Midostaurin and Azacitidine in Treating Elderly Patients With Acute Myelogenous Leukemia

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: NCT01093573
Recruitment Status : Unknown
Verified June 2016 by Brenda Cooper, MD, Case Comprehensive Cancer Center.
Recruitment status was:  Active, not recruiting
First Posted : March 26, 2010
Last Update Posted : June 10, 2016
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Brenda Cooper, MD, Case Comprehensive Cancer Center

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Untreated Adult Acute Myeloid Leukemia Drug: midostaurin Drug: azacitidine Other: laboratory biomarker analysis Other: bone marrow aspiration Other: liquid chromatography Other: flow cytometry Other: mutation analysis Other: pharmacological study Other: mass spectrometry Other: protein expression analysis Phase 1 Phase 2

Detailed Description:


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)


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)


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.

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 34 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I/II Study of Midostaurin (PKC412) and 5-Azacitidine for Elderly Patients With Acute Myelogenous Leukemia.
Study Start Date : July 2009
Actual Primary Completion Date : June 2016

Arm Intervention/treatment
Experimental: Arm I
Patients receive azacitidine IV over 10-20 minutes on days 1-7 and oral midostaurin twice daily on days 8-21.
Drug: midostaurin
Given orally
Other Names:
  • N-benzoyl-staurosporine
  • PKC412

Drug: azacitidine
Given IV
Other Names:
  • 5-AC
  • 5-azacytidine
  • 5-AZC
  • azacytidine
  • ladakamycin
  • Vidaza

Other: laboratory biomarker analysis
Correlative study

Other: bone marrow aspiration
Correlative study

Other: liquid chromatography
Correlative study
Other Name: LC

Other: flow cytometry
Correlative study

Other: mutation analysis
Correlative study

Other: pharmacological study
Correlative study
Other Name: pharmacological studies

Other: mass spectrometry
Correlative study

Other: protein expression analysis
Correlative study

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

  2. Rate of hematologic improvement [ Time Frame: 2 months ]
    Hematologic toxicity: For patients with ANC > 500/ μl at baseline, dose modifications will be made accordingly. Recovery is defined as neutrophil count > 500/ul if neutrophils nadir is below 500/ul: Hematologic response will be assessed on day 1 of each cycle of azacitidine.

  3. Complete and partial response rate of midostaurin and azacitidine in untreated acute myelogenous leukemia (Phase I/II) [ Time Frame: after 4 months of treatment ]
    Response will be assessed using the standard morphologic criteria for acute leukemia as follows: Complete remission (CR): ANC ≥ 1000/ uL and platelets of > 100,000/ uL without circulating blasts and bone marrow with < 5% blasts and no Auer rods; Partial remission (PR): This designation requires at least a 50% decrease in the bone marrow blasts to 5-25%.

Secondary Outcome Measures :
  1. 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 ]
  2. Time to disease progression [ Time Frame: Up to 3 years ]
    The Kaplan-Meier method will be used to estimate survivor function.

  3. Changes of phosphorylation status of FLT3 in blood and bone marrow samples (Phase I/II) [ Time Frame: Baseline to 4 cycles (16 weeks) ]
  4. Overall survival (Phase I/II) [ Time Frame: Up to 3 years ]
    The Kaplan-Meier method will be used to estimate survivor function.

  5. To correlate treatment response with FLT3 mutational status in a descriptive fashion.(Phase I) [ Time Frame: Baseline to 4 cycles (16 weeks) ]

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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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.

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): NCT01093573

United States, Ohio
Case Medical Center, University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center
Cleveland, Ohio, United States, 44106
United States, West Virginia
West Virginia University
Morgantown, West Virginia, United States, 26506
Sponsors and Collaborators
Brenda Cooper, MD
National Cancer Institute (NCI)
Principal Investigator: Brenda Cooper, MD Case Medical Center, University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center

Responsible Party: Brenda Cooper, MD, Principal Investigator, Case Comprehensive Cancer Center Identifier: NCT01093573     History of Changes
Other Study ID Numbers: CASE1908
NCI-2009-01285 ( Other Identifier: NCI/CTRP )
First Posted: March 26, 2010    Key Record Dates
Last Update Posted: June 10, 2016
Last Verified: June 2016

Keywords provided by Brenda Cooper, MD, Case Comprehensive Cancer Center:
Untreated myelodysplastic syndromes

Additional relevant MeSH terms:
Leukemia, Myeloid, Acute
Leukemia, Myeloid
Neoplasms by Histologic Type
Antimetabolites, Antineoplastic
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Enzyme Inhibitors
Protein Kinase Inhibitors