Midostaurin and Azacitidine in Treating Elderly Patients With Acute Myelogenous Leukemia - Full Text View

Sponsor:	Case Comprehensive Cancer Center
Information provided by (Responsible Party):	Case Comprehensive Cancer Center
ClinicalTrials.gov Identifier:	NCT01093573

Purpose

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	Intervention	Phase
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	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

Study Type:	Interventional
Study Design:	Endpoint Classification: Safety/Efficacy Study Intervention Model: Single Group Assignment Masking: 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.

Resource links provided by NLM:

Genetics Home Reference related topics: familial acute myeloid leukemia with mutated CEBPA

MedlinePlus related topics: Acute Myeloid Leukemia Cancer Leukemia Myelodysplastic Syndromes

Drug Information available for: Azacitidine

U.S. FDA Resources

Further study details as provided by Case Comprehensive Cancer Center:

Primary Outcome Measures:

Maximum tolerated dose of midostaurin in combination with azacitidine in patients with acute myelogenous leukemia (Phase I) [ Time Frame: Courses repeat every 28 days for up to 8 courses in the absence of unacceptable toxicity ] [ Designated as safety issue: Yes ]
Toxicity of the combination of midostaurin and azacitidine in patients with acute myelogenous leukemia (Phase I/II) [ Time Frame: Courses repeat every 28 days for up to 8 courses in the absence of unacceptable toxicity ] [ Designated as safety issue: Yes ]
Complete and partial response rate and rate of hematologic improvement of midostaurin and azacitidine in untreated acute myelogenous leukemia (Phase I/II) [ Time Frame: Courses repeat every 28 days for up to 8 courses in the absence of disease progression. ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Pharmacokinetic profile of midostaurin given with azacitidine (Phase I) [ Time Frame: Day 8-21 schedule ] [ Designated as safety issue: No ]
Correlation of treatment response with FLT3 mutational status (Phase I/II) [ Time Frame: prior to therapy and 2 days after the start of Midostaurin. ] [ Designated as safety issue: No ]
Changes of phosphorylation status of FLT3 in blood and bone marrow samples (Phase I/II) [ Time Frame: Before and during treatment ] [ Designated as safety issue: No ]
Overall survival (Phase I/II) [ Time Frame: After completion of study treatment, patients are followed every 3 months for 1 year, every 6 months for 2 years, and then annually thereafter. ] [ Designated as safety issue: No ]

Estimated Enrollment:	50
Study Start Date:	July 2009
Estimated Primary Completion Date:	July 2012 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
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

Arms

Assigned Interventions

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

Detailed Description:

PRIMARY OBJECTIVES: 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) SECONDARY OBJECTIVES: I. To describe pharmacokinetics of oral midostaurin given in combination with azacitidine on a day 8-21 schedule. (Phase I) II. To correlate treatment response with FLT3 mutational status in a descriptive fashion. (Phase I/II) III. To assess changes in phosphorylation status of FLT3 in blood and bone marrow samples before and during treatment using high resolution flow cytometry. A bone marrow for investigational studies is planned on the 3rd day of Midostaurin, or on day 10 of the first cycle of chemotherapy. (Phase I/II) IV. To assess overall survival. (Phase I/II) OUTLINE: This is a phase I, dose escalation study of midostaurin followed by a phase II study. Patients receive azacitidine IV over 10-20 minutes on days 1-7 and oral midostaurin twice daily 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 every 3 months for 1 year, every 6 months for 2 years, and then annually thereafter.

Eligibility

Ages Eligible for Study:	60 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion

Prior intensive induction therapy for acute leukemia is allowed only in the phase I portion of this study
Phase I and II portion: Subjects >= 60 years of 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), any subject > 70 years of age with untreated AML
Phase I portion only: Patients of any age who have received one prior attempt at induction chemotherapy (including consolidation), must have recovered from acute toxicities of therapy and be >= 4 weeks from last dose of cytotoxic treatment
Allowed prior treatments for pre-existing hematologic conditions (i.e., MDS, CMML) will include: hydroxyurea, thalidomide, hematopoietic growth factors, Zarnestra, Lenalidomide, arsenic, Imatinib, and corticosteroids, SAHA inhibitors
A minimum of 4 weeks must have elapsed since the administration of thalidomide, Zarnestra, Revlimid, arsenic, SAHA inhibitors, or any investigational medication
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
ECOG performance status 0-2
Please contact study investigator and/or consult protocol document for specific details on laboratory criteria
Congestive heart failure must be medically controlled
Life expectancy without treatment of at least 12 weeks
Patients with and without FLT3 mutations will be eligible to participate
Women and men of childbearing age must agree to use effective methods of contraception since chemotherapy may have harmful effects on the fetus. Furthermore, lactating females must not breastfeed while participating in this clinical trial. Barrier contraception is advised rather than the estro-progestins
Patients must have the ability and willingness to sign a written informed consent document
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 five days must have elapsed since the administration of growth factors Exclusion
Acute promyelocytic leukemia (FAB M3)
Prior autologous or allogeneic stem cell transplantation
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 any other known active cancer (except carcinoma in situ), concurrent severe and/or uncontrolled medical condition (e.g., uncontrolled diabetes, pulmonary, or cardiovascular disease including NYHA grade III-IV congestive heart failure, myocardial infarction within 6 months, and poorly controlled hypertension, chronic renal disease, or active uncontrolled infection)
Known allergy or hypersensitivity to azacitidine, mannitol, or midostaurin
Active or suspicion of CNS leukemia
Patients with HIV disease or active viral hepatitis
Patients with hepatitis B
Patients with pulmonary infiltrates will not be eligible unless resolving
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
Inhibitors of CYP3A4 within the past 7 days (>= 6 months for amiodarone): Antibiotics (clarithromycin, erythromycin, troleandomycin), antifungals (itraconazole, ketoconazole, fluconazole [doses > 200 mg/day], voriconazole, posaconazole), antidepressants (nefazodone, fluvoxamine), calcium channel blockers (verapamil, diltiazem), miscellaneous (amiodarone, grapefruit juice, bitter orange)
Inducers of CYP3A4 within the past 7 days: Anticonvulsants (phenytoin, carbamazepine, phenobarbital, oxcarbazepine), antibiotics (rifampin, rifabutin, rifapentine), miscellaneous (St. John's wort, modafinil)
Patients with bradycardia <50 beats per minute, QTc interval greater than 0. 47 mseconds, and uncontrolled arrhythmias are excluded
Patients with gastric bypass surgery

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT01093573

Locations

United States, Ohio
Case Medical Center, University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center	Recruiting
Cleveland, Ohio, United States, 44106
Contact: Brenda W Cooper, MD 216-844-3213 bxc12@case.edu
Principal Investigator: Brenda Wi Cooper
United States, West Virginia
West Virginia University	Recruiting
Morgantown, West Virginia, United States, 26506
Contact: Michael Craig, MD 304-598-4520 craigm@wvuhealthcare.com

Sponsors and Collaborators

Case Comprehensive Cancer Center

Investigators

Principal Investigator:

Brenda Cooper, MD

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

More Information

No publications provided

Responsible Party:	Case Comprehensive Cancer Center
ClinicalTrials.gov Identifier:	NCT01093573 History of Changes
Other Study ID Numbers:	CASE1908, NCI-2009-01285
Study First Received:	March 24, 2010
Last Updated:	March 16, 2012
Health Authority:	United States: Federal Government

Keywords provided by Case Comprehensive Cancer Center:

previously treated myelodysplastic syndromes

Additional relevant MeSH terms:

Leukemia
Leukemia, Myeloid, Acute
Leukemia, Myeloid
Leukemia, Myelomonocytic, Chronic
Myelodysplastic Syndromes
Preleukemia
Leukemia, Myelomonocytic, Acute
Neoplasms by Histologic Type
Neoplasms
Myelodysplastic-Myeloproliferative Diseases
Bone Marrow Diseases
Hematologic Diseases

Precancerous Conditions
Azacitidine
Staurosporine
4'-N-benzoylstaurosporine
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Enzyme Inhibitors

ClinicalTrials.gov processed this record on May 23, 2012