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Azacitidine

Midostaurin

Staurosporine

Antimetabolites

Enzyme Inhibitors

Protein Kinase Inhibitors

Aza at 75 mg/m2 D1-7 \& Midostaurin 25 mg BID D 8-21

Aza at 75 mg/m2 D1-7 \& Midostaurin 50 mg BID D 8-21

Azacitidine 75 mg/m2 IV D1-7 \& Midostaurin 75 mg PO BID D 8-21

midostaurin

azacitidine

Correlative study: Pretreatment bone marrow aspirates or blood \[(3 ml in EDTA tube (purple top)\] will be analyzed according to local institution guidelines to determine whether blasts contain wild type Flt3, ITD, or Flt 3 mutations.

bone marrow aspiration

mutation analysis

Correlative study: Concentrations of unchanged midostaurin and its major metabolites, CGP52421 and CGP62221 in plasma samples will be determined using a validated liquid chromatography / mass spectrometry method.

Pharmacokinetic study

Brenda Cooper, MD

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.

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.

Midostaurin and Azacitidine in Treating Elderly Patients With Acute Myelogenous Leukemia

A Phase I/II Study of Midostaurin (PKC412) and 5-Azacitidine for Elderly Patients With Acute Myelogenous Leukemia.

Change in Midostaurin trough levels and active metabolite levels between cycles one and two

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 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 .

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%.

Number of patients experiencing at least one instance of specific treatment emergent adverse events

Time to progression after confirmed response

Median time of overall survival of participants from initiation of midostaurin-azacitidine

Number of participants with FLT3 mutation that had a response to treatment

National Cancer Institute (NCI)

Principal Investigator

Patients receive azacitidine IV over 10-20 minutes on days 1-7 and oral midostaurin twice daily on days 8-21.

midostaurin: Given orally

azacitidine: Given IV

Dose Level 1

Dose Level 2

Dose Level 3

Total

50-59 years

60-69 years

70-79 years

80-89 years

Age, Customized

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Brenda Cooper MD

Patients receive Azacitidine at 75 mg/m2 D1-7 \& Midostaurin (25 mg bid, 50 mg bid, and 75 mg bid) mg BID D 8-21

midostaurin: Given orally

azacitidine: Given IV

Midostaurin Dose Escalation

All participants who received treatment for the Phase I part of the study

Maximum Tolerated Dose of Midostaurin in Combination With Azacitidine in Patients With Acute Myelogenous Leukemia (Phase I)

Patients receive azacitidine at 75 mg/m2 D1-7 \& Midostaurin 25 mg BID D 8-21

midostaurin: Given orally

azacitidine: Given IV

.

Patients receive azacitidine at 75 mg/m2 D1-7 \& Midostaurin 50 mg BID D 8-21

Patients receive azacitidine at 75 mg/m2 D1-7 \& Midostaurin 75mg BID D 8-21

Participants that received treatment on the phase I portion of the study.

Number of Participants With Hematologic Improvement (Phase I)

Patients receive azacitidine at 75 mg/m2 D1-7 \& Midostaurin 75 mg BID D 8-21

midostaurin: Given orally

azacitidine: Given IV

All participants that received at least 2 cycles of treatment at the MTD (Dose Level 3)

Overall Response Rate (Phase II)

Participants that received at least one dose of midostaurin at the MTD (Dose Level 3)

Toxicity Profile (Phase II)

All participants on phase II (dose level 3) that were evaluable for response.

Duration of Response

All participants that received treatment at the MTD (dose level 3)

Overall Survival (Phase II)

Patients receive azacitidine IV over 10-20 minutes on days 1-7 and oral midostaurin twice daily on days 8-21.

midostaurin: Given orally

azacitidine: Given IV

bone marrow aspiration: Correlative study: Pretreatment bone marrow aspirates or blood \[(3 ml in EDTA tube (purple top)\] will be analyzed according to local institution guidelines to determine whether blasts contain wild type Flt3, ITD, or Flt 3 mutations.

mutation analysis: Correlative study

Pharmacokinetic study: Correlative study: Concentrations of unchanged midostaurin and its major metabolites, CGP52421 and CGP62221 in plasma samples will be determined using a validated liquid chromatography / mass spectrometry method.

Azacitidine and Midostaurin

There were no subjects with FLT3 mutation, there for this outcome measure has no data.

Correlate Treatment Response With FLT3 Mutational Status in a Descriptive Fashion.(Phase I)

Pharmacokinetic Profile of Midostaurin Given With Azacitidine (Phase I)

Changes of Phosphorylation Status of FLT3 in Blood and Bone Marrow Samples (Phase I/II)

Aza at 75 mg/m2 D1-7 \& Midostaurin 25 mg BID D 8-21

midostaurin: Given orally

azacitidine: Given IV

bone marrow aspiration

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Midostaurin and Azacitidine in Treating Elderly Patients With Acute Myelogenous Leukemia	NCT01093573	Untreated Adult...	midostaurin azacitidine bone marrow asp... mutation analys... Pharmacokinetic...	-	Case Comprehensive Cancer Center
Midostaurin and Azacitidine in Treating Elderly Patients With Acute Myelogenous Leukemia	NCT01093573	Untreated Adult...	midostaurin azacitidine bone marrow asp... mutation analys... Pharmacokinetic...	-	Case Comprehensive Cancer Center

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