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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01883362
Recruitment Status : Completed
First Posted : June 21, 2013
Last Update Posted : April 23, 2019
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: Single Group 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. Relapse Free Survival (RFS) [ Time Frame: 18 months from date of transplant ]

Secondary Outcome Measures :
  1. Disease Free Survival (DFS) [ Time Frame: for at least 24 months from date of transplant or study completion ]
  2. Non-Relapse Mortality (NRM) [ Time Frame: for at least 24 months from date of transplant or study completion ]
  3. Overall Survival (OS) [ Time Frame: for at least 24 months from date of transplant or study completion ]
  4. FLT3-ITD mutation status centrally in archived material from diagnosis (if available) including mutant:wild type ratio [ Time Frame: upto 24 months from date of transplannt or at study completion ]
  5. Number of Participants with Adverse Events as a Measure of Safety and Tolerability [ Time Frame: 12 months ]
    The assessment of safety will be based mainly on the frequency of Adverse Events (AEs), on the number of laboratory values summarized by CTCAE grades and non-relapse mortality(NRM). The assessment of tolerability will be based on whether midostaurin can be administered at a daily dose of 50mg twice daily at least 80% of the time to 50% or more of patients during the first 100 days after allogeneic HSCT

  6. 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 (units ng/ml)

  7. Plasma Pharmacokinetics (PK) of midostaurin and the metabolites: CGP62221 and CGP52421: Pre-dose levels [ Time Frame: Pre-dose collection two weeks following initiation of strong CYP3A4 inhibitors ]
    Pre-dose levels (Cmin) will be directly determined from raw plasma concentration-time data (units ng/ml)

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years to 60 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Patients between 18 and 60 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 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 identifier (NCT number): NCT01883362

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Sponsors and Collaborators
Novartis Pharmaceuticals
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Study Director: Brian Elliott, MD Novartis Pharmaceuticals
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Responsible Party: Novartis Pharmaceuticals Identifier: NCT01883362    
Other Study ID Numbers: CPKC412AUS23
First Posted: June 21, 2013    Key Record Dates
Last Update Posted: April 23, 2019
Last Verified: April 2019

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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
allogeneic hematopoeitic stem cell tranplant
Additional relevant MeSH terms:
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Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action