:
Publications automatically indexed to this study by Identifier (NCT Number):
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Responsible Party: M.D. Anderson Cancer Center Identifier: NCT02196857     History of Changes
Other Study ID Numbers: 2014-0076
NCI-2014-01702 ( Registry Identifier: NCI CTRP )
First Posted: July 22, 2014    Key Record Dates
Last Update Posted: May 13, 2019
Last Verified: May 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by M.D. Anderson Cancer Center:
Acute myeloid leukemia
High risk myelodysplastic syndrome
FLT3-ITD mutation
BAY 43-9006
Additional relevant MeSH terms:
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Leukemia, Myeloid
Leukemia, Myeloid, Acute
Myelodysplastic Syndromes
Neoplasms by Histologic Type
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antimetabolites, Antineoplastic