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

Primary Purpose

Acute Myeloid Leukemia

Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Midostaurin
Standard of Care
Sponsored by
Novartis Pharmaceuticals
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Acute Myeloid Leukemia focused on measuring acute myeloid leukemia, AML, FLT3-ITD, midostaurin, PKC412, allogeneic hematopoeitic stem cell tranplant, SCT, HSCT, CR1, adult

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • University of California San Diego Moores Cancer Center
  • University of California at Los Angeles Oncology
  • SCRI- Colorado Blood Cancer Institute
  • H Lee Moffitt Cancer Center and Research Institute Oncology
  • Northside Hospital
  • University of Chicago Medical Center
  • Karmanos Cancer Institute Karmanos - Wayne State
  • Mayo Clinic - Rochester
  • Washington University School Of Medicine-Siteman Cancer Ctr Washington U School of Med
  • Hackensack University Medical Center Hackensack Univ Med Ctr (32)
  • University of North Carolina at Chapel Hill University of North Carolina 6
  • University Hospitals Case Medical Center
  • Oregon Health Sciences University
  • Tennessee Oncology Sarah Cannon Research Inst.
  • Vanderbilt Univeristy Oncology
  • Baylor Health Care System/Sammons Cancer Center Oncology
  • Texas Transplant Physicians Group Oncology 2
  • Fred Hutchinson Cancer Research Center Oncology
  • Novartis Investigative Site

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Standard of Care with Midostaurin

Standard of Care

Arm Description

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).

Patients received standard of care alone in the post SCT setting

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.
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.
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.
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.
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
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
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.

Full Information

First Posted
March 25, 2013
Last Updated
March 12, 2021
Sponsor
Novartis Pharmaceuticals
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1. Study Identification

Unique Protocol Identification Number
NCT01883362
Brief Title
Standard of Care +/- Midostaurin to Prevent Relapse Post Stem Cell Transplant in Patients With FLT3-ITD Mutated AML
Acronym
RADIUS
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
Study Type
Interventional

2. Study Status

Record Verification Date
March 2021
Overall Recruitment Status
Completed
Study Start Date
February 6, 2014 (Actual)
Primary Completion Date
April 30, 2018 (Actual)
Study Completion Date
April 30, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Novartis Pharmaceuticals

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No

5. Study Description

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,

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute Myeloid Leukemia
Keywords
acute myeloid leukemia, AML, FLT3-ITD, midostaurin, PKC412, allogeneic hematopoeitic stem cell tranplant, SCT, HSCT, CR1, adult

7. Study Design

Primary Purpose
Prevention
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
60 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Standard of Care with Midostaurin
Arm Type
Experimental
Arm Description
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).
Arm Title
Standard of Care
Arm Type
Active Comparator
Arm Description
Patients received standard of care alone in the post SCT setting
Intervention Type
Drug
Intervention Name(s)
Midostaurin
Other Intervention Name(s)
PKC412
Intervention Description
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.
Intervention Type
Other
Intervention Name(s)
Standard of Care
Intervention Description
Standard of Care was not defined per protocol. The investigator prescribed based on the commonly used medications given in the post SCT setting.
Primary Outcome Measure Information:
Title
Proportion of Participants With Relapse Free Survival (RFS) up to 18 Months Post Transplant (Full Analysis Set) by Kaplan-Meier Analysis
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.
Time Frame
date of transplant up to 18 months
Secondary Outcome Measure Information:
Title
Proportion of Participants With Relapse Free Survival (RFS) - Time From Randomization up to 18 Months (Full Analysis Set) by Kaplan-Meier Analysis
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.
Time Frame
Randomization to 18 months
Title
Proportion of Participants With Relapse Free Survival (RFS) - Time From Randomization up to 24 Months(Full Analysis Set) by Kaplan-Meier Analysis
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.
Time Frame
date of transplant up to 24 months
Title
Proportion of Participants With Relapse Free Survival (RFS) - Time From Transplant (Full Analysis Set) by Kaplan-Meier Analysis
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.
Time Frame
date of transplant up to 24 months
Title
Probability of Overall Survival - Date of Transplant up to 24 Months (Full Analysis Set) by Kaplan-Meier Analysis
Description
Overall survival was defined as the time from transplant to death due to any cause.
Time Frame
date of transplant up to 24 months
Title
Probability of Non-relapse Mortality (NRM) - Date of Transplant up to 24 Months (Full Analysis Set) by Kaplan-Meier Analysis
Description
Non-relapse mortality (NRM) was defined as the time from transplant to death due to reasons other than relapse/progressive disease
Time Frame
date of transplant up to 24 months
Title
FLT3-ITD Mutation Status Centrally in Archived Material From Diagnosis (if Available) Including Mutant:Wild Type Ratio.
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
Time Frame
up to 24 months from date of transplannt or at study completion
Title
Plasma Pharmacokinetics (PK) of Midostaurin and the Metabolites: CGP62221 and CGP52421: Pre-dose Levels
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.
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

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Brian Elliott, MD
Organizational Affiliation
Novartis Pharmaceuticals
Official's Role
Study Director
Facility Information:
Facility Name
University of California San Diego Moores Cancer Center
City
La Jolla
State/Province
California
ZIP/Postal Code
92093-0987
Country
United States
Facility Name
University of California at Los Angeles Oncology
City
Los Angeles
State/Province
California
ZIP/Postal Code
90095
Country
United States
Facility Name
SCRI- Colorado Blood Cancer Institute
City
Denver
State/Province
Colorado
ZIP/Postal Code
80218
Country
United States
Facility Name
H Lee Moffitt Cancer Center and Research Institute Oncology
City
Tampa
State/Province
Florida
ZIP/Postal Code
33612
Country
United States
Facility Name
Northside Hospital
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30342
Country
United States
Facility Name
University of Chicago Medical Center
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60637
Country
United States
Facility Name
Karmanos Cancer Institute Karmanos - Wayne State
City
Detroit
State/Province
Michigan
ZIP/Postal Code
48201
Country
United States
Facility Name
Mayo Clinic - Rochester
City
Rochester
State/Province
Minnesota
ZIP/Postal Code
55905
Country
United States
Facility Name
Washington University School Of Medicine-Siteman Cancer Ctr Washington U School of Med
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Facility Name
Hackensack University Medical Center Hackensack Univ Med Ctr (32)
City
Hackensack
State/Province
New Jersey
ZIP/Postal Code
07601
Country
United States
Facility Name
University of North Carolina at Chapel Hill University of North Carolina 6
City
Chapel Hill
State/Province
North Carolina
ZIP/Postal Code
27599-9500
Country
United States
Facility Name
University Hospitals Case Medical Center
City
Cleveland
State/Province
Ohio
ZIP/Postal Code
44106
Country
United States
Facility Name
Oregon Health Sciences University
City
Portland
State/Province
Oregon
ZIP/Postal Code
97239
Country
United States
Facility Name
Tennessee Oncology Sarah Cannon Research Inst.
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37203
Country
United States
Facility Name
Vanderbilt Univeristy Oncology
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37232
Country
United States
Facility Name
Baylor Health Care System/Sammons Cancer Center Oncology
City
Dallas
State/Province
Texas
ZIP/Postal Code
75246
Country
United States
Facility Name
Texas Transplant Physicians Group Oncology 2
City
San Antonio
State/Province
Texas
ZIP/Postal Code
78229
Country
United States
Facility Name
Fred Hutchinson Cancer Research Center Oncology
City
Seattle
State/Province
Washington
ZIP/Postal Code
98109
Country
United States
Facility Name
Novartis Investigative Site
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M5G 2M9
Country
Canada

12. IPD Sharing Statement

Citations:
PubMed Identifier
33288862
Citation
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.
Results Reference
derived

Learn more about this trial

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

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