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
	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
	Oakland
	Children's Hospital and Research Center Oakland
		Carla B Golden	Ph: 510-450-7600
	Palo Alto
	Lucile Packard Children's Hospital at Stanford University Medical Center
		Neyssa M Marina	Ph: 650-498-7061
			Email: clinicaltrials@med.stanford.edu
Idaho
	Boise
	Mountain States Tumor Institute at St. Luke's Regional Medical Center
		Eugenia Chang	Ph: 800-845-4624
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
Maryland
	Baltimore
	Alvin and Lois Lapidus Cancer Institute at Sinai Hospital
		Joseph M Wiley	Ph: 410-601-6120
			Email: pridgely@lifebridgehealth.org
	Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
		Patrick A Brown	Ph: 410-955-8804
			Email: jhcccro@jhmi.edu
Michigan
	Kalamazoo
	Western Michigan University School of Medicine Clinics
		Jeffrey S Lobel	Ph: 800-227-2345
Minnesota
	Rochester
	Mayo Clinic Cancer Center
		Vilmarie Rodriguez	Ph: 507-538-7623
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
	Summit
	Overlook Hospital
		Steven L Halpern	Ph: 973-971-5900
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
	Toledo
	Toledo Hospital
		Dagmar T Stein	Ph: 419-824-1842
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
South Carolina
	Greenville
	Cancer Centers of the Carolinas - Faris Road
		Cary E Stroud	Ph: 864-241-6251
Texas
	Austin
	Dell Children's Medical Center of Central Texas
		Sharon K Lockhart	Ph: 512-324-8022
	Houston
	Dan L. Duncan Cancer Center at Baylor College of Medicine
		Lisa R Bomgaars	Ph: 713-798-1354
			Email: burton@bcm.edu
Washington
	Tacoma
	Madigan Army Medical Center - Tacoma
		Melissa A Forouhar	Ph: 253-968-0129
			Email: mamcdci@amedd.army.mil
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
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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