Basic Trial Information
Trial Description
     Summary
     Further Trial Information
     Eligibility Criteria
Trial Contact Information

Basic Trial Information

Trial Description

Summary

RATIONALE: Drugs used in chemotherapy work in different ways to stop the growth of stop cancer cells, either by killing the cells or by stopping them from dividing. Lestaurtinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving more than one drug (combination chemotherapy) together with lestaurtinib may kill more cancer cells.

PURPOSE: This phase III trial is studying giving lestaurtinib together with combination chemotherapy to see how well it works compared to combination chemotherapy alone in treating infants with newly diagnosed acute lymphoblastic leukemia.

Further Study Information

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.

Eligibility 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

Trial Contact Information

Trial Lead Organizations/Sponsors

Children's Oncology Group

Joanne M. Hilden

Study Chair

Patrick A. Brown

U.S.A.
Alabama
	Birmingham
	Children's Hospital of Alabama at University of Alabama at Birmingham
		Alyssa T Reddy	Ph: 205-934-0309
	UAB Comprehensive Cancer Center
		Alyssa T Reddy	Ph: 205-934-0309
Arizona
	Phoenix
	Phoenix Children's Hospital
		Jessica Boklan	Ph: 602-546-0920
California
	Arcadia
	Children's Oncology Group
		Joanne M Hilden	Ph: 720-777-6538
			Email: Joanne.Hilden@childrenscolorado.org
	Downey
	Southern California Permanente Medical Group
		Robert M Cooper	Ph: 626-564-3455
	Loma Linda
	Loma Linda University Cancer Institute at Loma Linda University Medical Center
		Antranik A Bedros	Ph: 909-558-3375
	Madera
	Children's Hospital Central California
		Vonda L Crouse	Ph: 866-353-5437
	Oakland
	Children's Hospital and Research Center Oakland
		Carla B Golden	Ph: 510-450-7600
	Kaiser Permanente-Oakland
		Steven K Bergstrom	Ph: 626-564-3455
	Palo Alto
	Lucile Packard Children's Hospital at Stanford University Medical Center
		Neyssa M Marina	Ph: 650-498-7061
			Email: clinicaltrials@med.stanford.edu
	Sacramento
	University of California Davis Cancer Center
		Jay Michael S Balagtas	Ph: 916-734-3089
	San Diego
	Rady Children's Hospital - San Diego
		William D Roberts	Ph: 858-966-5934
	San Francisco
	UCSF Helen Diller Family Comprehensive Cancer Center
		Mignon Loh	Ph: 877-827-3222
Colorado
	Aurora
	Children's Hospital Colorado Center for Cancer and Blood Disorders
		Kelly W Maloney	Ph: 720-777-6672
Connecticut
	Hartford
	Connecticut Children's Medical Center
		Michael S Isakoff	Ph: 860-545-9981
	New Haven
	Yale Cancer Center
		Nina S Kadan-Lottick	Ph: 203-785-5702
District of Columbia
	Washington
	Children's National Medical Center
		Jeffrey S Dome	Ph: 202-884-2549
Florida
	Fort Myers
	Lee Cancer Care of Lee Memorial Health System
		Emad K Salman	Ph: 239-343-5333
	Orlando
	Florida Hospital Cancer Institute at Florida Hospital Orlando
		Clifford A Selsky	Ph: 407-303-5623
	Saint Petersburg
	All Children's Hospital
		Gregory A Hale	Ph: 727-767-2423
			Email: HamblinF@allkids.org
	West Palm Beach
	Kaplan Cancer Center at St. Mary's Medical Center
		Narayana Gowda	Ph: 888-823-5923
			Email: ctsucontact@westat.com
Georgia
	Atlanta
	AFLAC Cancer Center and Blood Disorders Service of Children's Healthcare of Atlanta - Egleston Campus
		Howard M Katzenstein	Ph: 888-785-1112
Hawaii
	Honolulu
	Cancer Research Center of Hawaii
		Robert W Wilkinson	Ph: 808-983-6090
Idaho
	Boise
	Mountain States Tumor Institute at St. Luke's Regional Medical Center
		Eugenia Chang	Ph: 800-845-4624
Illinois
	Chicago
	University of Illinois Cancer Center
		Mary L Schmidt	Ph: 312-355-3046
Indiana
	Indianapolis
	Riley's Children Cancer Center at Riley Hospital for Children
		Robert J Fallon	Ph: 317-274-2552
	St. Vincent Indianapolis Hospital
		Bassem I Razzouk	Ph: 317-338-2194
Iowa
	Des Moines
	Blank Children's Hospital
		Wendy L Woods-Swafford	Ph: 888-823-5923
			Email: ctsucontact@westat.com
Kentucky
	Lexington
	University of Kentucky Chandler Medical Center
		Martha F Greenwood	Ph: 859-257-3379
	Louisville
	Kosair Children's Hospital
		Salvatore J Bertolone	Ph: 866-530-5516
Maine
	Bangor
	CancerCare of Maine at Eastern Maine Medical Center
		Sarah J Fryberger	Ph: 207-973-4274
Maryland
	Baltimore
	Alvin and Lois Lapidus Cancer Institute at Sinai Hospital
		Joseph M Wiley	Ph: 410-601-6120
			Email: pridgely@lifebridgehealth.org
	Greenebaum Cancer Center at University of Maryland Medical Center
		Teresa A York	Ph: 800-888-8823
	Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
		Patrick A Brown	Ph: 410-955-8804
			Email: jhcccro@jhmi.edu
Michigan
	Kalamazoo
	Bronson Methodist Hospital
		Jeffrey S Lobel	Ph: 800-227-2345
	Western Michigan University School of Medicine Clinics
		Jeffrey S Lobel	Ph: 800-227-2345
	Lansing
	Breslin Cancer Center at Ingham Regional Medical Center
		Renuka Gera	Ph: 517-334-2765
Minnesota
	Minneapolis
	Masonic Cancer Center at University of Minnesota
		Michael J Burke	Ph: 612-624-2620
	Rochester
	Mayo Clinic Cancer Center
		Vilmarie Rodriguez	Ph: 507-538-7623
Missouri
	Columbia
	Ellis Fischel Cancer Center at University of Missouri - Columbia
		Thomas W Loew	Ph: 573-882-7440
Nevada
	Las Vegas
	CCOP - Nevada Cancer Research Foundation
		Jonathan Bernstein	Ph: 702-384-0013
New Jersey
	Hackensack
	Hackensack University Medical Center Cancer Center
		Burton E Appel	Ph: 201-996-2879
	Morristown
	Carol G. Simon Cancer Center at Morristown Memorial Hospital
		Steven L Halpern	Ph: 973-971-5900
	Paterson
	St. Joseph's Hospital and Medical Center
		Mary A Bonilla	Ph: 973-754-2909
	Summit
	Overlook Hospital
		Steven L Halpern	Ph: 973-971-5900
New York
	Bronx
	Montefiore Medical Center
		Rosanna J Ricafort	Ph: 718-904-2730
			Email: aecc@aecom.yu.edu
	New York
	New York University Medical Center
		Elizabeth A Raetz	Ph: 212-263-4434
			Email: prmc.coordinator@nyumc.org
	Rochester
	James P. Wilmot Cancer Center at University of Rochester Medical Center
		Jeffrey R Andolina	Ph: 585-275-5830
	Syracuse
	SUNY Upstate Medical University Hospital
		Karol H Kerr	Ph: 315-464-5476
North Carolina
	Chapel Hill
	Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill
		Stuart H Gold	Ph: 877-668-0683
	Charlotte
	Blumenthal Cancer Center at Carolinas Medical Center
		Joel A Kaplan	Ph: 704-355-2884
	Durham
	Duke Cancer Institute
		Susan G Kreissman	Ph: 888-275-3853
	Greenville
	Leo W. Jenkins Cancer Center at ECU Medical School
		Mauro Grossi	Ph: 252-744-2161
	Winston-Salem
	Wake Forest University Comprehensive Cancer Center
		Thomas W McLean	Ph: 336-713-6771
North Dakota
	Fargo
	Roger Maris Cancer Center at MeritCare Hospital
		Nathan L Kobrinsky	Ph: 701-234-6161
Ohio
	Akron
	Akron Children's Hospital
		Steven J Kuerbitz	Ph: 330-543-3193
	Cincinnati
	Cincinnati Children's Hospital Medical Center
		John P Perentesis	Ph: 513-636-2799
	Cleveland
	Seidman Cancer Center at University Hospitals/Case Medical Center
		Yousif (Joe) H Matloub	Ph: 216-844-5437
	Columbus
	Nationwide Children's Hospital
		Mark A Ranalli	Ph: 614-722-2708
	Dayton
	Dayton Children's - Dayton
		Emmett H Broxson	Ph: 800-228-4055
	Toledo
	Toledo Hospital
		Dagmar T Stein	Ph: 419-824-1842
Oklahoma
	Oklahoma City
	Oklahoma University Cancer Institute
		Rene Y McNall-Knapp	Ph: 405-271-4272
			Email: julie-traylor@ouhsc.edu
Oregon
	Portland
	Legacy Emanuel Children's Hospital
		Janice F Olson	Ph: 503-413-2560
	Legacy Emanuel Hospital and Health Center and Children's Hospital
		Janice F Olson	Ph: 503-413-2560
Pennsylvania
	Hershey
	Penn State Children's Hospital
		Lisa M McGregor	Ph: 717-531-6012
	Philadelphia
	Children's Hospital of Philadelphia
		Frank M Balis	Ph: 215-590-2810
	St. Christopher's Hospital for Children
		Gregory E Halligan	Ph: 215-427-8991
	Pittsburgh
	Children's Hospital of Pittsburgh of UPMC
		Arthur K Ritchey	Ph: 412-692-5573
South Carolina
	Columbia
	Palmetto Health South Carolina Cancer Center
		Ronnie W. Neuberg	Ph: 803-434-3680
	Greenville
	BI-LO Charities Children's Cancer Center
		Nichole L Bryant	Ph: 864-241-6251
	Cancer Centers of the Carolinas - Faris Road
		Cary E Stroud	Ph: 864-241-6251
South Dakota
	Sioux Falls
	Sanford Cancer Center at Sanford USD Medical Center
		Kayelyn J Wagner	Ph: 605-328-1367
Tennessee
	Nashville
	Vanderbilt-Ingram Cancer Center
		Haydar A Frangoul	Ph: 800-811-8480
Texas
	Amarillo
	Texas Tech University Health Sciences Center School of Medicine - Amarillo
		Osvaldo Regueira	Ph: 806-354-5411
	Austin
	Dell Children's Medical Center of Central Texas
		Sharon K Lockhart	Ph: 512-324-8022
	Corpus Christi
	Driscoll Children's Hospital
		M. C Johnson	Ph: 361-694-5311
	Houston
	Dan L. Duncan Cancer Center at Baylor College of Medicine
		Lisa R Bomgaars	Ph: 713-798-1354
			Email: burton@bcm.edu
	San Antonio
	University of Texas Health Science Center at San Antonio
		Anne-Marie R Langevin	Ph: 210-567-0653
			Email: che@uthscsa.edu
	Temple
	Scott and White Cancer Institute
		Guy H Grayson	Ph: 254-724-5407
Utah
	Salt Lake City
	Primary Children's Medical Center
		Phillip E Barnette	Ph: 801-585-5270
Vermont
	Burlington
	Vermont Cancer Center at University of Vermont
		Alan C Homans	Ph: 802-656-8990
Virginia
	Norfolk
	Children's Hospital of The King's Daughters
		Eric J Lowe	Ph: 757-668-7243
Washington
	Tacoma
	Madigan Army Medical Center - Tacoma
		Melissa A Forouhar	Ph: 253-968-0129
			Email: mamcdci@amedd.army.mil
	Mary Bridge Children's Hospital and Health Center - Tacoma
		Robert G Irwin	Ph: 888-823-5923
			Email: ctsucontact@westat.com
Wisconsin
	Green Bay
	St. Vincent Hospital Regional Cancer Center
		John R Hill	Ph: 920-433-8889
	Marshfield
	Marshfield Clinic - Marshfield Center
		Michael J McManus	Ph: 715-389-4457
	Milwaukee
	Midwest Children's Cancer Center at Children's Hospital of Wisconsin
		Michael E Kelly	Ph: 414-805-4380
New Zealand
Auckland
	Grafton
	Starship Children's Health
		Nyree O Cole	Ph:  0800 728 436

Link to the current ClinicalTrials.gov record.
NLM Identifer NCT00557193
Information obtained from ClinicalTrials.gov on April 04, 2013

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