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A Phase I/II Study of Midostaurin (PKC412) and 5-Azacitidine for Elderly Patients With Acute Myelogenous Leukemia.

Phase 1/Phase 2
60 Years
Open (Enrolling)
Hematopoietic/Lymphoid Cancer, Chronic Myelomonocytic Leukemia, de Novo Myelodysplastic Syndromes, Myelodysplastic Syndromes, Recurrent Adult Acute Myeloid Leukemia, Secondary Myelodysplastic Syndromes, Untreated Adult Acute Myeloid Leukemia

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Trial Information

A Phase I/II Study of Midostaurin (PKC412) and 5-Azacitidine for Elderly Patients With Acute Myelogenous Leukemia.


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 and overall 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

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.

Inclusion Criteria

Inclusion Criteria

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

- Subjects > 70 years of age with untreated AML, if not candidates for standard
induction chemotherapy or with poor risk AML (i.e. preceding myelodysplastic
syndromes [MDS], myeloproliferative syndromes, leukemia due to cytotoxic chemotherapy
for another condition, adverse cytogenetics or complex karyotype) Acute promyelocytic
leukemia (French-American-British [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

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

- 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 substrates, -inhibitors, and
inducers; an increased anticoagulant effect has been noted in patients treated with
warfarin and midostaurin; the following medications/substances are moderate to
significant inhibitors/inducers of CYP3A4 that, if administered concomitantly with
midostaurin may alter study drug exposure; the use of these medications/substances
within 7 days (>= 6 months for amiodarone) prior to the administration of the first
dose of midostaurin through discontinuation from the study is prohibited; inhibitors
of CYP3A4 and inducers of CYP3A4

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

- Female patients who are pregnant or breast feeding, or patients of reproductive
potential not employing an effective method of birth control; barrier contraceptives
must be used throughout the trial by both sexes, if applicable; women of childbearing
potential must have a negative serum pregnancy test =< 48 hours prior to the
administration of midostaurin

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Maximum tolerated dose of midostaurin in combination with azacitidine in patients with acute myelogenous leukemia (Phase I)

Outcome Description:

Defined as the dose level below 1 of 3 then 2 of 3 patients experience dose-limiting toxicity (DLT).

Outcome Time Frame:

Day 28

Safety Issue:


Principal Investigator

Brenda Cooper, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Case Medical Center, University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center


United States: Food and Drug Administration

Study ID:




Start Date:

July 2009

Completion Date:

Related Keywords:

  • Hematopoietic/Lymphoid Cancer
  • Chronic Myelomonocytic Leukemia
  • de Novo Myelodysplastic Syndromes
  • Myelodysplastic Syndromes
  • Recurrent Adult Acute Myeloid Leukemia
  • Secondary Myelodysplastic Syndromes
  • Untreated Adult Acute Myeloid Leukemia
  • previously treated myelodysplastic syndromes
  • Leukemia
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid
  • Leukemia, Myelomonocytic, Chronic
  • Myelodysplastic Syndromes
  • Preleukemia
  • Leukemia, Myelomonocytic, Acute



Case Medical Center, University Hospitals Seidman Cancer Center, Case Comprehensive Cancer CenterCleveland, Ohio  44106-5065
West Virginia UniversityMorgantown, West Virginia  26506