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A Combination of PKC412 and 5-Azacytidine for the Treatment of Patients With Refractory or Relapsed Acute Leukemia and Myelodysplastic Syndrome (MDS)

Phase 1/Phase 2
18 Years
Open (Enrolling)

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Trial Information

A Combination of PKC412 and 5-Azacytidine for the Treatment of Patients With Refractory or Relapsed Acute Leukemia and Myelodysplastic Syndrome (MDS)

The Study Drugs:

PKC412 is designed to block certain receptors (FLT3-Kinase) on cancer cells that are
responsible for cancer growth. This may cause the cancer cells to die.

5-azacytidine is designed to cause changes to certain genes that are thought to participate
in causing leukemia. These changes are thought to silence these genes so they cannot
contribute any longer to sustain the growth of leukemia and MDS.

Study Groups:

If you are found to be eligible to take part in this study, you will be assigned to a part
of the study based on when you join.

- If you are one of the first 6 participants, you will receive a pre-planned dose of the
study drugs. If 2 participants experience severe side effects, the rest of this group
will receive a lower dose.

- If you are not one of the first 6 participants, and fewer than 2 patients had severe
side effects in the first group, you will receive the drugs at a higher dose than the
first 6 participants.

Study Drug Administration:

You will receive 5-azacytidine by vein over about 30 minutes or through a needle under your
skin on Days 1-7 of each 28-day study cycle. Your doctor will decide if you will get the
drug by vein or under the skin. You will be required to return to MD Anderson for the
first 7 days of every cycle to receive 5-azacytidine.

On Days 8-21 of cycle 1, you will take PKC412 capsules by mouth 2 times a day. Starting
with Cycle 2, you will take PKC412 capsules by mouth every day. The research staff will
tell you how to take the study drug and you will also be given instructions.

If you have severe side effects from the study drug, the study doctor may decide to stop
drug dosing until your side effects improve.

Study Visits:

At every visit, you will be asked about any side effects you have experienced and to list
any drugs you may be taking.

- At the start of Cycles 1-2 (+/- 4 days) and then every 2-3 cycles, you will have a
complete physical exam.

- Every week during Cycles 1-3 (+/- 4 days) and then every 2-4 weeks, blood (about 1
tablespoon) will be drawn for routine tests and to test your kidney and liver function.

- On Day 28 of Cycle 1 (+/- 4 days) and then every 1-3 cycles, you will have a bone
marrow aspirate to check the status of the disease.

- On Day 8 (+/- 1 day) of each cycle for the first cycle before initiation of
Midostaurin, then before the start of Midostaurin on Cycle 2, then on Day 1 every 2-3
Cycles, you will have an ECG.

- On Days 8, 15, and 21 of Cycle 1 and Day 1 of Cycle 2, blood (about 1 teaspoon) will be
drawn for PK testing before you take the study drug.

If you stay on study for longer than 6 months, your doctor will decide what tests and
procedures you will have and when they will be performed. At least every 6-12 months you
will have a bone marrow aspirate.

Length of Study:

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

This is an investigational study. PKC412 is not FDA approved or commercially available. It
is currently being used for research purposes only. 5-azacytidine is FDA approved and
commercially available for the treatment of patients with MDS. The combination of these
drugs to treat refractory or relapsed acute leukemia and MDS is investigational.

Up to 54 patients will take part in this study. All will be enrolled at MD Anderson.

Inclusion Criteria:

1. Patients with MDS, CMML or AML, who have failed prior therapy. Patients with MDS or
CMML should have failed prior therapy with a hypomethylating agent and/or with
lenalidomide. Patients with AML should have failed any prior induction therapy or
have relapsed after prior therapy, or be previously untreated and unable or unwilling
to receive conventional chemotherapy (e.g., patients age >/=65 years). Patients with
MDS or CMML who received therapy with a hypomethylating agent and progress to AML are
eligible at the time of diagnosis of AML regardless any prior therapy for AML. The
WHO classification will be used for AML. Patients with MDS, CMML or AML who have
received no prior therapy are eligible if not candidates to receive or refuse
standard therapy.

2. Patients must have evidence of FLT3 activating mutations.

3. Age >/= 18 years

4. ECOG Performance Status
5. Adequate liver (bilirubin ULN) function

6. Patients must provide written informed consent.

7. Patients must have been off chemotherapy for 2 weeks prior to entering this study,
unless there is evidence of rapidly progressive disease, and must have recovered from
the toxic effects of that therapy to at least grade 1. Use of hydroxyurea for
patients with rapidly proliferative disease is allowed before the start of study
therapy and for the first four weeks on therapy.

8. Women of childbearing potential must practice contraception. Women considered not of
childbearing potential include any of the following: no menses for at least 5 years
or menses within 5 years but amenorrheic for at least 2 months and luteinizing
hormone (LH) and follicular stimulating hormone (FSH) values within normal range
(according to definition of postmenopausal for laboratory used) or bilateral
oophorectomy or radiation castration and amenorrheic for at least 3 months. Females
of childbearing potential: Recommendation is for 2 effective contraceptive methods
during the study. 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.

9. **continued from above: 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.

10. Sexually active males should use a condom during intercourse while taking drug and
for 3 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 .

11. Negative urine or serum pregnancy test within 2 weeks.

Exclusion Criteria:

1. Patients with known allergy or hypersensitivity to PKC412, mannitol or 5-azacytidine,
or any of their components.

2. Patients who have received any treatment of midostaurin prior to study entry.

3. Patients with known impairment of gastrointestinal (GI) function or GI disease that
may significantly alter the absorption of PKC412.

4. Patients who demonstrated primary resistance to any FLT3 inhibitor or who relapsed
while on therapy with a FLT3 inhibitor.

5. Patients with any other known disease (except carcinoma in-situ) concurrent severe
and/or uncontrolled medical condition (e.g. uncontrolled diabetes with fasting
glucose > 200 mg/dl despite optimal management, cardiovascular disease including
congestive heart failure (NYHA Class III or IV), myocardial infarction within 6
months and poorly controlled hypertension with systolic > 160 mmHg and diastolic >
100 mmHg, chronic renal disease, or active uncontrolled systemic infection) which
could compromise participation in the study.

6. Patients with a known confirmed diagnosis of HIV infection or active viral hepatitis.
HIV patients not on specific antiretroviral therapy are eligible for participation.

7. Patients who have had any major surgical procedure within 14 days of Day 1.

8. Patients unwilling or unable to comply with the protocol.

9. Patients with known advanced malignant disease of the central nervous system.

10. Impaired cardiac function including any of the following: Screening ECG with a QTc >
470 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 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; CHF NY Heart Association
class III or IV; Patients with an ejection fraction < 50% assessed by MUGA or ECHO
scan within 14 days of Day 1.

Type of Study:


Study Design:

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

Outcome Measure:

Number of Patients with Complete Response (CR)

Outcome Time Frame:

6 months

Safety Issue:


Principal Investigator

Jorge Cortes, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

UT MD Anderson Cancer Center


United States: Food and Drug Administration

Study ID:




Start Date:

March 2011

Completion Date:

Related Keywords:

  • Leukemia
  • Myelodysplastic Syndrome
  • MDS
  • Refractory acute leukemias
  • Relapsed acute leukemia
  • Acute myeloid leukemia
  • AML
  • 5-Azacytidine
  • Azacitidine
  • 5-aza
  • Vidaza
  • 5-AZC
  • AZA-CR
  • Ladakamycin
  • NSC-102816
  • PKC412
  • Leukemia
  • Myelodysplastic Syndromes
  • Preleukemia



UT MD Anderson Cancer Center Houston, Texas  77030