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A Phase III Randomized, Double-Blind Study of Induction (Daunorubicin/Cytarabine) and Consolidation (High-Dose Cytarabine) Chemotherapy + Midostaurin (PKC412) (IND #101261) or Placebo in Newly Diagnosed Patients < 60 Years of Age With FLT3 Mutated Acute Myeloid Leukemia (AML)


Phase 3
18 Years
59 Years
Open (Enrolling)
Both
Leukemia

Thank you

Trial Information

A Phase III Randomized, Double-Blind Study of Induction (Daunorubicin/Cytarabine) and Consolidation (High-Dose Cytarabine) Chemotherapy + Midostaurin (PKC412) (IND #101261) or Placebo in Newly Diagnosed Patients < 60 Years of Age With FLT3 Mutated Acute Myeloid Leukemia (AML)


OBJECTIVES:

Primary

- To determine if the addition of midostaurin (vs placebo) to induction therapy
comprising daunorubicin hydrochloride and cytarabine, consolidation therapy comprising
high-dose cytarabine, and continuation therapy improves overall survival of patients
with newly diagnosed acute myeloid leukemia with FLT3-internal tandem duplication (ITD)
or FLT-3 tyrosine kinase domain (TKD) mutations.

Secondary

- To compare the complete response rate in patients treated with these regimens.

- To compare the event-free survival (EFS) of patients treated with these regimens.

- To compare the disease-free survival (DFS) of patients treated with these regimens.

- To compare the DFS rate of these patients after 1 year of continuation therapy.

- To compare the overall survival (OS) in the two groups using an analysis in which
patients who receive a stem cell transplant are censored at the time of transplant.

- To assess the toxicity of these regimens in these patients.

- To describe the interaction between treatment outcome and pretreatment characteristics
such as age, performance status, white blood cell count, morphology, cytogenetics, and
molecular and pharmacodynamic features.

- To assess the population pharmacokinetics (PK) of midostaurin and its two major
metabolites, CGP52421 and CGP62221.

- To explore the potential association between PK exposure and FLT3 status, overall
survival, EFS, and clinical response in patients treated with these regimens.

OUTLINE: This is a multicenter study. Patients are stratified according to FLT3 mutation
status (internal tandem duplication [ITD] allelic ratio < 0.7 vs ITD allelic ratio ≥ 0.7 vs
tandem kinase domain [TKD]).

- Remission induction therapy: Patients are randomized to 1 of 2 treatment arms.

- Arm I: Patients receive cytarabine IV continuously on days 1-7 and daunorubicin
hydrochloride IV on days 1-3. Patients also receive oral midostaurin twice daily
on days 8-21.

- Arm II: Patients receive cytarabine and daunorubicin hydrochloride as in arm I.
Patients also receive oral placebo twice daily on days 8-21.

Patients undergo bone marrow aspiration on day 21 to assess response. If residual leukemia
is present on day 21 or upon subsequent bone marrow aspiration, patients proceed to second
remission induction therapy.

- Second remission induction therapy: Patients receive a second course of remission
induction therapy according to their initial randomization. Treatment begins on or
shortly after day 24 (i.e., at least 3 days after completing prior midostaurin or
placebo therapy). Within 1 week after hematologic recovery and 60 days after initiating
protocol treatment, patients undergo assessment of response. Patients with residual
acute myeloid leukemia are removed from study. Patients with complete response (CR)
proceed to consolidation therapy.

- Remission consolidation therapy: Beginning within 2 weeks after hematologic recovery
and at least 4 weeks after initiation of the last course of induction therapy, patients
with CR receive high-dose cytarabine (HiDAC) IV over 3 hours every 12 hours on days 1,
3, and 5 and oral midostaurin or placebo therapy according to the initial
randomization. Treatment repeats every 4 weeks for up to 4 courses in the absence of
disease progression or unacceptable toxicity.

- Continuation therapy: Patients who continue in CR after four courses of HiDAC
consolidation therapy receive continuation therapy with midostaurin or placebo alone
according to their initial randomization. Patients who are unable to complete four
courses of HiDAC consolidation therapy because of toxicity may receive continuation
therapy at the discretion of the principal investigator. Beginning at least 14 days
after the last dose of consolidation midostaurin or placebo and after recovery from
hematologic and other significant acute toxicity, patients receive oral midostaurin or
placebo twice daily on days 1-28. Treatment repeats every 28 days for up to 12 months
or until relapse.

Patients may also enroll on optional pharmacokinetics study CALGB-60706.

After completion of study therapy, patients are followed periodically for up to 10 years.

Inclusion Criteria


DISEASE CHARACTERISTICS:

- Unequivocal diagnosis of acute myeloid leukemia (AML) meeting the following criteria:

- More than 20% blasts present in the bone marrow, as defined by WHO
classification

- Documented FLT3 mutation (i.e., internal tandem duplication [ITD] or point
mutation), determined by analysis in a protocol-designated FLT3 screening
laboratory

- No acute promyelocytic leukemia (M3)

- Patients with antecedent myelodysplasia (MDS) allowed, provided they received no
prior cytotoxic (including azacytidine or decitabine) therapy for MDS

- No therapy-related AML after prior radiotherapy or chemotherapy for another disorder
or cancer

- Patients with neurologic symptoms suggestive of CNS leukemia may undergo a lumbar
puncture

- Patients with a positive CSF for AML blasts are not eligible

PATIENT CHARACTERISTICS:

- No symptomatic congestive heart failure

- Total bilirubin < 2.5 times upper limit of normal

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use 2 methods of effective contraception during and for 12
weeks after completion of study therapy

PRIOR CONCURRENT THERAPY:

- See Disease Characteristics

- No prior therapy for leukemia or myelodysplasia, except for the following:

- Emergency leukapheresis

- Emergency treatment for hyperleukocytosis with hydroxyurea for ≤ 5 days

- Cranial radiotherapy for CNS leukostasis (one dose only)

- Growth factor or cytokine support

- No concurrent hormones or other chemotherapy, except steroids given for
hypersensitivity or transfusion reactions or hormones for non-disease-related
conditions (e.g., insulin for diabetes)

- No concurrent apprepitant

- No concurrent enrollment on another clinical trial with investigational agents

Type of Study:

Interventional

Study Design:

Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Outcome Measure:

Overall survival (OS)

Outcome Time Frame:

Duration of study (Up to 10 years)

Safety Issue:

No

Principal Investigator

Richard M. Stone, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Dana-Farber Cancer Institute

Authority:

United States: Food and Drug Administration

Study ID:

CDR0000590404

NCT ID:

NCT00651261

Start Date:

April 2008

Completion Date:

Related Keywords:

  • Leukemia
  • adult acute basophilic leukemia
  • adult acute eosinophilic leukemia
  • adult acute lymphoblastic leukemia
  • adult acute megakaryoblastic leukemia (M7)
  • adult acute minimally differentiated myeloid leukemia (M0)
  • adult acute monoblastic leukemia (M5a)
  • adult acute monocytic leukemia (M5b)
  • adult acute myeloblastic leukemia with maturation (M2)
  • adult acute myeloblastic leukemia without maturation (M1)
  • adult acute myeloid leukemia with 11q23 (MLL) abnormalities
  • adult acute myeloid leukemia with inv(16)(p13;q22)
  • adult acute myeloid leukemia with t(16;16)(p13;q22)
  • adult acute myeloid leukemia with t(8;21)(q22;q22)
  • adult acute myelomonocytic leukemia (M4)
  • adult erythroleukemia (M6a)
  • adult pure erythroid leukemia (M6b)
  • untreated adult acute myeloid leukemia
  • Leukemia
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid

Name

Location

Roswell Park Cancer InstituteBuffalo, New York  14263
Mayo Clinic Cancer CenterRochester, Minnesota  55905
Cardinal Bernardin Cancer Center at Loyola University Medical CenterMaywood, Illinois  60153-5500
University of Chicago Cancer Research CenterChicago, Illinois  60637
Duke Comprehensive Cancer CenterDurham, North Carolina  27710
CCOP - Christiana Care Health ServicesWilmington, Delaware  19899
CCOP - North Shore University HospitalManhasset, New York  11030
Beth Israel Deaconess Medical CenterBoston, Massachusetts  02215
CCOP - Metro-MinnesotaSaint Louis Park, Minnesota  55416
Aurora Presbyterian HospitalAurora, Colorado  80012
Boulder Community HospitalBoulder, Colorado  80301-9019
Penrose Cancer Center at Penrose HospitalColorado Springs, Colorado  80933
CCOP - Colorado Cancer Research ProgramDenver, Colorado  80224-2522
Porter Adventist HospitalDenver, Colorado  80210
Presbyterian - St. Luke's Medical CenterDenver, Colorado  80218
St. Joseph HospitalDenver, Colorado  80218
Rose Medical CenterDenver, Colorado  80220
Swedish Medical CenterEnglewood, Colorado  80110
Sky Ridge Medical CenterLone Tree, Colorado  80124
Hope Cancer Care Center at Longmont United HospitalLongmont, Colorado  80502
North Suburban Medical CenterThornton, Colorado  80229
Mercy Medical Center - Sioux CitySioux City, Iowa  51104
Siouxland Hematology-Oncology Associates, LLPSioux City, Iowa  51101
St. Luke's Regional Medical CenterSioux City, Iowa  51104
Baystate Regional Cancer Program at D'Amour Center for Cancer CareSpringfield, Massachusetts  01199
Bronson Methodist HospitalKalamazoo, Michigan  49007
West Michigan Cancer CenterKalamazoo, Michigan  49007-3731
Borgess Medical CenterKalamazooaa, Michigan  49001
Fairview Ridges HospitalBurnsville, Minnesota  55337
Mercy and Unity Cancer Center at Mercy HospitalCoon Rapids, Minnesota  55433
Fairview Southdale HospitalEdina, Minnesota  55435
Mercy and Unity Cancer Center at Unity HospitalFridley, Minnesota  55432
Minnesota Oncology Hematology, PA - MaplewoodMaplewood, Minnesota  55109
HealthEast Cancer Care at St. John's HospitalMaplewood, Minnesota  55109
Hennepin County Medical Center - MinneapolisMinneapolis, Minnesota  55415
Virginia Piper Cancer Institute at Abbott - Northwestern HospitalMinneapolis, Minnesota  55407
Hubert H. Humphrey Cancer Center at North Memorial Outpatient CenterRobbinsdale, Minnesota  55422-2900
Park Nicollet Cancer CenterSt. Louis Park, Minnesota  55416
Regions Hospital Cancer Care CenterSt. Paul, Minnesota  55101
United HospitalSt. Paul, Minnesota  55102
Ridgeview Medical CenterWaconia, Minnesota  55387
Minnesota Oncology Hematology, PA - WoodburyWoodbury, Minnesota  55125
St. Rita's Medical CenterLima, Ohio  45801
Geisinger Medical Group - Scenery ParkState College, Pennsylvania  16801
Frank M. and Dorothea Henry Cancer Center at Geisinger Wyoming Valley Medical CenterWilkes-Barre, Pennsylvania  18711
Sanford Cancer Center at Sanford USD Medical CenterSioux Falls, South Dakota  57117-5039
Avera Cancer InstituteSioux Falls, South Dakota  57105
Vanderbilt-Ingram Cancer CenterNashville, Tennessee  37232-6838
University of Wisconsin Paul P. Carbone Comprehensive Cancer CenterMadison, Wisconsin  53792-6164
Marshfield Clinic - Marshfield CenterMarshfield, Wisconsin  54449
Marshfield Clinic - Indianhead CenterRice Lake, Wisconsin  54868
Methodist Medical Center of IllinoisPeoria, Illinois  61636
CCOP - GreenvilleGreenville, South Carolina  29615
Holden Comprehensive Cancer Center at University of IowaIowa City, Iowa  52242-1002
CCOP - Grand RapidsGrand Rapids, Michigan  49503
Ellis Fischel Cancer Center at University of Missouri - ColumbiaColumbia, Missouri  65203
Norris Cotton Cancer Center at Dartmouth-Hitchcock Medical CenterLebanon, New Hampshire  03756-0002
Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel HillChapel Hill, North Carolina  27599-7570
Charles M. Barrett Cancer Center at University HospitalCincinnati, Ohio  45267-0526
Cancer Research Center of HawaiiHonolulu, Hawaii  96813
Veterans Affairs Medical Center - HoustonHouston, Texas  77030
University of California Davis Cancer CenterSacramento, California  95817
Fletcher Allen Health Care - University Health Center CampusBurlington, Vermont  05401
Medical Center of Central GeorgiaMacon, Georgia  31201
Sunrise Hospital and Medical CenterLas Vegas, Nevada  89109-2306
Arkansas Cancer Research Center at University of Arkansas for Medical SciencesLittle Rock, Arkansas  72205
Blumenthal Cancer Center at Carolinas Medical CenterCharlotte, North Carolina  28232-2861
Winthrop University HospitalMineola, New York  11501
Waukesha Memorial Hospital Regional Cancer CenterWaukesha, Wisconsin  53188
Long Island Jewish Medical CenterNew Hyde Park, New York  11040
University of Florida Shands Cancer CenterGainesville, Florida  32610-0232
Florida Hospital Cancer Institute at Florida Hospital OrlandoOrlando, Florida  32803-1273
Mount Sinai Medical CenterNew York, New York  10029
SUNY Upstate Medical University HospitalSyracuse, New York  13210
Wake Forest University Comprehensive Cancer CenterWinston-Salem, North Carolina  27157-1096
Hollings Cancer Center at Medical University of South CarolinaCharleston, South Carolina  29425
Baylor University Medical Center - HoustonHouston, Texas  77030-2399
Mary Babb Randolph Cancer Center at West Virginia University HospitalsMorgantown, West Virginia  26506
St. Vincent Hospital Regional Cancer CenterGreen Bay, Wisconsin  54307-3508
James P. Wilmot Cancer Center at University of Rochester Medical CenterRochester, New York  14642
St. Mary's Hospital Medical Center - Green BayGreen Bay, Wisconsin  54303
Green Bay Oncology, Limited at St. Vincent Hospital Regional Cancer CenterGreen Bay, Wisconsin  54301-3526
Green Bay Oncology, Limited at St. Mary's HospitalGreen Bay, Wisconsin  54303
Bay Area Cancer Care Center at Bay Area Medical CenterMarinette, Wisconsin  54143
North Colorado Medical CenterGreeley, Colorado  80631
McKee Medical CenterLoveland, Colorado  80539
Baptist Cancer Institute - JacksonvilleJacksonville, Florida  32207
Battle Creek Health System Cancer Care CenterBattle Creek, Michigan  49017
Munson Medical CenterTraverse City, Michigan  49684
Greenebaum Cancer Center at University of Maryland Medical CenterBaltimore, Maryland  21201
UNMC Eppley Cancer Center at the University of Nebraska Medical CenterOmaha, Nebraska  68198-7680
Memorial Cancer Institute at Memorial Regional HospitalHollywood, Florida  33021
New York Weill Cornell Cancer Center at Cornell UniversityNew York, New York  10021
MBCCOP - Medical College of Georgia Cancer CenterAugusta, Georgia  30912-3730
University of Illinois Cancer CenterChicago, Illinois  60612-7243
Lucille P. Markey Cancer Center at University of KentuckyLexington, Kentucky  40536-0093
Tulane Cancer Center Office of Clinical ResearchAlexandria, Louisiana  71315-3198
Dana-Farber/Harvard Cancer Center at Dana-Farber Cancer InstituteBoston, Massachusetts  02115
Butterworth Hospital at Spectrum HealthGrand Rapids, Michigan  49503-2560
Masonic Cancer Center at University of MinnesotaMinneapolis, Minnesota  55455
University of Mississippi Cancer ClinicJackson, Mississippi  39216-4505
Siteman Cancer Center at Barnes-Jewish Hospital - Saint LouisSt. Louis, Missouri  63110
CCOP - Nevada Cancer Research FoundationLas Vegas, Nevada  89109-2306
University of New Mexico Cancer CenterAlbuquerque, New Mexico  87131-5636
Don Monti Comprehensive Cancer Center at North Shore University HospitalManhasset, New York  11030
Oklahoma University Cancer InstituteOklahoma City, Oklahoma  73104
Geisinger Cancer Institute at Geisinger HealthDanville, Pennsylvania  17822-0001
Virginia Commonwealth University Massey Cancer CenterRichmond, Virginia  23298-0037
West Virginia University Health Sciences Center - CharlestonCharleston, West Virginia  25302
Robert H. Lurie Comprehensive Cancer Center at Northwestern UniversityChicago, Illinois  60611
Decatur Memorial Hospital Cancer Care InstituteDecatur, Illinois  62526
Helen and Harry Gray Cancer Center at Hartford HospitalHartford, Connecticut  06102-5037
University Medical Center of Southern NevadaLas Vegas, Nevada  89102
UPMC Cancer CentersPittsburgh, Pennsylvania  15232
Charles B. Eberhart Cancer Center at DeKalb Medical CenterDecatur, Georgia  30033
BroMenn Regional Medical CenterNormal, Illinois  61761
Oncology Hematology Associates of Central Illinois, PC - PeoriaPeoria, Illinois  61615
Fort Wayne Medical Oncology and HematologyFort Wayne, Indiana  46815
Feist-Weiller Cancer Center at Louisiana State University Health SciencesShreveport, Louisiana  71130-3932
Mecosta County Medical CenterBig Rapids, Michigan  49307
Providence Cancer Institute at Providence Hospital - Southfield CampusSouthfield, Michigan  48075
Mountainview MedicalBerlin, Vermont  05602
Holy Family Memorial Medical Center Cancer Care CenterManitowoc, Wisconsin  54221-1450
Massachusetts General HospitalBoston, Massachusetts  02114-2617
St. Anthony Central HospitalDenver, Colorado  80204-1335
Exempla Lutheran Medical CenterWheat Ridge, Colorado  80033
H. Lee Moffitt Cancer Center and Research Institute at University of South FloridaTampa, Florida  33612
Western Pennsylvania Cancer Institute at Western Pennsylvania HospitalPittsburgh, Pennsylvania  15224-1791
UAB Comprehensive Cancer CenterBirmingham, Alabama  35294
Tunnell Cancer Center at Beebe Medical CenterLewes, Delaware  19958
Nancy N. and J. C. Lewis Cancer and Research Pavilion at St. Joseph's/CandlerSavannah, Georgia  31405
McFarland Clinic, PCAmes, Iowa  50010
Monter Cancer Center of the North Shore-LIJ Health SystemLake Success, New York  11042
Leo W. Jenkins Cancer Center at ECU Medical SchoolGreenville, North Carolina  27834
Summa Center for Cancer Care at Akron City HospitalAkron, Ohio  44309-2090
Barberton Citizens HospitalBarberton, Ohio  44203
Arthur G. James Cancer Hospital and Richard J. Solove Research Institute at Ohio State University Comprehensive Cancer CenterColumbus, Ohio  43210-1240
Cleo Craig Cancer Research ClinicLawton, Oklahoma  73505
Geisinger Hazleton Cancer CenterHazleton, Pennsylvania  18201
Penn State Hershey Cancer Institute at Milton S. Hershey Medical CenterHershey, Pennsylvania  17033-0850
Marshfield Clinic - Chippewa CenterChippewa Falls, Wisconsin  54729
Center for Cancer Treatment & Prevention at Sacred Heart HospitalEau Claire, Wisconsin  54701
Marshfield Clinic Cancer Care at Regional Cancer CenterEau Claire, Wisconsin  54701
Saint Joseph's HospitalMarshfield, Wisconsin  54449
Marshfield Clinic - Lakeland CenterMinocqua, Wisconsin  54548
Ministry Medical Group at Saint Mary's HospitalRhinelander, Wisconsin  54501
Marshfield Clinic at Saint Michael's HospitalStevens Point, Wisconsin  54481
Marshfield Clinic - Weston CenterWeston, Wisconsin  54476
Marshfield Clinic - Wisconsin Rapids CenterWisconsin Rapids, Wisconsin  54494
Ben Taub General HospitalHouston, Texas  77030
Queen's Cancer Institute at Queen's Medical CenterHonolulu, Hawaii  96813
Tucker Center for Cancer Care at Orange Regional Medical CenterMiddletown, New York  10940-4199
Regional Cancer Center at Oconomowoc Memorial HospitalOconomowoc, Wisconsin  53066
Kinston Medical SpecialistsKinston, North Carolina  28501
Greenville Hospital Cancer CenterGreenville, South Carolina  29605
Cancer Centers of the Carolinas - Grove CommonsGreenville, South Carolina  29605
Cancer Centers of the Carolinas - Faris RoadGreenville, South Carolina  29605
Cancer Centers of the Carolinas - Greer Medical OncologyGreer, South Carolina  29650
Cancer Centers of the Carolinas - SenecaSeneca, South Carolina  29672
Cancer Centers of the Carolinas - SpartanburgSpartanburg, South Carolina  29307
Lacks Cancer Center at Saint Mary's Health CareGrand Rapids, Michigan  49503
Metro Health HospitalGrand Rapids, Michigan  49506
Boston University Cancer Research CenterBoston, Massachusetts  02118
University of Tennessee Cancer Institute - MemphisMemphis, Tennessee  38104
Illinois CancerCare - BloomingtonBloomington%, Illinois  61701
Cancer Centers of the Carolinas - EasleyEasley, South Carolina  29640
Self Regional Cancer Center at Self Regional Medical CenterGreenwood, South Carolina  29646
D.N. Greenwald CenterMukwonago, Wisconsin  53149
Tennessee Oncology, PLLC at Sarah Cannon Cancer CenterNashville, Tennessee  37203
Ministry Saint Clare's HospitalWeston, Wisconsin  54476