Clinical Trials /

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

NCT02196857

Description:

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.

Related Conditions:
  • Acute Myeloid Leukemia
  • Myelodysplastic Syndromes
Recruiting Status:

Completed

Phase:

Phase 2

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: 2014-0076
  • SECONDARY ID: NCI-2014-01702
  • NCT ID: NCT02196857

Conditions

  • Leukemia

Interventions

DrugSynonymsArms
Azacytidine5-Azacytidine, 5-AZA, Vidaza, 5-AZC, AZA-CR, Ladakamycin, NSC-102816Azacytidine + Sorafenib
SorafenibNexavar, BAY 43-9006Azacytidine + Sorafenib

Purpose

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.

Detailed Description

      Study Drug Administration:

      If you are found to be eligible to take part in this study, you will receive 5-azacitidine
      either as an injection under the skin or by vein on Days 1-7 of each 28-day cycle. If by
      vein, the infusion will take about 10-40 minutes.

      You will take sorafenib by mouth 2 times a day about 12 hours apart, with at least 1 cup (8
      ounces) of water on an empty stomach, every day. If you vomit a dose, do not make it up. You
      should wait and take your next scheduled dose.

      Each study cycle may last a little longer than 28 days, depending on how you are doing.

      Study Visits:

      Each week, blood (about 1 tablespoon) will be drawn for routine tests.

      Each week for the first 6 weeks, and then as often as your doctor thinks it is needed, you
      will have your blood pressure measured.

      Before each cycle, you will have a physical exam.

      Before every 2-4 cycles, you will have a bone marrow aspirate to check the status of the
      disease.

      Length of Study:

      You may continue taking the study drugs for as long as your doctor thinks it is in your best
      interest. You will no longer be able to take the study drugs if the disease gets worse or
      intolerable side effects occur, or if you are unable to follow study directions.

      Your participation on the study will be over after the follow-up visits.

      End-of-Study Visit:

      After you have stopped taking the study drugs, the following tests and procedures will be
      performed:

        -  You will have a physical exam.

        -  You will have a bone marrow aspirate to check the status of disease.

        -  Blood (about 2 tablespoons) will be drawn for routine tests.

      Follow-Up Visits:

      After your end-of-study visit, you will return to the clinic every 3 months and have the
      following tests and procedures:

        -  You will have a physical exam.

        -  Blood (about 2 tablespoons) will be drawn for routine tests.

      This is an investigational study. Sorafenib is FDA approved and commercially available for
      the treatment of kidney cancer and liver cancer. 5-azacitidine is FDA approved for the
      treatment of MDS, but combining it with sorafenib is investigational. The study doctor can
      tell you how the study drugs are designed to work.

      Up to 52 participants will be enrolled in this study. All will take part at MD Anderson.
    

Trial Arms

NameTypeDescriptionInterventions
Azacytidine + SorafenibExperimentalAzacitidine 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.
  • Azacytidine
  • Sorafenib

Eligibility Criteria

        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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall Response of Azacytidine and Sorafenib
Time Frame:After 3, 28 day cycles
Safety Issue:
Description: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

Measure:Toxicity Profile of Azacytidine and Sorafenib
Time Frame:After 3, 28 day cycles
Safety Issue:
Description: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.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:M.D. Anderson Cancer Center

Trial Keywords

  • Leukemia
  • Acute myeloid leukemia
  • AML
  • High risk myelodysplastic syndrome
  • MDS
  • FLT3-ITD mutation
  • Azacytidine
  • 5-Azacytidine
  • 5-AZA
  • Vidaza
  • 5-AZC
  • AZA-CR
  • Ladakamycin
  • NSC-102816
  • Sorafenib
  • Nexavar
  • BAY 43-9006

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