Clinical Trials /

Midostaurin and Azacitidine in Treating Elderly Patients With Acute Myelogenous Leukemia

NCT01093573

Description:

RATIONALE: Midostaurin may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as azacitidine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Midostaurin may help azacitidine kill more cancer cells by making the cancer cells more sensitive to the drug. PURPOSE: This phase I/II trial is studying the side effects and best dose of midostaurin when given together with azacitidine and to see how well it works in treating elderly patients with acute myelogenous leukemia.

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Unknown status

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Midostaurin and Azacitidine in Treating Elderly Patients With Acute Myelogenous Leukemia
  • Official Title: A Phase I/II Study of Midostaurin (PKC412) and 5-Azacitidine for Elderly Patients With Acute Myelogenous Leukemia.

Clinical Trial IDs

  • ORG STUDY ID: CASE1908
  • SECONDARY ID: NCI-2009-01285
  • NCT ID: NCT01093573

Conditions

  • Untreated Adult Acute Myeloid Leukemia

Interventions

DrugSynonymsArms
midostaurinN-benzoyl-staurosporine, PKC412Arm I
azacitidine5-AC, 5-azacytidine, 5-AZC, azacytidine, ladakamycin, VidazaArm I

Purpose

RATIONALE: Midostaurin may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as azacitidine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Midostaurin may help azacitidine kill more cancer cells by making the cancer cells more sensitive to the drug. PURPOSE: This phase I/II trial is studying the side effects and best dose of midostaurin when given together with azacitidine and to see how well it works in treating elderly patients with acute myelogenous leukemia.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the safe and tolerable dose of midostaurin in combination with azacitidine in
      patients with acute myelogenous leukemia. (Phase I) II. To describe the toxicity profile of
      the combination of midostaurin and azacitidine in patients with acute myelogenous leukemia.
      (Phase I/II) III. To determine the complete and partial response rate and rate of hematologic
      improvement of midostaurin and 5-azacitidine in untreated acute myelogenous leukemia. (Phase
      I/II)

      SECONDARY OBJECTIVES:

      I. To describe pharmacokinetics of oral midostaurin given in combination with azacitidine on
      a day 8-21 schedule. (Phase I/II) II. To correlate treatment response with FLT3 mutational
      status in a descriptive fashion. (Phase I/II) III. To assess overall survival of patients
      from initiation of midostaurin-azacitidine toxicities. (Phase I/II) IV. To determine median
      disease-free survival of the regimen in untreated patients. (Phase II)

      TERTIARY OBJECTIVES:

      I. To describe signaling in CD117+ committed myeloid precursors in whole blood and bone
      marrow samples before and during treatment. (Phase I/II) II. To measure in vivo FLT3
      inhibition using plasma inhibition assay (PIA) and Flt ligand (FL) levels in patients
      enrolled on this trial before and during treatment. (Phase I/II)

      OUTLINE: This is a phase I, dose escalation study of midostaurin followed by a phase II
      study.

      Patients receive azacitidine intravenously (IV) over 10-20 minutes on days 1-7 and
      midostaurin orally (PO) twice daily (BID) on days 8-21. Courses repeat every 28 days for up
      to 8 courses in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up every 3 months for 1 year,
      every 6 months for 2 years, and then annually thereafter.
    

Trial Arms

NameTypeDescriptionInterventions
Arm IExperimentalPatients receive azacitidine IV over 10-20 minutes on days 1-7 and oral midostaurin twice daily on days 8-21.
  • midostaurin
  • azacitidine

Eligibility Criteria

        Inclusion Criteria

          -  Patients must have histologic proof of active AML at time of enrollment

          -  Phase I and II portion: Subjects of any age with untreated AML, if not candidates for
             standard induction chemotherapy or with poor risk AML (i.e. preceding MDS,
             myeloproliferative syndromes, leukemia due to cytotoxic chemotherapy for another
             condition, adverse cytogenetics or complex karyotype), or any subjects > 70 years of
             age with untreated AML. Acute promyelocytic leukemia (FAB M3) is excluded

          -  Please note: prior intensive induction therapy for acute leukemia is allowed only in
             the phase I portion of this study

             • PHASE I PORTION ONLY: Patients of any age who have received no more than one prior
             attempt at induction chemotherapy (and may have received treatment consolidation),
             must have recovered from acute toxicities of therapy and be >= 4 weeks from last dose
             of cytotoxic treatment; patients who have received prior autologous or allogeneic stem
             cell transplantation are not eligible; patients may have received 1 or 2 cycles of
             cytarabine-based therapy as attempted induction.

          -  Phase II portion: Patients must have not received any prior intensive induction
             therapy for AML.

               -  Intensive induction includes standard induction chemotherapy such as 7 & 3, high
                  dose cytarabine, mitoxantrone-etoposide, low-dose subcutaneous cytarabine.

               -  Allowed "non-intensive" prior treatments for pre-existing hematologic conditions
                  (i.e., MDS, chronic myelomonocytic leukemia [CMML]) will include: hydroxyurea,
                  thalidomide, hematopoietic growth factors, Zarnestra, Lenalidomide, arsenic,
                  Imatinib, and corticosteroids, suberoylanilide hydroxamic acid [SAHA] inhibitors;
                  hydroxyurea is allowed up to 24 hours before initiating treatment and to control
                  blood counts during the first cycle of chemotherapy after azacitidine has
                  completed; a minimum of 4 weeks must have elapsed since the administration of
                  thalidomide, Zarnestra, Revlimid, arsenic, SAHA inhibitors, or any
                  investigational medication; a minimum of five days must have elapsed since the
                  administration of growth factors

                    -  Prior cytotoxic chemotherapy for another condition treated with curative
                       intent is allowed provided at least 18 months has elapsed between last
                       treatment and enrollment on protocol

                    -  Eastern Cooperative Oncology Group (ECOG) performance status 0-2

                    -  Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 1.5 times
                       the upper limits of normal

                    -  Serum bilirubin =< 1.5x upper limit of normal

                    -  Creatinine =< 1.5x upper limit of normal

                    -  No exclusion for blood counts; however, at the time of treatment initiation,
                       white blood cell (WBC) should be < 30,000/uL (can be controlled with
                       hydroxyurea)

                    -  Life expectancy without treatment of at least 12 weeks

                    -  Patients with and without FLT3 mutations will be eligible to participate

                    -  Patients must have the ability and willingness to sign a written informed
                       consent document

        Exclusion Criteria

          -  Acute promyelocytic leukemia (FAB M3)

          -  Prior autologous or allogeneic stem cell transplant

          -  Prior azacitidine, decitabine, or midostaurin

          -  Patients with known impairment of gastrointestinal (GI) function or GI disease that
             may significantly alter the absorption of midostaurin; patients with gastric bypass
             surgery are excluded

          -  Patients with any other known active cancer (except carcinoma in-situ), concurrent
             severe and/or uncontrolled medical condition (e.g. uncontrolled diabetes, pulmonary,
             chronic renal disease, active uncontrolled infection)

          -  Cardiovascular Criteria will exclude a patient from participation in the study will
             include:

               -  Screening electrocardiogram (ECG) with a QTc > 450 msec;

               -  Patients with congenital long QT syndrome;

               -  History or presence of sustained ventricular tachycardia;

               -  Any history of ventricular fibrillation or torsades de pointes;

               -  Bradycardia defined as heart rate (HR) < 50 bpm;

               -  Right bundle branch block + left anterior hemiblock (bifascicular block);

               -  Patients with myocardial infarction or unstable angina < 6 months prior to
                  starting study drug;

               -  Congestive heart failure (CHF) New York (NY) Heart Association class III or IV;

               -  Patients with an ejection fraction =< 45% assessed by multi gated acquisition
                  scan (MUGA) or echocardiogram (ECHO) scan within 14 days of day 1

               -  Poorly controlled hypertension

          -  Known allergy or hypersensitivity to azacitidine, mannitol, or midostaurin

          -  Active or suspicion of central nervous system (CNS) leukemia

          -  Patients with human immunodeficiency virus (HIV) disease or active viral hepatitis

          -  Patients with hepatitis B

          -  Patients with an abnormal chest X-ray and/or any pulmonary infiltrate including those
             suspected to be of infectious origin; in particular, patients with resolution of
             clinical symptoms of pulmonary infection but with residual pulmonary infiltrates on
             chest x-ray are not eligible until pulmonary infiltrates have completely resolved

          -  Pregnant or lactating women

          -  Prohibited medications: PKC412 and its two major metabolites may have a potential of
             drug-drug interactions with P-gp substrates and CYP3A4 inhibitors, and inducers. An
             increased anticoagulant effect has been noted in patients treated with warfarin and
             midostaurin.

          -  Patients who have received any investigational agent within 30 days prior to day 1

          -  Women of child-bearing potential, defined as all women physiologically capable of
             becoming pregnant, unless they are using highly effective methods of contraception
             during dosing and for 3 months of midostaurin medication. Highly effective
             contraception methods include:

               -  Total abstinence (when this is in line with the preferred and usual lifestyle of
                  the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal,
                  post-ovulation methods) and withdrawal are not acceptable methods of
                  contraception

               -  Female sterilization (have had surgical bilateral oophorectomy with or without
                  hysterectomy) or tubal ligation at least six weeks before taking study treatment.
                  In case of oophorectomy alone, only when the reproductive status of the woman has
                  been confirmed by follow up hormone level assessment

               -  Male sterilization (at least 6 months prior to screening). For female subjects on
                  the study the vasectomized male partner should be the sole partner for that
                  subject.

               -  Combination of any two of the following (a+b or a+c, or b+c):

                    1. Use of oral, injected or implanted hormonal methods of contraception or
                       other forms of hormonal contraception that have comparable efficacy (failure
                       rate <1%), for example hormone vaginal ring or transdermal hormone
                       contraception.

                    2. Placement of an intrauterine device (IUD) or intrauterine system (IUS)

                    3. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or
                       cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal
                       suppository

        In case of use of oral contraception women should have been stable on the same pill for a
        minimum of 3 months before taking study treatment Sexually active males unless they use a
        condom during intercourse while taking drug and for 5 months after stopping midostaurin
        medication. They should not father a child in this period. A condom is required to be used
        also by vasectomized men in order to prevent delivery of the drug via seminal fluid.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:N/A
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose of midostaurin in combination with azacitidine in patients with acute myelogenous leukemia (Phase I)
Time Frame:Day 28
Safety Issue:
Description:Defined as the dose level below 1 of 3 then 2 of 3 patients experience dose-limiting toxicity (DLT).

Secondary Outcome Measures

Measure:Pharmacokinetic profile of midostaurin given with azacitidine (Phase I)
Time Frame:Before dosing of midostaurin on days 8, 15, and 21 of courses 1 and 2
Safety Issue:
Description:
Measure:Time to disease progression
Time Frame:Up to 3 years
Safety Issue:
Description:The Kaplan-Meier method will be used to estimate survivor function.
Measure:Changes of phosphorylation status of FLT3 in blood and bone marrow samples (Phase I/II)
Time Frame:Baseline to 4 cycles (16 weeks)
Safety Issue:
Description:
Measure:Overall survival (Phase I/II)
Time Frame:Up to 3 years
Safety Issue:
Description:The Kaplan-Meier method will be used to estimate survivor function.
Measure:To correlate treatment response with FLT3 mutational status in a descriptive fashion.(Phase I)
Time Frame:Baseline to 4 cycles (16 weeks)
Safety Issue:
Description:

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Unknown status
Lead Sponsor:Brenda Cooper, MD

Trial Keywords

  • Untreated myelodysplastic syndromes

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