Description:
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,
Title
- Brief Title: Standard of Care +/- Midostaurin to Prevent Relapse Post Stem Cell Transplant in Patients With FLT3-ITD Mutated AML
- Official Title: 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
Clinical Trial IDs
- ORG STUDY ID:
CPKC412AUS23
- NCT ID:
NCT01883362
Conditions
Interventions
| Drug | Synonyms | Arms |
|---|
| Midostaurin | PKC412 | Standard of Care with Midostaurin |
Purpose
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,
Trial Arms
| Name | Type | Description | Interventions |
|---|
| Standard of Care with Midostaurin | Experimental | 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). | |
| Standard of Care | Active Comparator | Patients received standard of care alone in the post SCT setting | |
Eligibility Criteria
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
| Maximum Eligible Age: | 70 Years |
| Minimum Eligible Age: | 18 Years |
| Eligible Gender: | All |
| Healthy Volunteers: | No |
Primary Outcome Measures
| Measure: | Proportion of Participants With Relapse Free Survival (RFS) up to 18 Months Post Transplant (Full Analysis Set) by Kaplan-Meier Analysis |
| Time Frame: | date of transplant up to 18 months |
| Safety Issue: | |
| Description: | 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. |
Secondary Outcome Measures
| Measure: | Proportion of Participants With Relapse Free Survival (RFS) - Time From Randomization up to 18 Months (Full Analysis Set) by Kaplan-Meier Analysis |
| Time Frame: | Randomization to 18 months |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Proportion of Participants With Relapse Free Survival (RFS) - Time From Randomization up to 24 Months(Full Analysis Set) by Kaplan-Meier Analysis |
| Time Frame: | date of transplant up to 24 months |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Proportion of Participants With Relapse Free Survival (RFS) - Time From Transplant (Full Analysis Set) by Kaplan-Meier Analysis |
| Time Frame: | date of transplant up to 24 months |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Probability of Overall Survival - Date of Transplant up to 24 Months (Full Analysis Set) by Kaplan-Meier Analysis |
| Time Frame: | date of transplant up to 24 months |
| Safety Issue: | |
| Description: | Overall survival was defined as the time from transplant to death due to any cause. |
| Measure: | Probability of Non-relapse Mortality (NRM) - Date of Transplant up to 24 Months (Full Analysis Set) by Kaplan-Meier Analysis |
| Time Frame: | date of transplant up to 24 months |
| Safety Issue: | |
| Description: | Non-relapse mortality (NRM) was defined as the time from transplant to death due to reasons other than relapse/progressive disease |
| Measure: | FLT3-ITD Mutation Status Centrally in Archived Material From Diagnosis (if Available) Including Mutant:Wild Type Ratio. |
| Time Frame: | up to 24 months from date of transplannt or at study completion |
| Safety Issue: | |
| Description: | 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 |
| Measure: | Plasma Pharmacokinetics (PK) of Midostaurin and the Metabolites: CGP62221 and CGP52421: Pre-dose Levels |
| Time Frame: | 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 |
| Safety Issue: | |
| Description: | 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. |
Details
| Phase: | Phase 2 |
| Primary Purpose: | Interventional |
| Overall Status: | Completed |
| Lead Sponsor: | Novartis Pharmaceuticals |
Trial Keywords
- acute myeloid leukemia
- AML
- FLT3-ITD
- midostaurin
- PKC412
- allogeneic hematopoeitic stem cell tranplant
- SCT
- HSCT
- CR1
- adult
Last Updated
March 17, 2021
