Trial Outcomes & Findings for Midostaurin and Azacitidine in Treating Elderly Patients With Acute Myelogenous Leukemia (NCT NCT01093573)

Last Updated: 2022-06-30

Results Overview

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

Recruitment status

COMPLETED

Study phase

PHASE1/PHASE2

Target enrollment

34 participants

Primary outcome timeframe

Day 28

Results posted on

2022-06-30

Participant Flow

Participant milestones

Participant milestones
Measure	Dose Level 1 Aza at 75 mg/m2 D1-7 \& Midostaurin 25 mg BID D 8-21 midostaurin: Given orally azacitidine: Given IV bone marrow aspiration	Dose Level 2 Aza at 75 mg/m2 D1-7 \& Midostaurin 50 mg BID D 8-21	Dose Level 3 Azacitidine 75 mg/m2 IV D1-7 \& Midostaurin 75 mg PO BID D 8-21
Overall Study STARTED	3	3	28
Overall Study COMPLETED	3	3	26
Overall Study NOT COMPLETED	0	0	2

Reasons for withdrawal

Reasons for withdrawal
Measure	Dose Level 1 Aza at 75 mg/m2 D1-7 \& Midostaurin 25 mg BID D 8-21 midostaurin: Given orally azacitidine: Given IV bone marrow aspiration	Dose Level 2 Aza at 75 mg/m2 D1-7 \& Midostaurin 50 mg BID D 8-21	Dose Level 3 Azacitidine 75 mg/m2 IV D1-7 \& Midostaurin 75 mg PO BID D 8-21
Overall Study Physician Decision	0	0	1
Overall Study Insurance Denied	0	0	1

Baseline Characteristics

Midostaurin and Azacitidine in Treating Elderly Patients With Acute Myelogenous Leukemia

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Dose Level 1 n=3 Participants Aza at 75 mg/m2 D1-7 \& Midostaurin 25 mg BID D 8-21	Dose Level 2 n=3 Participants Aza at 75 mg/m2 D1-7 \& Midostaurin 50 mg BID D 8-21	Dose Level 3 n=28 Participants Azacitidine 75 mg/m2 IV D1-7 \& Midostaurin 75 mg PO BID D 8-21	Total n=34 Participants Total of all reporting groups
Age, Customized 50-59 years	0 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	1 Participants n=4 Participants
Age, Customized 60-69 years	1 Participants n=5 Participants	1 Participants n=7 Participants	4 Participants n=5 Participants	6 Participants n=4 Participants
Age, Customized 70-79 years	1 Participants n=5 Participants	2 Participants n=7 Participants	16 Participants n=5 Participants	19 Participants n=4 Participants
Age, Customized 80-89 years	1 Participants n=5 Participants	0 Participants n=7 Participants	7 Participants n=5 Participants	8 Participants n=4 Participants
Sex: Female, Male Female	2 Participants n=5 Participants	2 Participants n=7 Participants	15 Participants n=5 Participants	19 Participants n=4 Participants
Sex: Female, Male Male	1 Participants n=5 Participants	1 Participants n=7 Participants	13 Participants n=5 Participants	15 Participants n=4 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	3 Participants n=5 Participants	3 Participants n=7 Participants	28 Participants n=5 Participants	34 Participants n=4 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	1 Participants n=7 Participants	4 Participants n=5 Participants	5 Participants n=4 Participants
Race (NIH/OMB) White	3 Participants n=5 Participants	2 Participants n=7 Participants	24 Participants n=5 Participants	29 Participants n=4 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Region of Enrollment United States	3 participants n=5 Participants	3 participants n=7 Participants	28 participants n=5 Participants	34 participants n=4 Participants

PRIMARY outcome

Timeframe: Day 28

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

Outcome measures

Outcome measures
Measure	Midostaurin Dose Escalation n=11 Participants 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	Dose Level 2 Patients receive azacitidine at 75 mg/m2 D1-7 \& Midostaurin 50 mg BID D 8-21	Dose Level 3 Patients receive azacitidine at 75 mg/m2 D1-7 \& Midostaurin 75mg BID D 8-21
Maximum Tolerated Dose of Midostaurin in Combination With Azacitidine in Patients With Acute Myelogenous Leukemia (Phase I)	75 mg/bid	—	—

PRIMARY outcome

Timeframe: After 2 cycles of therapy

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

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 .

Outcome measures

Outcome measures
Measure	Midostaurin Dose Escalation n=3 Participants 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	Dose Level 2 n=3 Participants Patients receive azacitidine at 75 mg/m2 D1-7 \& Midostaurin 50 mg BID D 8-21	Dose Level 3 n=11 Participants Patients receive azacitidine at 75 mg/m2 D1-7 \& Midostaurin 75mg BID D 8-21
Number of Participants With Hematologic Improvement (Phase I)	0 Participants	0 Participants	2 Participants

PRIMARY outcome

Timeframe: after 4 months of treatment

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

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%.

Outcome measures

Outcome measures
Measure	Midostaurin Dose Escalation n=24 Participants 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	Dose Level 2 Patients receive azacitidine at 75 mg/m2 D1-7 \& Midostaurin 50 mg BID D 8-21	Dose Level 3 Patients receive azacitidine at 75 mg/m2 D1-7 \& Midostaurin 75mg BID D 8-21
Overall Response Rate (Phase II) Complete Remission (CR)	4 Participants	—	—
Overall Response Rate (Phase II) Complete Remission with incomplete recovery (CRi)	1 Participants	—	—
Overall Response Rate (Phase II) Partial Remission	2 Participants	—	—
Overall Response Rate (Phase II) No remission/response	17 Participants	—	—
Overall Response Rate (Phase II) Hematologic improvement without CR/PR	0 Participants	—	—

PRIMARY outcome

Timeframe: during treatment up to 10 cycles

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

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

Outcome measures

Outcome measures
Measure	Midostaurin Dose Escalation n=24 Participants 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	Dose Level 2 Patients receive azacitidine at 75 mg/m2 D1-7 \& Midostaurin 50 mg BID D 8-21	Dose Level 3 Patients receive azacitidine at 75 mg/m2 D1-7 \& Midostaurin 75mg BID D 8-21
Toxicity Profile (Phase II)	24 Participants	—	—

SECONDARY outcome

Timeframe: Up to 3 years

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

Time to progression after confirmed response

Outcome measures

Outcome measures
Measure	Midostaurin Dose Escalation n=7 Participants 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	Dose Level 2 Patients receive azacitidine at 75 mg/m2 D1-7 \& Midostaurin 50 mg BID D 8-21	Dose Level 3 Patients receive azacitidine at 75 mg/m2 D1-7 \& Midostaurin 75mg BID D 8-21
Duration of Response	252 days Interval 14.0 to 517.0	—	—

SECONDARY outcome

Timeframe: Up to 3 years

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

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

Outcome measures

Outcome measures
Measure	Midostaurin Dose Escalation n=24 Participants 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	Dose Level 2 Patients receive azacitidine at 75 mg/m2 D1-7 \& Midostaurin 50 mg BID D 8-21	Dose Level 3 Patients receive azacitidine at 75 mg/m2 D1-7 \& Midostaurin 75mg BID D 8-21
Overall Survival (Phase II)	244 days Interval 203.0 to 467.0	—	—

SECONDARY outcome

Timeframe: Baseline to 4 cycles (16 weeks)

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

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

Outcome measures

Outcome data not reported

OTHER_PRE_SPECIFIED outcome

Timeframe: after 2 cycles

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

Outcome measures

Outcome data not reported

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline to 4 cycles (16 weeks)

Outcome measures

Outcome data not reported

Adverse Events

Dose Level 1

Serious events: 3 serious events

Other events: 3 other events

Deaths: 1 deaths

Dose Level 2

Serious events: 1 serious events

Other events: 3 other events

Deaths: 1 deaths

Dose Level 3

Serious events: 22 serious events

Other events: 26 other events

Deaths: 3 deaths

Serious adverse events

Other adverse events

Additional Information

Brenda Cooper MD

Case Comprehensive Cancer Center

Phone: (216) 844-3213

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Dose Level 1 n=3 participants at risk 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 2 n=3 participants at risk 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 3 n=28 participants at risk 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
Gastrointestinal disorders Abdominal pain	0.00% 0/3 • Adverse events collected while participants were on study for up to 3 years.	0.00% 0/3 • Adverse events collected while participants were on study for up to 3 years.	3.8% 1/26 • Number of events 1 • Adverse events collected while participants were on study for up to 3 years.
Metabolism and nutrition disorders Alkalosis	0.00% 0/3 • Adverse events collected while participants were on study for up to 3 years.	0.00% 0/3 • Adverse events collected while participants were on study for up to 3 years.	3.6% 1/28 • Number of events 1 • Adverse events collected while participants were on study for up to 3 years.
Blood and lymphatic system disorders Anemia	0.00% 0/3 • Adverse events collected while participants were on study for up to 3 years.	0.00% 0/3 • Adverse events collected while participants were on study for up to 3 years.	3.6% 1/28 • Number of events 1 • Adverse events collected while participants were on study for up to 3 years.
Infections and infestations Anorectal infection	0.00% 0/3 • Adverse events collected while participants were on study for up to 3 years.	0.00% 0/3 • Adverse events collected while participants were on study for up to 3 years.	3.6% 1/28 • Number of events 1 • Adverse events collected while participants were on study for up to 3 years.
Cardiac disorders Atrial fibrillation	0.00% 0/3 • Adverse events collected while participants were on study for up to 3 years.	0.00% 0/3 • Adverse events collected while participants were on study for up to 3 years.	3.6% 1/28 • Number of events 2 • Adverse events collected while participants were on study for up to 3 years.
Infections and infestations Catheter related infection	0.00% 0/3 • Adverse events collected while participants were on study for up to 3 years.	0.00% 0/3 • Adverse events collected while participants were on study for up to 3 years.	3.6% 1/28 • Number of events 2 • Adverse events collected while participants were on study for up to 3 years.
Cardiac disorders Chest pain - cardiac	0.00% 0/3 • Adverse events collected while participants were on study for up to 3 years.	0.00% 0/3 • Adverse events collected while participants were on study for up to 3 years.	3.6% 1/28 • Number of events 1 • Adverse events collected while participants were on study for up to 3 years.
Gastrointestinal disorders Colitis	33.3% 1/3 • Number of events 1 • Adverse events collected while participants were on study for up to 3 years.	0.00% 0/3 • Adverse events collected while participants were on study for up to 3 years.	0.00% 0/28 • Adverse events collected while participants were on study for up to 3 years.
Gastrointestinal disorders Colonic perforation	0.00% 0/3 • Adverse events collected while participants were on study for up to 3 years.	0.00% 0/3 • Adverse events collected while participants were on study for up to 3 years.	3.6% 1/28 • Number of events 1 • Adverse events collected while participants were on study for up to 3 years.
Infections and infestations Conjunctivitis infective	33.3% 1/3 • Number of events 1 • Adverse events collected while participants were on study for up to 3 years.	0.00% 0/3 • Adverse events collected while participants were on study for up to 3 years.	0.00% 0/28 • Adverse events collected while participants were on study for up to 3 years.
Investigations Creatinine increased	0.00% 0/3 • Adverse events collected while participants were on study for up to 3 years.	0.00% 0/3 • Adverse events collected while participants were on study for up to 3 years.	3.6% 1/28 • Number of events 1 • Adverse events collected while participants were on study for up to 3 years.
General disorders Death NOS	33.3% 1/3 • Number of events 1 • Adverse events collected while participants were on study for up to 3 years.	33.3% 1/3 • Number of events 1 • Adverse events collected while participants were on study for up to 3 years.	3.6% 1/28 • Number of events 1 • Adverse events collected while participants were on study for up to 3 years.
Metabolism and nutrition disorders Dehydration	33.3% 1/3 • Number of events 1 • Adverse events collected while participants were on study for up to 3 years.	0.00% 0/3 • Adverse events collected while participants were on study for up to 3 years.	0.00% 0/28 • Adverse events collected while participants were on study for up to 3 years.
Gastrointestinal disorders Diarrhea	33.3% 1/3 • Number of events 1 • Adverse events collected while participants were on study for up to 3 years.	0.00% 0/3 • Adverse events collected while participants were on study for up to 3 years.	0.00% 0/28 • Adverse events collected while participants were on study for up to 3 years.
Gastrointestinal disorders Dyspepsia	0.00% 0/3 • Adverse events collected while participants were on study for up to 3 years.	0.00% 0/3 • Adverse events collected while participants were on study for up to 3 years.	3.6% 1/28 • Number of events 1 • Adverse events collected while participants were on study for up to 3 years.
Blood and lymphatic system disorders Febrile neutropenia	0.00% 0/3 • Adverse events collected while participants were on study for up to 3 years.	33.3% 1/3 • Number of events 2 • Adverse events collected while participants were on study for up to 3 years.	21.4% 6/28 • Number of events 6 • Adverse events collected while participants were on study for up to 3 years.
General disorders Fever	33.3% 1/3 • Number of events 1 • Adverse events collected while participants were on study for up to 3 years.	0.00% 0/3 • Adverse events collected while participants were on study for up to 3 years.	3.6% 1/28 • Number of events 3 • Adverse events collected while participants were on study for up to 3 years.
Vascular disorders Hypotension	0.00% 0/3 • Adverse events collected while participants were on study for up to 3 years.	0.00% 0/3 • Adverse events collected while participants were on study for up to 3 years.	10.7% 3/28 • Number of events 3 • Adverse events collected while participants were on study for up to 3 years.
Infections and infestations Pneumonia	0.00% 0/3 • Adverse events collected while participants were on study for up to 3 years.	0.00% 0/3 • Adverse events collected while participants were on study for up to 3 years.	3.6% 1/28 • Number of events 1 • Adverse events collected while participants were on study for up to 3 years.
Gastrointestinal disorders Intra-abdominal hemorrhage	33.3% 1/3 • Number of events 1 • Adverse events collected while participants were on study for up to 3 years.	0.00% 0/3 • Adverse events collected while participants were on study for up to 3 years.	0.00% 0/28 • Adverse events collected while participants were on study for up to 3 years.
Infections and infestations Lung infection	0.00% 0/3 • Adverse events collected while participants were on study for up to 3 years.	0.00% 0/3 • Adverse events collected while participants were on study for up to 3 years.	3.6% 1/28 • Number of events 1 • Adverse events collected while participants were on study for up to 3 years.
General disorders Multi-organ failure	0.00% 0/3 • Adverse events collected while participants were on study for up to 3 years.	0.00% 0/3 • Adverse events collected while participants were on study for up to 3 years.	3.6% 1/28 • Number of events 1 • Adverse events collected while participants were on study for up to 3 years.
Gastrointestinal disorders Nausea	0.00% 0/3 • Adverse events collected while participants were on study for up to 3 years.	0.00% 0/3 • Adverse events collected while participants were on study for up to 3 years.	3.6% 1/28 • Number of events 1 • Adverse events collected while participants were on study for up to 3 years.
Investigations Neutrophil count decreased	0.00% 0/3 • Adverse events collected while participants were on study for up to 3 years.	0.00% 0/3 • Adverse events collected while participants were on study for up to 3 years.	7.1% 2/28 • Number of events 4 • Adverse events collected while participants were on study for up to 3 years.
Infections and infestations Penile infection	0.00% 0/3 • Adverse events collected while participants were on study for up to 3 years.	0.00% 0/3 • Adverse events collected while participants were on study for up to 3 years.	3.6% 1/28 • Number of events 1 • Adverse events collected while participants were on study for up to 3 years.
Respiratory, thoracic and mediastinal disorders Respiratory failure	0.00% 0/3 • Adverse events collected while participants were on study for up to 3 years.	0.00% 0/3 • Adverse events collected while participants were on study for up to 3 years.	3.6% 1/28 • Number of events 1 • Adverse events collected while participants were on study for up to 3 years.
Gastrointestinal disorders Salivary duct inflammation	0.00% 0/3 • Adverse events collected while participants were on study for up to 3 years.	0.00% 0/3 • Adverse events collected while participants were on study for up to 3 years.	3.6% 1/28 • Number of events 1 • Adverse events collected while participants were on study for up to 3 years.
Infections and infestations Sepsis-2ndary to AML	0.00% 0/3 • Adverse events collected while participants were on study for up to 3 years.	0.00% 0/3 • Adverse events collected while participants were on study for up to 3 years.	3.6% 1/28 • Number of events 1 • Adverse events collected while participants were on study for up to 3 years.
Infections and infestations Sepsis	0.00% 0/3 • Adverse events collected while participants were on study for up to 3 years.	0.00% 0/3 • Adverse events collected while participants were on study for up to 3 years.	3.6% 1/28 • Number of events 2 • Adverse events collected while participants were on study for up to 3 years.
Infections and infestations Soft tissue infection	0.00% 0/3 • Adverse events collected while participants were on study for up to 3 years.	0.00% 0/3 • Adverse events collected while participants were on study for up to 3 years.	3.6% 1/28 • Number of events 1 • Adverse events collected while participants were on study for up to 3 years.
Nervous system disorders Syncope	0.00% 0/3 • Adverse events collected while participants were on study for up to 3 years.	0.00% 0/3 • Adverse events collected while participants were on study for up to 3 years.	10.7% 3/28 • Number of events 3 • Adverse events collected while participants were on study for up to 3 years.
Renal and urinary disorders Urinary retention	0.00% 0/3 • Adverse events collected while participants were on study for up to 3 years.	0.00% 0/3 • Adverse events collected while participants were on study for up to 3 years.	3.6% 1/28 • Number of events 1 • Adverse events collected while participants were on study for up to 3 years.