PKC412 and 5-Azacytidine

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: NCT01202877
Recruitment Status : Completed
First Posted : September 16, 2010
Results First Posted : November 7, 2016
Last Update Posted : November 7, 2016
Novartis Pharmaceuticals
Celgene Corporation
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

Brief Summary:
The goal of this clinical research study is to learn if the combination of PKC412 (also called Midostaurin) and 5-azacytidine can help to control refractory or relapsed acute leukemia and MDS. The safety and best dose of the combination of the drugs will also be studied.

Condition or disease Intervention/treatment Phase
Leukemia Drug: 5-azacytidine Drug: PKC412 Phase 1 Phase 2

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 54 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Combination of PKC412 and 5-Azacytidine for the Treatment of Patients With Refractory or Relapsed Acute Leukemia and Myelodysplastic Syndrome (MDS)
Study Start Date : March 2011
Actual Primary Completion Date : July 2015
Actual Study Completion Date : July 2015

Arm Intervention/treatment
Experimental: 5-azacytidine + PKC412
5-azacytidine 75 mg/m2/d subcutaneously (SQ) or by vein (IV) on days 1-7 of a 28 day cycle. PKC412 50 mg by mouth twice daily for 14 days (days 8-21), of every 28 day cycle. Starting with cycle 2, PKC412 administered continuously (daily).
Drug: 5-azacytidine
Starting dose: 75 mg/m2/d subcutaneously (SQ) or by vein (IV) on days 1-7 of a 28 day cycle.
Other Names:
  • Azacitidine
  • 5-aza
  • Vidaza
  • 5-AZC
  • AZA-CR
  • Ladakamycin
  • NSC-102816

Drug: PKC412
Starting dose: 50 mg by mouth twice daily for 14 days (days 8-21), of every 28 day cycle. Starting with cycle 2, PKC412 administered continuously (daily).
Other Name: Midostaurin

Primary Outcome Measures :
  1. Participant Best Response Assessed Using Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1 [ Time Frame: 6 months ]
    Criteria for response per international working group for Myelodysplastic Syndrome (MDS) & acute myeloid leukemia (AML) where responders obtained a complete remission (CR), a CR with incomplete bone marrow recovery (CRi), a morphologic leukemia-free status (MLFS), or a partial remission (PR). CR: <5% bone marrow blasts, neutrophil count>1.0 X10⁹/L, & platelet count>100 X10⁹/L. CRi: all CR criteria except residual neutropenia (<1.0 X10⁹/L) or thrombocytopenia (<100 X10⁹/L). MLFS: <5% blasts in bone marrow regardless of neutrophil & platelet count in peripheral blood. PR: all CR criteria, except reduction> 50% in bone marrow blasts, but still >5%. Clinical responses evaluated using RECIST version 1.1 criteria after every two cycles, with confirmation of clinical response at 4 weeks after achieving response.

  2. Overall Response (OR) Within 6 Months [ Time Frame: 6 Months ]
    Overall response defined as percentage of participants with response as follows: (OR = CR [complete response (CR) rate] + CRi [complete remission with incomplete count recovery] + PR [partial remission] + HI [hematologic improvement]) within 6 months of treatment initiation

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. Patients with MDS, chronic myelomonocytic leukemia (CMML), AML or biphenotypic or bilineage leukemia 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. Eastern Cooperative Oncology Group (ECOG) Performance Status </= 2
  5. Adequate liver (bilirubin </= 2x ULN, ALT </= 2.5x ULN) and renal (creatinine </= 2x 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 corrected QT interval (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; congestive heart failure (CHF) NY Heart Association class III or IV; Patients with an ejection fraction < 50% assessed by multigated radionuclide angiography (MUGA) or ECHO scan within 14 days of Day 1.

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): NCT01202877

United States, Texas
University of Texas MD Anderson Cancer Center
Houston, Texas, United States, 77030
Sponsors and Collaborators
M.D. Anderson Cancer Center
Novartis Pharmaceuticals
Celgene Corporation
Principal Investigator: Jorge Cortes, MD M.D. Anderson Cancer Center

Additional Information:
Responsible Party: M.D. Anderson Cancer Center Identifier: NCT01202877     History of Changes
Other Study ID Numbers: 2010-0374
NCI-2012-01896 ( Registry Identifier: NCI CTRP )
First Posted: September 16, 2010    Key Record Dates
Results First Posted: November 7, 2016
Last Update Posted: November 7, 2016
Last Verified: July 2015

Keywords provided by M.D. Anderson Cancer Center:
Myelodysplastic Syndrome
Refractory acute leukemias
Relapsed acute leukemia
Acute myeloid leukemia

Additional relevant MeSH terms:
Myelodysplastic Syndromes
Neoplasms by Histologic Type
Bone Marrow Diseases
Hematologic Diseases
Antimetabolites, Antineoplastic
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Enzyme Inhibitors
Protein Kinase Inhibitors