Midostaurin and Azacitidine in Treating Elderly Patients With Acute Myelogenous Leukemia

Phase 1

Completed

• Conditions: Untreated Adult Acute Myeloid Leukemia
• Interventions: Drug: midostaurin; Drug: azacitidine; Other: bone marrow aspiration; Other: mutation analysis; Other: Pharmacokinetic study

• Registration Number: NCT01093573
• Lead Sponsor: Brenda Cooper, MD

Brief Summary

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.

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) 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 survival of the regimen in untreated patients. (Phase II)

TERTIARY OBJECTIVES:

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.

Study Timeline

• Study Start: 2009-07
• Study First Submitted: 2010-03-24
• Study First Submitted QC: 2010-03-25
• Study First Posted: 2010-03-26
• Primary Completion: 2016-09-08
• Study Completion: 2017-05-05
• Results First Submitted: 2019-03-19
• Results First Submitted QC: 2020-04-22
• Results First Posted: 2020-05-01
• Status Verified: 2022-06
• Last Update Submitted: 2022-06-10
• Last Update Posted: 2022-06-30

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 34

Inclusion Criteria

Not provided

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Exclusion Criteria

Not provided

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Dose Level 1	midostaurin	Aza at 75 mg/m2 D1-7 \& Midostaurin 25 mg BID D 8-21
Dose Level 1	azacitidine	Aza at 75 mg/m2 D1-7 \& Midostaurin 25 mg BID D 8-21
Dose Level 1	bone marrow aspiration	Aza at 75 mg/m2 D1-7 \& Midostaurin 25 mg BID D 8-21
Dose Level 1	mutation analysis	Aza at 75 mg/m2 D1-7 \& Midostaurin 25 mg BID D 8-21
Dose Level 1	Pharmacokinetic study	Aza at 75 mg/m2 D1-7 \& Midostaurin 25 mg BID D 8-21
Dose Level 2	midostaurin	Aza at 75 mg/m2 D1-7 \& Midostaurin 50 mg BID D 8-21
Dose Level 2	azacitidine	Aza at 75 mg/m2 D1-7 \& Midostaurin 50 mg BID D 8-21
Dose Level 2	bone marrow aspiration	Aza at 75 mg/m2 D1-7 \& Midostaurin 50 mg BID D 8-21
Dose Level 2	mutation analysis	Aza at 75 mg/m2 D1-7 \& Midostaurin 50 mg BID D 8-21
Dose Level 2	Pharmacokinetic study	Aza at 75 mg/m2 D1-7 \& Midostaurin 50 mg BID D 8-21
Dose Level 3	midostaurin	Azacitidine 75 mg/m2 IV D1-7 \& Midostaurin 75 mg PO BID D 8-21
Dose Level 3	azacitidine	Azacitidine 75 mg/m2 IV D1-7 \& Midostaurin 75 mg PO BID D 8-21
Dose Level 3	bone marrow aspiration	Azacitidine 75 mg/m2 IV D1-7 \& Midostaurin 75 mg PO BID D 8-21
Dose Level 3	mutation analysis	Azacitidine 75 mg/m2 IV D1-7 \& Midostaurin 75 mg PO BID D 8-21
Dose Level 3	Pharmacokinetic study	Azacitidine 75 mg/m2 IV D1-7 \& Midostaurin 75 mg PO BID D 8-21

Primary Outcome Measures

Name	Time	Method
Maximum Tolerated Dose of Midostaurin in Combination With Azacitidine in Patients With Acute Myelogenous Leukemia (Phase I)	Day 28	Patients received azacitidine 75 mg/m intravenous over 30 minutes daily for 7 consecutive days followed by escalating doses of oral midostaurin (25 mg bid, 50 mg bid, and 75 mg bid) days 8-21. Determination of the maximum tolerated dose (MTD) was based on dose-limiting toxicities (DLT) observed during the first cycle of treatment
Number of Participants With Hematologic Improvement (Phase I)	After 2 cycles of therapy	Number of participants with HI. Hematologic improvement (HI): must last at least 2 months in the absence of ongoing cytotoxic therapy and will be another endpoint of interest (although it will not be considered in the final statistical analysis) and will be defined according to IWG criteria .
Overall Response Rate (Phase II)	after 4 months of treatment	Number of participants with CR, CRi, PR and Hematologic improvement (HI). 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; Morphologic complete remission with incomplete blood recovery (CRi): Patients fulfills all of the criteria for remission except for residual neutropenia (ANC \< 1000/ uL) or thrombocytopenia (platelet count \< 100,000/uL). Partial remission (PR): This designation requires at least a 50% decrease in the bone marrow blasts to 5-25%.
Toxicity Profile (Phase II)	during treatment up to 10 cycles	Number of patients experiencing at least one instance of specific treatment emergent adverse events

Secondary Outcome Measures

Name	Time	Method
Correlate Treatment Response With FLT3 Mutational Status in a Descriptive Fashion.(Phase I)	Baseline to 4 cycles (16 weeks)	Number of participants with FLT3 mutation that had a response to treatment
Duration of Response	Up to 3 years	Time to progression after confirmed response
Overall Survival (Phase II)	Up to 3 years	Median time of overall survival of participants from initiation of midostaurin-azacitidine

Trial Locations

Locations (2)

University Hospitals Cleveland Medical Center, Seidman Cancer Center, Case Comprehensive Cancer Center; 🇺🇸 Cleveland, Ohio, United States

West Virginia University; 🇺🇸 Morgantown, West Virginia, United States