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

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

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,

Study Overview

• Status: Completed
• Conditions: Acute Myeloid Leukemia
• Intervention / Treatment: Drug: Midostaurin; Other: Standard of Care

• Study Type: Interventional
• Enrollment (Actual): 60
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 2M9
      • Novartis Investigative Site
• United States
  • California
    • La Jolla, California, United States, 92093-0987
      • University of California San Diego Moores Cancer Center
    • Los Angeles, California, United States, 90095
      • University of California at Los Angeles Oncology
  • Colorado
    • Denver, Colorado, United States, 80218
      • SCRI- Colorado Blood Cancer Institute
  • Florida
    • Tampa, Florida, United States, 33612
      • H Lee Moffitt Cancer Center and Research Institute Oncology
  • Georgia
    • Atlanta, Georgia, United States, 30342
      • Northside Hospital
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago Medical Center
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Karmanos Cancer Institute Karmanos - Wayne State
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic - Rochester
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School Of Medicine-Siteman Cancer Ctr Washington U School of Med
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Hackensack University Medical Center Hackensack Univ Med Ctr (32)
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599-9500
      • University of North Carolina at Chapel Hill University of North Carolina 6
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • University Hospitals Case Medical Center
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health Sciences University
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Tennessee Oncology Sarah Cannon Research Inst.
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt Univeristy Oncology
  • Texas
    • Dallas, Texas, United States, 75246
      • Baylor Health Care System/Sammons Cancer Center Oncology
    • San Antonio, Texas, United States, 78229
      • Texas Transplant Physicians Group Oncology 2
  • Washington
    • Seattle, Washington, United States, 98109
      • Fred Hutchinson Cancer Research Center Oncology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Standard of Care with 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).	Drug: Midostaurin; 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.; Other Names: PKC412
Active Comparator: Standard of Care; Patients received standard of care alone in the post SCT setting	Other: Standard of Care; Standard of Care was not defined per protocol. The investigator prescribed based on the commonly used medications given in the post SCT setting.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals
• Investigators: Study Director: Brian Elliott, MD, Novartis Pharmaceuticals

Publications and helpful links

General Publications

• Maziarz RT, Levis M, Patnaik MM, Scott BL, Mohan SR, Deol A, Rowley SD, Kim DDH, Hernandez D, Rajkhowa T, Haines K, Bonifacio G, Rine P, Purkayastha D, Fernandez HF. Midostaurin after allogeneic stem cell transplant in patients with FLT3-internal tandem duplication-positive acute myeloid leukemia. Bone Marrow Transplant. 2021 May;56(5):1180-1189. doi: 10.1038/s41409-020-01153-1. Epub 2020 Dec 7.

Study record dates

Study Major Dates

• Study Start (Actual): February 6, 2014
• Primary Completion (Actual): April 30, 2018
• Study Completion (Actual): April 30, 2018

Study Registration Dates

• First Submitted: March 25, 2013
• First Submitted That Met QC Criteria: June 19, 2013
• First Posted (Estimate): June 21, 2013

Study Record Updates

• Last Update Posted (Actual): March 17, 2021
• Last Update Submitted That Met QC Criteria: March 12, 2021
• Last Verified: March 1, 2021

More Information

Terms related to this study

• Keywords: adult; AML; acute myeloid leukemia; HSCT; FLT3-ITD; PKC412; SCT; midostaurin; allogeneic hematopoeitic stem cell tranplant; CR1
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Midostaurin
• Other Study ID Numbers: CPKC412AUS23

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No