PKC412 and 5-Azacytidine

NCT01202877 | Completed Phase 1 Results

• 2 other identifiers: 2010-0374NCI-2012-01896
• Study Type: interventional
• Target: 54
• Locations: 1 country
• Sites: 1

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.

Conditions

Leukemia

Keywords

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

Outcome Measures

Primary Outcomes (2)

• Participant Best Response Assessed Using Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1

  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.

  6 months

• Overall Response (OR) Within 6 Months

  Overall response defined as number 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. 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%.

  6 Months

Study Arms (1)

5-azacytidine + PKC412

EXPERIMENTAL

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; Drug: PKC412

Interventions

5-azacytidine DRUG

Starting dose: 75 mg/m2/d subcutaneously (SQ) or by vein (IV) on days 1-7 of a 28 day cycle.

Also known as: Azacitidine, 5-aza, Vidaza, 5-AZC, AZA-CR, Ladakamycin, NSC-102816

5-azacytidine + PKC412

PKC412 DRUG

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).

Also known as: Midostaurin

5-azacytidine + PKC412

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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 World Health Organization (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.
• Patients must have evidence of FLT3 activating mutations.
• Age \>/= 18 years
• Eastern Cooperative Oncology Group (ECOG) Performance Status \</= 2
• Adequate liver (bilirubin \</= 2x ULN, alanine aminotransferase (ALT) \</= 2.5x ULN) and renal (creatinine \</= 2x ULN) function
• Patients must provide written informed consent.
• 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.
• 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.
• \*\*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.
• 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 .
• Negative urine or serum pregnancy test within 2 weeks.

You may not qualify if:

• Patients with known allergy or hypersensitivity to PKC412, mannitol or 5-azacytidine, or any of their components.
• Patients who have received any treatment of midostaurin prior to study entry.
• Patients with known impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of PKC412.
• Patients who demonstrated primary resistance to any FLT3 inhibitor or who relapsed while on therapy with a FLT3 inhibitor.
• 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.
• Patients with a known confirmed diagnosis of HIV infection or active viral hepatitis. HIV patients not on specific antiretroviral therapy are eligible for participation.
• Patients who have had any major surgical procedure within 14 days of Day 1.
• Patients unwilling or unable to comply with the protocol.
• Patients with known advanced malignant disease of the central nervous system.
• 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 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) NY Heart Association class III or IV; Patients with an ejection fraction \< 50% assessed by multigated radionuclide angiography (MUGA) or echocardiogram (ECHO) scan within 14 days of Day 1.

Sponsors & Collaborators

• M.D. Anderson Cancer Center: lead
• Novartis Pharmaceuticals: collaborator
• Celgene Corporation: collaborator

Study Sites (1)

University of Texas MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Related Links

• University of Texas MD Anderson Cancer Center Website

MeSH Terms

Conditions

Leukemia; Myelodysplastic Syndromes; Leukemia, Myeloid, Acute

Interventions

Azacitidine; midostaurin

Condition Hierarchy (Ancestors)

Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Bone Marrow Diseases; Leukemia, Myeloid

Intervention Hierarchy (Ancestors)

Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides

Results Point of Contact

• Title: Jorge Cortes, MD/Professor, Leukemia
• Organization: The University of Texas (UT) MD Anderson Cancer Center

CR_Study_Registration@mdanderson.org

1-877-632-6789

Study Officials

• Jorge Cortes, MD

  M.D. Anderson Cancer Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 14, 2010
• First Posted: September 16, 2010
• Study Start: March 1, 2011
• Primary Completion: July 1, 2015
• Study Completion: July 1, 2015
• Last Updated: October 16, 2018
• Results First Posted: November 7, 2016

Record last verified: 2015-07

Locations

US (1)