Standard of Care +/- Midostaurin to Prevent Relapse Post Stem Cell Transplant in Patients With FLT3-ITD Mutated AML

Study Overview
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Brief Summary
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To determine if the addition of midostaurin (PKC412) to Standard of Care (SOC) therapy reduces relapse in FLT3-ITD mutated AML patients receiving an allogenetic hematopoietic stem cell transplant,

Official Title
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A Phase II, Randomized Trial of Standard of Care, With or Without Midostaruin to Prevent Relapse Following Allogeneic Hematopoietic Stem Cell Transplantation in Patients With FLT3-ITD Mutated Acute Myeloid Leukemia

Conditions
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Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: Midostaurin
* Other: Standard of Care


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients between 18 and 70 years of age Patients with ECOG Performance Status of ≤ 2 Patients with a documented unequivocal diagnosis of AML according to WHO 2008 classification (>20% blasts in the bone marrow), excluding M3 (acute promyelocytic leukemia). Patients with a documented FLT3 ITD mutation, determined by local laboratory for eligibility (historical tissue will be requested for central analysis confirmation) Patients who undersent allogeneic HSCT in CR1 from a matched related or matched unrelated donor. All of the following criteria had to be met: HLA typing to include available 8/8 or 7/8 allele HLA matched donor (at A,B,C, DRB1) Single allelic mismatch allowed Patients who had received a conditioning regimen which included one of the following: Busulfan/Fludarabine (Bu/Flu) Busulfan (16 mg/kg PO or 12.8 mg/kg IV) Fludarabine (120-180 mg/m2) Fludarabine / Melphalan (Flu/Mel) Fludarabine (120-180 mg/m2) Melphalan (≤ 150 mg/m2) Busulfan/Cyclophosphamide (Bu/Cy) Busulfan (16 mg/kg PO or 12.8 mg/kg IV) Cyclophosphamide (120 mg/kg) Cyclophosphamide/Total Body Irradiation (Cy/TBI) Cyclophosphamide (120 mg/kg) TBI (1200-1420 cGy) • Recovery of counts by day 42 and was able to start midostaurin by day 60 post-HSCT (first dose of midostaurin to start no earlier than 28 days post-HSCT); ANC >1000µL, platelets ≥20,000 without platelet transfusion Exclusion Criteria: Patients eligible for this study must not have met any of the following criteria: Patients who failed prior attempts at allogeneic HSCT Patients who had received an autologous transplant Patients with Acute GVHD Grade III-IV Patients with a known confirmed diagnosis of HIV infection or active viral hepatitis. Impaired cardiac function including any of the following: Screening ECG with a QTc > 450 msec. If QTc > 450 and electrolytes were not within normal ranges, electrolytes should be corrected and then the patient rescreened for QTc. Patients with congenital long QT syndrome History or presence of sustained ventricular tachycardia Any history of ventricular fibrillation or torsades de pointes Bradycardia defined as HR. < 50 bpm Right bundle branch block + left anterior hemiblock (bifascicular block) Patients with myocardial infarction or unstable angina < 6 months prior to starting study Congestive Heart Failure NY Heart Association class III or IV Patients with an ejection fraction < 45% assessed by MUGA or ---ECHO within 28 days prior to starting study cycle 1 (of midostaurin or control group) Patients with any pulmonary infiltrate including those suspected to be of infectious origin (unless resolves to ≤ Grade 1 within screening timeframe) Patient required treatment with strong CYP3A4 inhibitors or moderate or strong CYP3A4 inducers other than those required for GVH or infection prophylaxis or treatment Pregnant or nursing (lactating) women, or women of child-bearing potential, must have used highly effective methods of contraception during dosing and for 30 days after treatment completion

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Standard of Care with Midostaurin<br>Patients received standard of care in the post stem cell transplant (SCT) setting in addition to Midostaurin 50mg twice a day for 12 months (cycles). | Drug: Midostaurin<br>* Midostaurin was supplied in 25mg soft gelatin capsule taken orally twice a day for 28 days of each cycle. Patients will be treated for 12 cycles.<br>* Other names: PKC412;|
| Active Comparator: Standard of Care<br>Patients received standard of care alone in the post SCT setting | Other: Standard of Care<br>* Standard of Care was not defined per protocol. The investigator prescribed based on the commonly used medications given in the post SCT setting.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Participants With Relapse Free Survival (RFS) up to 18 Months Post Transplant (Full Analysis Set) by Kaplan-Meier Analysis | Relapse-free survival assesses the clinical benefit of remaining in remission free from relapse or death due to the disease. It was defined as the time from transplant to relapse or death due to the disease. Relapse following complete response was defined as reappearance of leukemic blasts in the peripheral blood or finding more than 5% blasts in the bone marrow. | date of transplant up to 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Participants With Relapse Free Survival (RFS) - Time From Randomization up to 18 Months (Full Analysis Set) by Kaplan-Meier Analysis | Relapse-free survival assesses the clinical benefit of remaining in remission free from relapse or death due to the disease. It was defined as the time from transplant to relapse or death due to the disease. Relapse following complete response was defined as reappearance of leukemic blasts in the peripheral blood or finding more than 5% blasts in the bone marrow. | Randomization to 18 months | 
| Proportion of Participants With Relapse Free Survival (RFS) - Time From Randomization up to 24 Months(Full Analysis Set) by Kaplan-Meier Analysis | DFS was defined as the time from transplant to relapse or death due to any cause. If a patient had more than 1 event (e.g., relapse then death) then the earliest date was taken into account. | date of transplant up to 24 months | 
| Proportion of Participants With Relapse Free Survival (RFS) - Time From Transplant (Full Analysis Set) by Kaplan-Meier Analysis | Relapse-free survival was defined as the time from transplant to relapse or death due to the disease 24 months post-transplant. If a patient had more than one event (e.g., relapse then death) then the earliest date was taken into account. | date of transplant up to 24 months | 
| Probability of Overall Survival - Date of Transplant up to 24 Months (Full Analysis Set) by Kaplan-Meier Analysis | Overall survival was defined as the time from transplant to death due to any cause. | date of transplant up to 24 months | 
| Probability of Non-relapse Mortality (NRM) - Date of Transplant up to 24 Months (Full Analysis Set) by Kaplan-Meier Analysis | Non-relapse mortality (NRM) was defined as the time from transplant to death due to reasons other than relapse/progressive disease | date of transplant up to 24 months | 
| FLT3-ITD Mutation Status Centrally in Archived Material From Diagnosis (if Available) Including Mutant:Wild Type Ratio. | Unable to retrieve a sufficient amount of archived samples to perform an analysis therefore the study was not able to verify the FLT3-ITD mutation status | up to 24 months from date of transplannt or at study completion | 
| Plasma Pharmacokinetics (PK) of Midostaurin and the Metabolites: CGP62221 and CGP52421: Pre-dose Levels | Pre-dose levels (Cmin) will be directly determined from raw plasma concentration-time data. Values below the lower limit of quantification (LLOQ) will be treated as zero in any calculations of summary statistics. | Pre-dose on days 1 and 15 of Cycle 1, on day 1 of Cycles 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HSCT, CR1, adult, acute myeloid leukemia, AML, FLT3-ITD, midostaurin, PKC412, allogeneic hematopoeitic stem cell tranplant, SCT