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

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ClinicalTrials.gov Identifier: NCT01883362
Recruitment Status : Completed
First Posted : June 21, 2013
Results First Posted : March 17, 2021
Last Update Posted : March 17, 2021
Sponsor:
Information provided by (Responsible Party):
Novartis ( 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,

Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia Drug: Midostaurin Other: Standard of Care Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 60 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
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
Actual Study Start Date : February 6, 2014
Actual Primary Completion Date : April 30, 2018
Actual Study Completion Date : April 30, 2018


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 Name: 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.




Primary Outcome Measures :
  1. 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 ]
    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 :
  1. 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 ]
    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.

  2. 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 ]
    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.

  3. 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 ]
    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.

  4. 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 ]
    Overall survival was defined as the time from transplant to death due to any cause.

  5. 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 ]
    Non-relapse mortality (NRM) was defined as the time from transplant to death due to reasons other than relapse/progressive disease

  6. 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 ]
    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

  7. 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 ]
    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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01883362


Locations
Show Show 19 study locations
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
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Study Director: Brian Elliott, MD Novartis Pharmaceuticals
  Study Documents (Full-Text)

Documents provided by Novartis ( Novartis Pharmaceuticals ):
Study Protocol  [PDF] July 2, 2015
Statistical Analysis Plan  [PDF] February 7, 2018

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT01883362    
Other Study ID Numbers: CPKC412AUS23
First Posted: June 21, 2013    Key Record Dates
Results First Posted: March 17, 2021
Last Update Posted: March 17, 2021
Last Verified: March 2021

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Novartis ( Novartis Pharmaceuticals ):
acute myeloid leukemia
AML
FLT3-ITD
midostaurin
PKC412
allogeneic hematopoeitic stem cell tranplant
SCT
HSCT
CR1
adult
Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type
Neoplasms
Midostaurin
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action