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A Phase III Study of Risk Directed Therapy for Infants With Acute Lymphoblastic Leukemia (ALL): Randomization of Highest Risk Infants to Intensive Chemotherapy +/- FLT3 Inhibition (CEP-701, Lestaurtinib; IND#76431; NSC#617807)


Phase 3
N/A
1 Year
Open (Enrolling)
Both
Leukemia

Thank you

Trial Information

A Phase III Study of Risk Directed Therapy for Infants With Acute Lymphoblastic Leukemia (ALL): Randomization of Highest Risk Infants to Intensive Chemotherapy +/- FLT3 Inhibition (CEP-701, Lestaurtinib; IND#76431; NSC#617807)


OBJECTIVES:

Primary

- To compare the 3-year event-free survival of infants with mixed lineage leukemia
rearranged (MLL-R) acute lymphoblastic leukemia (ALL) randomized to treatment with a
modified P9407 chemotherapy backbone with or without the FLT3 inhibitor lestaurtinib.

Secondary

- To determine a safe, tolerable, and biologically active dose of lestaurtinib given in
sequential combination with chemotherapy in MLL-R infants.

- To characterize the pharmacokinetics and pharmacodynamics of lestaurtinib in infants
when given at the proposed dose in sequential combination with chemotherapy.

- To identify molecular mechanisms of resistance to lestaurtinib in leukemic blasts.

- To describe levels of minimal residual disease in infants with ALL within the context
of the proposed therapy, and correlate with outcome.

- To identify gene expression patterns in diagnostic infant leukemia samples that
correlate with outcome within the context of the proposed therapy.

- To describe the outcome of infants with MLL-germline ALL treated with a modified P9407
chemotherapy backbone that includes an extended continuation phase.

OUTLINE: Patients are stratified according to risk group (standard risk [MLL-G: germline or
non-rearranged] vs intermediate risk [MLL-R: rearranged, age ≥ 90 days at diagnosis] vs high
risk [MLL-R, age < 90 days at diagnosis]).

All patients receive induction therapy (weeks 1-5) comprising vincristine IV on days 8,15,
22, and 29; daunorubicin hydrochloride IV over 30 minutes on days 8 and 9; cyclophosphamide
IV over 30 minutes every 12 hours on days 3 and 4; pegaspargase intramuscularly (IM) on days
15, 18, 22, 25, 29, and 33; oral prednisone or methylprednisolone IV three times daily (TID)
on days 1-7; dexamethasone IV or orally TID on days 8-28; cytarabine IV over 30 minutes on
days 8-21; triple intrathecal (IT) chemotherapy comprising methotrexate, cytarabine, and
hydrocortisone on days 1, 15, and 29; and filgrastim IV or subcutaneously (SC) beginning on
day 5 and continuing until blood counts recover.

Standard-risk patients are nonrandomly assigned to receive a less-intensive chemotherapy
regimen without lestaurtinib (post-induction therapy A).

- Post-induction therapy A (for standard-risk patients [MLL-G]):

- Induction intensification (weeks 6-9): Patients receive high-dose methotrexate IV
continuously over 24 hours on days 1 and 8; triple IT chemotherapy on days 1 and
8; leucovorin calcium IV every 6 hours beginning 42 hours after start of high-dose
methotrexate and continuing until methotrexate level is < 0.1 μM; cyclophosphamide
IV over 30 minutes on days 15-19; etoposide IV over 2 hours on days 15-19; and
filgrastim IV or SC beginning on day 20 and continuing until blood counts recover.
Patients in morphologic remission proceed to re-induction therapy.

- Re-induction (weeks 10-12): Patients receive vincristine IV on days 1, 8, and 15;
daunorubicin hydrochloride IV over 30 minutes on days 1 and 2; cyclophosphamide IV
over 30 minutes every 12 hours on days 3 and 4; pegaspargase IM on day 4;
dexamethasone IV or orally twice daily on days 1-7 and 15-21; triple IT
chemotherapy on days 1 and 15; and filgrastim IV or SC beginning on day 5 and
continuing until blood counts recover.

- Consolidation (weeks 13-19): Patients receive high-dose methotrexate IV
continuously over 24 hours on days 1 and 8; leucovorin calcium IV every 6 hours
beginning 42 hours after start of high-dose methotrexate and continuing until
methotrexate level is < 0.1 μM; triple IT chemotherapy on day 1; etoposide IV over
2 hours on days 15-19; cyclophosphamide IV over 30 minutes on days 15-19;
high-dose cytarabine IV over 3 hours every 12 hours on days 29 and 30;
pegaspargase IM on day 30; and filgrastim IV or SC beginning on day 20 and day 31
and continuing until blood counts recover.

- Continuation I (weeks 20-41): Patients receive vincristine IV on day 1 in weeks 20
and 24; dexamethasone IV or orally twice daily on days 1-5 in weeks 20 and 24;
triple IT chemotherapy on day 1 in weeks 20 and 24; methotrexate IV on day 1 in
weeks 21-23 and 25-27; etoposide IV over 2 hours on days 1-5 in week 28;
cyclophosphamide IV over 30 minutes on days 1-5 in week 28; oral mercaptopurine on
days 1-7 in weeks 21-23 and 25-27; and filgrastim SC or IV beginning on day 6 in
week 28 and continuing until blood counts recover. This course is repeated in
weeks 31-41.

- Continuation II (weeks 42-104): Patients receive vincristine IV on days 1, 29, and
57; dexamethasone IV or orally twice daily on days 1-5, 29-33, and 57-61;
intrathecal methotrexate (IT MTX) on day 1; oral methotrexate on days 8, 15, 22,
36, 43, 50, 64, 71, and 78; and oral mercaptopurine on days 8-28, 36-56, and
64-84. Treatment repeats every 12 weeks for 2 years from diagnosis.

A safety/activity phase is conducted separately for the intermediate-risk (IR) and high-risk
(HR) patients to identify a safe, tolerable, and biologically active dose of lestaurtinib
combined with P9407-based chemotherapy backbone. Once a tolerable/active dose of
lestaurtinib has been identified for IR patients, subsequent IR patients are eligible to
proceed to an efficacy phase (efficacy phase began on 01/28/2011), where they are randomized
to P9407-based chemotherapy backbone with or without lestaurtinib. HR patients separately
proceed to the randomized efficacy phase if a tolerable/active dose is identified for the HR
stratum (efficacy phase began on 02/03/2012). IR and HR patients are randomized to 1 of 2
post-induction therapy regimens (post-induction therapy B or C).

- Post-induction therapy B (chemotherapy only for IR/HR patients classified as MLL-R; age
≥ 90 days at diagnosis):

- Induction intensification (weeks 6-9): Patients receive high-dose methotrexate,
leucovorin calcium, cyclophosphamide, etoposide, and filgrastim as in
post-induction therapy A induction intensification. Patients in morphologic
remission proceed to re-induction.

- Re-induction (weeks 10-12): Patients receive vincristine, daunorubicin
hydrochloride, cyclophosphamide, pegaspargase, dexamethasone, triple IT
chemotherapy, and filgrastim as in post-induction therapy A re-induction.

- Consolidation (weeks 13-19): Patients receive high-dose methotrexate, leucovorin
calcium, triple IT chemotherapy, etoposide, cyclophosphamide, high-dose
cytarabine, pegaspargase, and filgrastim as in post-induction therapy A
consolidation.

- Continuation I (weeks 20-49): Patients receive vincristine on day 1 in weeks 20,
24, 33, 37, and 46; dexamethasone orally or IV twice daily on days 1-5 in weeks
20, 24, 33, 37, and 46; triple IT chemotherapy on day 1 in weeks 20, 24, 33, 37,
and 46; methotrexate IV on day 1 in weeks 21-23, 25-26 and 37-45; oral
mercaptopurine on days 1-7 in weeks 21-23, 25-26 and 37-45; etoposide IV over 2
hours on days 1-5 in week 27; cyclophosphamide IV over 30 minutes on days 1-5 in
week 27: high-dose cytarabine IV over 3 hours every 12 hours on days 1 and 2 in
week 30; pegaspargase IM on day 2 in week 30; and filgrastim SC or IV beginning on
day 3 in week 30 and continuing until blood counts recover.

- Continuation II (weeks 50-104): Patients receive vincristine, dexamethasone, IT
methotrexate, oral methotrexate, and oral mercaptopurine as in post-induction
therapy A continuation II. Treatment repeats every 12 weeks for 2 years from
diagnosis.

- Post-induction therapy C (chemotherapy and lestaurtinib for IR/HR patients classified
as MLL-R; age < 90 days at diagnosis):

- Induction intensification therapy (weeks 6-9): Patients receive high-dose
methotrexate, leucovorin calcium, cyclophosphamide, etoposide, and filgrastim as
in post-induction therapy B induction intensification. Patients also receive oral
lestaurtinib twice daily on days 20-27. Patients in morphologic remission proceed
to re-induction.

- Re-induction (weeks 10-12): Patients receive vincristine, daunorubicin
hydrochloride, cyclophosphamide, pegaspargase, dexamethasone, triple IT
chemotherapy, and filgrastim as in post-induction therapy B re-induction. Patients
also receive oral lestaurtinib on days 5-20.

- Consolidation (weeks 13-19): Patients receive high-dose methotrexate, leucovorin
calcium, triple IT chemotherapy, etoposide, cyclophosphamide, high-dose
cytarabine, pegaspargase, and filgrastim as in post-induction therapy B
consolidation. Patients also receive oral lestaurtinib on days 20-27 and 31-42.

- Continuation I (weeks 20-49): Patients receive vincristine, dexamethasone, triple
IT chemotherapy, methotrexate, mercaptopurine, etoposide, high-dose cytarabine,
pegaspargase, and filgrastim as in post-induction therapy B continuation I.
Patients also receive oral lestaurtinib on days 2-6 in weeks 20 and 24, days 27-41
in weeks 27-29, and days 45-56 in weeks 30-32.

- Continuation II (weeks 50-104): Patients receive vincristine, dexamethasone, IT
methotrexate, oral methotrexate, and oral mercaptopurine as in post-induction
therapy B continuation II. Patients also receive lestaurtinib on days 2-6, 30-34,
and 58-62. Treatment repeats every 12 weeks for 2 years from diagnosis.

Blood samples are collected periodically for pharmacokinetic studies and plasma inhibitory
activity assay.

After completion of study treatment, all patients are followed every 1-6 months for 4 years
and then annually thereafter.

Inclusion Criteria


DISEASE CHARACTERISTICS:

- Newly diagnosed acute lymphoblastic leukemia (ALL) or acute undifferentiated leukemia

- T-cell ALL allowed

- Bilineage or biphenotypic acute leukemia allowed provided the morphology and
immunophenotype are predominately lymphoid

- No mature B-cell ALL or acute myelogenous leukemia (AML)

- Must be < 366 days of age at diagnosis; neonates in the first month of life must be >
36 weeks gestational age at diagnosis

- Must be enrolled on protocol COG-AALL08B1 prior to enrollment on this protocol

- Previously untreated except for the following:

- Any amount of steroid pretreatment allowed, provided that the patient meets all
other eligibility requirements

- Inhalation steroids are not considered as pretreatment

- Intrathecal (IT) chemotherapy (per protocol) is allowed for patient convenience
at the time of the diagnostic bone marrow or venous line placement to avoid
second lumbar puncture

- No B-cell ALL or acute myelogenous leukemia

PATIENT CHARACTERISTICS:

- No Down syndrome

PRIOR CONCURRENT THERAPY:

- See Disease Characteristics

- No concurrent chronic steroid treatment for another disease

- No other concurrent non-protocol chemotherapy or investigational therapy

Type of Study:

Interventional

Study Design:

Allocation: Randomized, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Event-free survival at 3 years

Safety Issue:

No

Principal Investigator

Joanne M. Hilden, MD

Investigator Role:

Study Chair

Investigator Affiliation:

St. Vincent Indianapolis Hospital

Authority:

Unspecified

Study ID:

CDR0000573996

NCT ID:

NCT00557193

Start Date:

January 2008

Completion Date:

Related Keywords:

  • Leukemia
  • untreated childhood acute lymphoblastic leukemia
  • T-cell childhood acute lymphoblastic leukemia
  • acute undifferentiated leukemia
  • Leukemia
  • Leukemia, Lymphoid
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma

Name

Location

Roswell Park Cancer InstituteBuffalo, New York  14263
Children's Hospital of PhiladelphiaPhiladelphia, Pennsylvania  19104
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
Barbara Ann Karmanos Cancer InstituteDetroit, Michigan  48201
Hurley Medical CenterFlint, Michigan  48503
Medical City Dallas HospitalDallas, Texas  75230
University of Texas Health Science Center at San AntonioSan Antonio, Texas  78284-7811
Presbyterian - St. Luke's Medical CenterDenver, Colorado  80218
Bronson Methodist HospitalKalamazoo, Michigan  49007
CCOP - MeritCare HospitalFargo, North Dakota  58122
Sanford Cancer Center at Sanford USD Medical CenterSioux Falls, South Dakota  57117-5039
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
Newark Beth Israel Medical CenterNewark, New Jersey  07112
New York Medical CollegeValhalla, New York  10595
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
CCOP - Scott and White HospitalTemple, Texas  76508
Sidney Kimmel Comprehensive Cancer Center at Johns HopkinsBaltimore, Maryland  21231-2410
Cancer Research Center of HawaiiHonolulu, Hawaii  96813
Cleveland Clinic Taussig Cancer CenterCleveland, Ohio  44195
Children's Hospital of Orange CountyOrange, California  92668
Children's National Medical CenterWashington, District of Columbia  20010-2970
Children's Mercy HospitalKansas City, Missouri  64108
St. Joseph's Hospital and Medical CenterPaterson, New Jersey  07503
University of California Davis Cancer CenterSacramento, California  95817
Nemours Children's ClinicJacksonville, Florida  32207
All Children's HospitalSt. Petersburg, Florida  33701
Children's Memorial Hospital - ChicagoChicago, Illinois  60614
Children's Hospital of New OrleansNew Orleans, Louisiana  70118
St. Christopher's Hospital for ChildrenPhiladelphia, Pennsylvania  19134-1095
Driscoll Children's HospitalCorpus Christi, Texas  78466
Cook Children's Medical Center - Fort WorthFort Worth, Texas  76104
Inova Fairfax HospitalFalls Church, Virginia  22042-3300
Fletcher Allen Health Care - University Health Center CampusBurlington, Vermont  05401
Phoenix Children's HospitalPhoenix, Arizona  85016-7710
Southern California Permanente Medical GroupDowney, California  90242
Children's Hospital Central CaliforniaMadera, California  93638-8762
Kosair Children's HospitalLouisville, Kentucky  40202-3830
Palmetto Health South Carolina Cancer CenterColumbia, South Carolina  29203
East Tennessee Children's HospitalKnoxville, Tennessee  37901
Covenant Children's HospitalLubbock, Texas  79410
Children's Hospital of the King's DaughtersNorfolk, Virginia  23507
Midwest Children's Cancer Center at Children's Hospital of WisconsinMilwaukee, Wisconsin  53226
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
Carol G. Simon Cancer Center at Morristown Memorial HospitalMorristown, New Jersey  07962
Winthrop University HospitalMineola, New York  11501
Loma Linda University Cancer Institute at Loma Linda University Medical CenterLoma Linda, California  92354
Jonathan Jaques Children's Cancer Center at Miller Children's HospitalLong Beach, California  90801
Kaiser Permanente Medical Center - OaklandSacramento, California  95825
Lee Cancer Care of Lee Memorial Health SystemFort Myers, Florida  33901
Baptist-South Miami Regional Cancer ProgramMiami, Florida  33176
Nemours Children's Clinic - OrlandoOrlando, Florida  32806
Florida Hospital Cancer Institute at Florida Hospital OrlandoOrlando, Florida  32803-1273
St. Joseph's Cancer Institute at St. Joseph's HospitalTampa, Florida  33607
Kaplan Cancer Center at St. Mary's Medical CenterWest Palm Beach, Florida  33407
St. Vincent Indianapolis HospitalIndianapolis, Indiana  46260
Blank Children's HospitalDes Moines, Iowa  50309
Alvin and Lois Lapidus Cancer Institute at Sinai HospitalBaltimore, Maryland  21215
Floating Hospital for Children at Tufts - New England Medical CenterBoston, Massachusetts  02111
Breslin Cancer Center at Ingham Regional Medical CenterLansing, Michigan  48910
Hackensack University Medical Center Cancer CenterHackensack, New Jersey  07601
Albert Einstein Cancer Center at Albert Einstein College of MedicineBronx, New York  10461
NYU Cancer Institute at New York University Medical CenterNew York, New York  10016
SUNY Upstate Medical University HospitalSyracuse, New York  13210
Mission Hospitals - Memorial CampusAsheville, North Carolina  28801
Presbyterian Cancer Center at Presbyterian HospitalCharlotte, North Carolina  28233-3549
Wake Forest University Comprehensive Cancer CenterWinston-Salem, North Carolina  27157-1096
Cincinnati Children's Hospital Medical CenterCincinnati, Ohio  45229-3039
Rainbow Babies and Children's HospitalCleveland, Ohio  44106-5000
Toledo HospitalToledo, Ohio  43606
Rhode Island Hospital Comprehensive Cancer CenterProvidence, Rhode Island  02903
Texas Tech University Health Sciences Center School of Medicine - AmarilloAmarillo, Texas  79106
Simmons Comprehensive Cancer Center at University of Texas Southwestern Medical Center - DallasDallas, Texas  75390
Baylor University Medical Center - HoustonHouston, Texas  77030-2399
Methodist Children's Hospital of South TexasSan Antonio, Texas  78229-3993
Primary Children's Medical CenterSalt Lake City, Utah  84113-1100
Providence Cancer Center at Sacred Heart Medical CenterSpokane, Washington  99220-2555
St. Vincent Hospital Regional Cancer CenterGreen Bay, Wisconsin  54307-3508
Saint Peter's University HospitalNew Brunswick, New Jersey  08901-1780
James P. Wilmot Cancer Center at University of Rochester Medical CenterRochester, New York  14642
David C. Pratt Cancer Center at St. John's MercySt. Louis, Missouri  63141
Greenebaum Cancer Center at University of Maryland Medical CenterBaltimore, Maryland  21201
Samuel Oschin Comprehensive Cancer Institute at Cedars-Sinai Medical CenterLos Angeles, California  90048-1865
Children's Hospital and Research Center OaklandOakland, California  94609
Lucile Packard Children's Hospital at Stanford University Medical CenterPalo Alto, California  95798
Rady Children's Hospital - San DiegoSan Diego, California  92123-4282
UCSF Helen Diller Family Comprehensive Cancer CenterSan Francisco, California  94115
Alfred I. duPont Hospital for ChildrenWilmington, Delaware  19803
Lombardi Comprehensive Cancer Center at Georgetown University Medical CenterWashington, District of Columbia  20007
M.D. Anderson Cancer Center at OrlandoOrlando, Florida  32806
AFLAC Cancer Center and Blood Disorders Service of Children's Healthcare of Atlanta - Egleston CampusAtlanta, Georgia  30322
Curtis and Elizabeth Anderson Cancer Institute at Memorial Health University Medical CenterSavannah, Georgia  31403-3089
Mountain States Tumor Institute at St. Luke's Regional Medical CenterBoise, Idaho  83712-6297
University of Illinois Cancer CenterChicago, Illinois  60612-7243
Keyser Family Cancer Center at Advocate Hope Children's HospitalOak Lawn, Illinois  60453
Advocate Lutheran General Cancer Care CenterPark Ridge, Illinois  60068-1174
Lucille P. Markey Cancer Center at University of KentuckyLexington, Kentucky  40536-0093
Tulane Cancer Center Office of Clinical ResearchAlexandria, Louisiana  71315-3198
C.S. Mott Children's Hospital at University of Michigan Medical CenterAnn Arbor, Michigan  48109-0286
Masonic Cancer Center at University of MinnesotaMinneapolis, Minnesota  55455
Children's Hospitals and Clinics of Minnesota - MinneapolisMinneapolis, Minnesota  55404
University of Mississippi Cancer ClinicJackson, Mississippi  39216-4505
CCOP - Nevada Cancer Research FoundationLas Vegas, Nevada  89109-2306
St. Barnabas Medical Center Cancer CenterLivingston, New Jersey  07039
Cancer Institute of New Jersey at UMDNJ - Robert Wood Johnson Medical SchoolNew Brunswick, New Jersey  08903
University of New Mexico Cancer CenterAlbuquerque, New Mexico  87131-5636
Albany Medical Center HospitalAlbany, New York  12208-3419
Akron Children's HospitalAkron, Ohio  44308-1062
Nationwide Children's HospitalColumbus, Ohio  43205-2696
Dayton Children's - DaytonDayton, Ohio  45404-1815
Oklahoma University Cancer InstituteOklahoma City, Oklahoma  73104
Geisinger Cancer Institute at Geisinger HealthDanville, Pennsylvania  17822-0001
Penn State Children's HospitalHershey, Pennsylvania  17033-0850
Children's Hospital of Pittsburgh of UPMCPittsburgh, Pennsylvania  15213
Dell Children's Medical Center of Central TexasAustin, Texas  78723
Madigan Army Medical Center - TacomaTacoma, Washington  98431
Mary Bridge Children's Hospital and Health Center - TacomaTacoma, Washington  98405
West Virginia University Health Sciences Center - CharlestonCharleston, West Virginia  25302
Riley's Children Cancer Center at Riley Hospital for ChildrenIndianapolis, Indiana  46202-5225
University of Miami Sylvester Comprehensive Cancer Center - MiamiMiami, Florida  33136
Leo W. Jenkins Cancer Center at ECU Medical SchoolGreenville, North Carolina  27834
Duke Cancer InstituteDurham, North Carolina  27710
Connecticut Children's Medical CenterHartford, Connecticut  06106
Children's Hospital Colorado Center for Cancer and Blood DisordersAurora, Colorado  80045
Nemours Children's Clinic - PensacolaPensacola, Florida  32504
Helen DeVos Children's Hospital at Spectrum HealthGrand Rapids, Michigan  49503
Mercy Children's HospitalToledo, Ohio  43608
Legacy Emanuel Children's HospitalPortland, Oregon  97227
BI-LO Charities Children's Cancer CenterGreenville, South Carolina  29605
Children's Hospital of Alabama at University of Alabama at BirminghamBirmingham, Alabama  35233