Midostaurin and Azacitidine in Treating Elderly Patients With Acute Myelogenous Leukemia
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.
Chronic Myelomonocytic Leukemia
de Novo Myelodysplastic Syndromes
Recurrent Adult Acute Myeloid Leukemia
Secondary Myelodysplastic Syndromes
Untreated Adult Acute Myeloid Leukemia
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
|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.|
- Maximum tolerated dose of midostaurin in combination with azacitidine in patients with acute myelogenous leukemia (Phase I) [ Time Frame: Day 28 ] [ Designated as safety issue: Yes ]Defined as the dose level below 1 of 3 then 2 of 3 patients experience dose-limiting toxicity (DLT).
- Rate of hematologic improvement [ Time Frame: 2 months ] [ Designated as safety issue: No ]Hematologic toxicity: For patients with ANC > 500/ μl at baseline, dose modifications will be made accordingly. Recovery is defined as neutrophil count > 500/ul if neutrophils nadir is below 500/ul: Hematologic response will be assessed on day 1 of each cycle of azacitidine.
- Complete and partial response rate of midostaurin and azacitidine in untreated acute myelogenous leukemia (Phase I/II) [ Time Frame: after 4 months of treatment ] [ Designated as safety issue: No ]Response will be assessed using the standard morphologic criteria for acute leukemia as follows: Complete remission (CR): ANC ≥ 1000/ uL and platelets of > 100,000/ uL without circulating blasts and bone marrow with < 5% blasts and no Auer rods; Partial remission (PR): This designation requires at least a 50% decrease in the bone marrow blasts to 5-25%.
- Pharmacokinetic profile of midostaurin given with azacitidine (Phase I) [ Time Frame: Before dosing of midostaurin on days 8, 15, and 21 of courses 1 and 2 ] [ Designated as safety issue: No ]
- Time to disease progression [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]The Kaplan-Meier method will be used to estimate survivor function.
- Changes of phosphorylation status of FLT3 in blood and bone marrow samples (Phase I/II) [ Time Frame: Baseline to 4 cycles (16 weeks) ] [ Designated as safety issue: No ]
- Overall survival (Phase I/II) [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]The Kaplan-Meier method will be used to estimate survivor function.
- To correlate treatment response with FLT3 mutational status in a descriptive fashion.(Phase I) [ Time Frame: Baseline to 4 cycles (16 weeks) ] [ Designated as safety issue: No ]
|Study Start Date:||July 2009|
|Estimated Primary Completion Date:||December 2013 (Final data collection date for primary outcome measure)|
Experimental: Arm I
Patients receive azacitidine IV over 10-20 minutes on days 1-7 and oral midostaurin twice daily on days 8-21.
Other Names:Drug: azacitidine
Other Names:Other: laboratory biomarker analysis
Correlative studyOther: bone marrow aspiration
Correlative studyOther: liquid chromatography
Other Name: LCOther: flow cytometry
Correlative studyOther: mutation analysis
Correlative studyOther: pharmacological study
Other Name: pharmacological studiesOther: mass spectrometry
Correlative studyOther: protein expression analysis
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 study.
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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01093573
|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 firstname.lastname@example.org|
|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 email@example.com|
|Principal Investigator:||Brenda Cooper, MD||Case Medical Center, University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center|