Clinical trial NCT01883362: Standard of Care +/- Midostaurin to Prevent Relapse Post Stem Cell Transplant in Patients With FLT3-ITD Mutated AML
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
Overall status: COMPLETED
Phase: PHASE2
Conditions: Acute Myeloid Leukemia
Keywords: acute myeloid leukemia
AML
FLT3-ITD
midostaurin
PKC412
allogeneic hematopoeitic stem cell tranplant
SCT
HSCT
CR1
adult
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2013-06-21
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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,


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

Primary outcomes:
measure: Proportion of Participants With Relapse Free Survival (RFS) up to 18 Months Post Transplant (Full Analysis Set) by Kaplan-Meier Analysis
timeFrame: date of transplant up to 18 months
Secondary outcomes:
measure: Proportion of Participants With Relapse Free Survival (RFS) - Time From Randomization up to 18 Months (Full Analysis Set) by Kaplan-Meier Analysis
timeFrame: Randomization to 18 months
measure: Proportion of Participants With Relapse Free Survival (RFS) - Time From Randomization up to 24 Months(Full Analysis Set) by Kaplan-Meier Analysis
timeFrame: date of transplant up to 24 months
measure: Proportion of Participants With Relapse Free Survival (RFS) - Time From Transplant (Full Analysis Set) by Kaplan-Meier Analysis
timeFrame: date of transplant up to 24 months
measure: Probability of Overall Survival - Date of Transplant up to 24 Months (Full Analysis Set) by Kaplan-Meier Analysis
timeFrame: date of transplant up to 24 months
measure: Probability of Non-relapse Mortality (NRM) - Date of Transplant up to 24 Months (Full Analysis Set) by Kaplan-Meier Analysis
timeFrame: date of transplant up to 24 months
measure: FLT3-ITD Mutation Status Centrally in Archived Material From Diagnosis (if Available) Including Mutant:Wild Type Ratio.
timeFrame: up to 24 months from date of transplannt or at study completion
measure: Plasma Pharmacokinetics (PK) of Midostaurin and the Metabolites: CGP62221 and CGP52421: Pre-dose Levels
timeFrame: 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
Other outcomes:
Locations:
city: La Jolla
country: United States
facility: University of California San Diego Moores Cancer Center
state: California
city: Los Angeles
country: United States
facility: University of California at Los Angeles Oncology
state: California
city: Denver
country: United States
facility: SCRI- Colorado Blood Cancer Institute
state: Colorado
city: Tampa
country: United States
facility: H Lee Moffitt Cancer Center and Research Institute Oncology
state: Florida
city: Atlanta
country: United States
facility: Northside Hospital
state: Georgia
city: Chicago
country: United States
facility: University of Chicago Medical Center
state: Illinois
city: Detroit
country: United States
facility: Karmanos Cancer Institute Karmanos - Wayne State
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic - Rochester
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University School Of Medicine-Siteman Cancer Ctr Washington U School of Med
state: Missouri
city: Hackensack
country: United States
facility: Hackensack University Medical Center Hackensack Univ Med Ctr (32)
state: New Jersey
city: Chapel Hill
country: United States
facility: University of North Carolina at Chapel Hill University of North Carolina 6
state: North Carolina
city: Cleveland
country: United States
facility: University Hospitals Case Medical Center
state: Ohio
city: Portland
country: United States
facility: Oregon Health Sciences University
state: Oregon
city: Nashville
country: United States
facility: Tennessee Oncology Sarah Cannon Research Inst.
state: Tennessee
city: Nashville
country: United States
facility: Vanderbilt Univeristy Oncology
state: Tennessee
city: Dallas
country: United States
facility: Baylor Health Care System/Sammons Cancer Center Oncology
state: Texas
city: San Antonio
country: United States
facility: Texas Transplant Physicians Group Oncology 2
state: Texas
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Research Center Oncology
state: Washington
city: Toronto
country: Canada
facility: Novartis Investigative Site
state: Ontario
Study officials:
affiliation: Novartis Pharmaceuticals
name: Brian Elliott, MD
role: STUDY_DIRECTOR
References:
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.