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

Phase 2

Completed

• Conditions: Acute Myeloid Leukemia
• Interventions: Other: Standard of Care; Drug: Midostaurin

• Registration Number: NCT01883362
• Lead Sponsor: Novartis Pharmaceuticals

Brief Summary

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,

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2013-03-25
• Study First Submitted QC: 2013-06-19
• Study First Posted: 2013-06-21
• Study Start: 2014-02-06
• Primary Completion: 2018-04-30
• Study Completion: 2018-04-30
• Results First Submitted: 2019-04-29
• Status Verified: 2021-03
• Results First Submitted QC: 2021-03-12
• Last Update Submitted: 2021-03-12
• Results First Posted: 2021-03-17
• Last Update Posted: 2021-03-17

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 60

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

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Standard of Care	Standard of Care	Patients received standard of care alone in the post SCT setting
Standard of Care with Midostaurin	Midostaurin	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).

Primary Outcome Measures

Name	Time	Method
Proportion of Participants With Relapse Free Survival (RFS) up to 18 Months Post Transplant (Full Analysis Set) by Kaplan-Meier Analysis	date of transplant up to 18 months	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

Name	Time	Method
Proportion of Participants With Relapse Free Survival (RFS) - Time From Randomization up to 24 Months(Full Analysis Set) by Kaplan-Meier Analysis	date of transplant up to 24 months	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.
Probability of Overall Survival - Date of Transplant up to 24 Months (Full Analysis Set) by Kaplan-Meier Analysis	date of transplant up to 24 months	Overall survival was defined as the time from transplant to death due to any cause.
Plasma Pharmacokinetics (PK) of Midostaurin and the Metabolites: CGP62221 and CGP52421: Pre-dose Levels	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	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.
Proportion of Participants With Relapse Free Survival (RFS) - Time From Randomization up to 18 Months (Full Analysis Set) by Kaplan-Meier Analysis	Randomization to 18 months	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.
Proportion of Participants With Relapse Free Survival (RFS) - Time From Transplant (Full Analysis Set) by Kaplan-Meier Analysis	date of transplant up to 24 months	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.
FLT3-ITD Mutation Status Centrally in Archived Material From Diagnosis (if Available) Including Mutant:Wild Type Ratio.	up to 24 months from date of transplannt or at study completion	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
Probability of Non-relapse Mortality (NRM) - Date of Transplant up to 24 Months (Full Analysis Set) by Kaplan-Meier Analysis	date of transplant up to 24 months	Non-relapse mortality (NRM) was defined as the time from transplant to death due to reasons other than relapse/progressive disease

Trial Locations

Locations (19)

University of California at Los Angeles Oncology; 🇺🇸 Los Angeles, California, United States

Northside Hospital; 🇺🇸 Atlanta, Georgia, United States

Washington University School Of Medicine-Siteman Cancer Ctr Washington U School of Med; 🇺🇸 Saint Louis, Missouri, United States

Mayo Clinic - Rochester; 🇺🇸 Rochester, Minnesota, United States

University of North Carolina at Chapel Hill University of North Carolina 6; 🇺🇸 Chapel Hill, North Carolina, United States

Baylor Health Care System/Sammons Cancer Center Oncology; 🇺🇸 Dallas, Texas, United States

H Lee Moffitt Cancer Center and Research Institute Oncology; 🇺🇸 Tampa, Florida, United States

University of Chicago Medical Center; 🇺🇸 Chicago, Illinois, United States

Vanderbilt Univeristy Oncology; 🇺🇸 Nashville, Tennessee, United States

Karmanos Cancer Institute Karmanos - Wayne State; 🇺🇸 Detroit, Michigan, United States

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

Oregon Health Sciences University; 🇺🇸 Portland, Oregon, United States

Tennessee Oncology Sarah Cannon Research Inst.; 🇺🇸 Nashville, Tennessee, United States

SCRI- Colorado Blood Cancer Institute; 🇺🇸 Denver, Colorado, United States

Texas Transplant Physicians Group Oncology 2; 🇺🇸 San Antonio, Texas, United States

Fred Hutchinson Cancer Research Center Oncology; 🇺🇸 Seattle, Washington, United States

University of California San Diego Moores Cancer Center; 🇺🇸 La Jolla, California, United States

Hackensack University Medical Center Hackensack Univ Med Ctr (32); 🇺🇸 Hackensack, New Jersey, United States

Novartis Investigative Site; 🇨🇦 Toronto, Ontario, Canada