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

Basic Trial Information

Trial Description

Summary

RATIONALE: Alisertib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

PURPOSE: This phase II trial is studying the side effects of and how well alisertib works in treating young patients with relapsed or refractory solid tumors or leukemia.

Further Study Information

OBJECTIVES:

Primary

• To determine the objective response rate in pediatric patients with relapsed or refractory solid tumors or leukemia treated with aurora A kinase inhibitor alisertib (MLN8237).

Secondary

• To define and describe the toxicities of this regimen in these patients.

• To characterize the pharmacokinetics of this regimen in these patients.

• To evaluate aurora A kinase expression in tissue samples obtained at diagnosis and at relapse.

• To explore the relationship between polymorphic variations in the UDP-glucuronosyltransferase gene UGT1A1 and exposure to MLN8237.

• To assess two common polymorphic variants in the aurora A kinase gene (Phe31Ile and Val57Ile) associated with tumorigenesis.

OUTLINE: This is a multicenter study. Patients are stratified according to type of tumor ( measurable neuroblastoma vs neuroblastoma with MIBG-positive lesions vs osteosarcoma vs Ewing sarcoma/PNET vs rhabdosarcoma vs non-RMS soft tissue sarcoma vs hepatoblastoma vs rhabdoid tumor vs malignant germ cell tumor vs Wilms tumor vs AML vs ALL).

Patients receive oral alisertib once daily on days 1-7. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity.

Plasma samples are collected from all patients at baseline and periodically during course 1 for pharmacokinetic and other studies.

After completion of study therapy, patients are followed up for 5 years.

Eligibility Criteria

DISEASE CHARACTERISTICS:

• Diagnosis of 1 of the following:

• Histologically confirmed malignant solid tumor at original diagnosis or relapse

• Neuroblastoma

• Rhabdomyosarcoma (RMS)

• Osteosarcoma

• Ewing sarcoma/peripheral primitive neuroectodermal tumor

• Non-RMS soft tissue sarcoma

• Hepatoblastoma

• Malignant germ cell tumor

• Wilms tumor

• Rhabdoid tumor

• Morphology and immunophenotypic panel consistent with rhabdoid tumor (required)

• Loss of INI1 confirmed by immunohistochemistry

• Molecular confirmation of tumor-specific bi-allelic INI1 loss/mutation if INI1 immunohistochemistry is not available

• Histologically confirmed leukemia recurrent or refractory to ≥ 2 prior induction or treatment regimens (must not be known to be refractory to red blood cell or platelet transfusions)

• Acute lymphoblastic leukemia

• > 25% blasts in the bone marrow (M3 bone marrow), excluding known CNS disease

• Acute myeloid leukemia

• ≥ 5 % blasts in the bone marrow (M2/M3 bone marrow), excluding known CNS disease

• Radiographically measurable disease for solid tumors

• Patients with neuroblastoma who do not have measurable disease but have iodine-123 metaiodobenzylguanidine (¹²³ I-MIBG)-positive lesions allowed

• None of the following qualify as measurable disease:

• Malignant fluid collections (e.g., ascites, pleural effusions)

• Bone marrow infiltration

• Lesions detected by nuclear medicine studies (e.g., bone, gallium, or PET scans)

• Elevated tumor markers in plasma or cerebrospinal fluid

• Previously irradiated lesions that have not demonstrated clear progression after radiotherapy

• No CNS disease (leukemia patients)

PATIENT CHARACTERISTICS:

• ECOG performance score (PS) 0-2

• Karnofsky PS 50-100% (for patients > 16 years of age)

• Lansky PS 50-100% (for patients ≤ 16 years of age)

• ANC ≥ 1,000/mm³

• ANC ≥ 750/mm³ (solid tumor and known bone marrow metastatic disease)

• Transfusion allowed

• Hemoglobin ≥ 8.0 g/dL (RBC transfusion allowed)

• Platelet count ≥ 100,000/mm³ (transfusion independent, > 7 days since platelet transfusion )

• Platelet count ≥ 50,000/mm³ (solid tumor and known bone marrow metastatic disease)

• Transfusion allowed

• Not refractory to RBC or platelet transfusions

• Creatinine clearance or radioisotope GFR ≥ 70 mL/min OR a serum creatinine based on age and/or gender as follows:

• 0.6 mg/dL (1 to < 2 years of age)

• 0.8 mg/dL (2 to < 6 years of age)

• 1.0 mg/dL (6 to < 10 years of age)

• 1.2 mg/dL (10 to < 13 years of age)

• 1.5 mg/dL (male) and 1.4 mg/dL (female) (13 to < 16 years of age)

• 1.7 mg/dL (male) and 1.4 mg/dL (female) (≥ 16 years of age)

• Total bilirubin ≤ 1.5 times upper limit of normal (ULN)

• ALT ≤ 5.0 times ULN

• Serum albumin ≥ 2 g/dL

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective contraception during and for ≥ 3 months after completion of study therapy

• Not unable to swallow capsules

• No uncontrolled infection

• No patient who, in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics

• Fully recovered from all prior chemotherapy, immunotherapy, or radiotherapy

• More than 3 weeks since prior myelosuppressive chemotherapy (6 weeks for nitrosourea) (solid tumor patients)

• At least 14 days since prior cytotoxic therapy (leukemia patients)

• Patients who relapse during standard maintenance therapy are not required to wait 14 days

• At least 24 hours since prior cytoreduction with hydroxyurea

• More than 7 days since prior growth factors (14 days for pegfilgrastim [Neulasta])

• At least 7 days since prior biologic agent (antineoplastic agent)

• At least 3 half-lives since prior monoclonal antibody therapy

• At least 2 weeks since prior local palliative radiotherapy (small port)

• At least 6 weeks since prior therapeutic doses of ¹²³ I-MIBG or other substantial bone marrow irradiation

• At least 6 months since prior craniospinal radiotherapy, radiotherapy to ≥ 50% of the pelvis, or total-body irradiation

• At least 3 months since stem cell transplantation with no evidence of active graft-vs-host disease

• Concurrent corticosteroids allowed provided patient is on a stable or decreasing dose for ≥ 7 days before study enrollment

• No other concurrent investigational drugs

• No other concurrent anticancer agents, including chemotherapy, radiotherapy, or immunomodulating agents

• No concurrent daily benzodiazepine therapy

• No concurrent P-glycoprotein substrates (e.g., digoxin, cyclosporine, tacrolimus, or sirolimus)

Trial Contact Information

Trial Lead Organizations/Sponsors

Children's Oncology Group

Amy Kun Pass

Principal Investigator

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
Arkansas
	Little Rock
	Arkansas Cancer Research Center at University of Arkansas for Medical Sciences
		David L Becton	Ph: 501-364-7373
California
	Arcadia
	Children's Oncology Group
		Yael P. Mosse	Ph: 215-590-0965
			Email: mosse@chop.edu
	Downey
	Southern California Permanente Medical Group
		Robert M Cooper	Ph: 626-564-3455
	Long Beach
	Jonathan Jaques Children's Cancer Center at Miller Children's Hospital
		Amanda M Termuhlen	Ph: 562-933-5437
	Los Angeles
	Childrens Hospital Los Angeles
		Leo Mascarenhas	Ph: 323-361-4110
	Samuel Oschin Comprehensive Cancer Institute at Cedars-Sinai Medical Center
		Carole H Hurvitz	Ph: 310-423-8965
	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
	Orange
	Children's Hospital of Orange County
		Violet Shen	Ph: 714-997-3000
	San Diego
	Rady Children's Hospital - San Diego
		William D Roberts	Ph: 858-966-5934
	San Francisco
	UCSF Helen Diller Family Comprehensive Cancer Center
		Katherine K Matthay	Ph: 877-827-3222
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
Delaware
	Wilmington
	Alfred I. duPont Hospital for Children
		Christopher N Frantz	Ph: 302-651-5755
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
	Jacksonville
	Nemours Children's Clinic
		Eric S Sandler	Ph: 904-697-3529
	Orlando
	Florida Hospital Cancer Institute at Florida Hospital Orlando
		Clifford A Selsky	Ph: 407-303-5623
	M.D. Anderson Cancer Center at Orlando
		Vincent F Giusti	Ph: 321-841-7246
	Nemours Children's Clinic - Orlando
		Ramamoorthy Nagasubramanian	Ph: 407-650-7150
	Pensacola
	Nemours Children's Clinic - Pensacola
		Jeffrey H Schwartz	Ph: 904-697-3529
	Saint Petersburg
	All Children's Hospital
		Gregory A Hale	Ph: 727-767-2423
			Email: HamblinF@allkids.org
	Tampa
	St. Joseph's Children's Hospital of Tampa
		Hardeo K Panchoosingh	Ph: 800-882-4123
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
Illinois
	Chicago
	Ann and Robert H. Lurie Children's Hospital of Chicago
		David O Walterhouse	Ph: 773-880-4562
	University of Chicago Cancer Research Center
		Stephen X Skapek	Ph: 214-648-7097
	University of Illinois Cancer Center
		Mary L Schmidt	Ph: 312-355-3046
	Peoria
	Saint Jude Midwest Affiliate
		Pedro A De Alarcon	Ph: 309-655-3258
	Springfield
	Simmons Cooper Cancer Institute
		Gregory P Brandt	Ph: 217-545-7929
Indiana
	Indianapolis
	Riley's Children Cancer Center at Riley Hospital for Children
		Robert J Fallon	Ph: 317-274-2552
Iowa
	Iowa City
	Holden Comprehensive Cancer Center at University of Iowa
		Ayman A El-Sheikh	Ph: 800-237-1225
Kentucky
	Lexington
	University of Kentucky Chandler Medical Center
		Martha F Greenwood	Ph: 859-257-3379
Louisiana
	New Orleans
	Tulane Cancer Center at Tulane University Hospital and Clinic
		Tammuella C Singleton	Ph: 504-988-6121
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
		David M Loeb	Ph: 410-955-8804
			Email: jhcccro@jhmi.edu
Massachusetts
	Boston
	Dana-Farber/Harvard Cancer Center at Dana-Farber Cancer Institute
		Carlos Rodriguez-Galindo	Ph: 866-790-4500
Michigan
	Detroit
	Wayne State University
		Maxim Y Yankelevich	Ph: 313-576-9363
Minnesota
	Minneapolis
	Children's Hospitals and Clinics of Minnesota - Minneapolis
		Bruce C Bostrom	Ph: 612-813-5193
	Masonic Cancer Center at University of Minnesota
		Brenda J Weigel	Ph: 612-624-2620
	Rochester
	Mayo Clinic Cancer Center
		Carola A. S. Arndt	Ph: 507-538-7623
Mississippi
	Jackson
	University of Mississippi Cancer Clinic
		Gail C Megason	Ph: 601-815-6700
Missouri
	Kansas City
	Children's Mercy Hospital
		Kathleen A Neville	Ph: 816-234-3265
	Saint Louis
	David C. Pratt Cancer Center at St. John's Mercy
		Bethany G. Sleckman	Ph: 913-948-5588
	Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis
		Robert J Hayashi	Ph: 800-600-3606
			Email: info@siteman.wustl.edu
Nebraska
	Omaha
	Children's Hospital
		Minnie Abromowitch	Ph: 402-955-3949
New Jersey
	Hackensack
	Hackensack University Medical Center Cancer Center
		Michael B Harris	Ph: 201-996-2879
	Morristown
	Carol G. Simon Cancer Center at Morristown Memorial Hospital
		Steven L Halpern	Ph: 973-971-5900
	New Brunswick
	Cancer Institute of New Jersey at UMDNJ - Robert Wood Johnson Medical School
		Richard A Drachtman	Ph: 732-235-8675
	Summit
	Overlook Hospital
		Steven L Halpern	Ph: 973-971-5900
New Mexico
	Albuquerque
	University of New Mexico Cancer Center
		Koh B Boayue	Ph: 505-272-6972
New York
	Bronx
	Montefiore Medical Center
		Rosanna J Ricafort	Ph: 718-904-2730
			Email: aecc@aecom.yu.edu
	Buffalo
	Roswell Park Cancer Institute
		Martin L Brecher	Ph: 877-275-7724
	Mineola
	Winthrop University Hospital
		Mark E Weinblatt	Ph: 866-946-8476
	Syracuse
	SUNY Upstate Medical University Hospital
		Karol H Kerr	Ph: 315-464-5476
	Valhalla
	New York Medical College
		Mehmet F Ozkaynak	Ph: 914-594-3794
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
	Presbyterian Cancer Center at Presbyterian Hospital
		Paulette C Bryant	Ph: 704-384-5369
	Winston-Salem
	Wake Forest University Comprehensive Cancer Center
		Thomas W McLean	Ph: 336-713-6771
Ohio
	Cincinnati
	Cincinnati Children's Hospital Medical Center
		John P Perentesis	Ph: 513-636-2799
	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
	Mercy Children's Hospital
		Rama Jasty	Ph: 419-251-8210
Oklahoma
	Oklahoma City
	Oklahoma University Cancer Institute
		Rene Y McNall-Knapp	Ph: 405-271-4272
			Email: julie-traylor@ouhsc.edu
	Tulsa
	Natalie Warren Bryant Cancer Center at St. Francis Hospital
		Gregory B Kirkpatrick	Ph: 918-494-2200
Oregon
	Portland
	Knight Cancer Institute at Oregon Health and Science University
		Linda C. Stork	Ph: 503-494-1080
			Email: trials@ohsu.edu
	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
		John F Kuttesch	Ph: 505-272-6972
			Email: CTO@hmc.psu.edu
	Philadelphia
	Children's Hospital of Philadelphia
		Elizabeth Fox	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
Tennessee
	Knoxville
	East Tennessee Children's Hospital
		Ray C Pais	Ph: 865-541-8266
	Memphis
	St. Jude Children's Research Hospital
		Wayne L Furman	Ph: 901-595-4644
	Nashville
	Vanderbilt-Ingram Cancer Center
		Scott C Borinstein	Ph: 800-811-8480
Texas
	Corpus Christi
	Driscoll Children's Hospital
		M. C Johnson	Ph: 361-694-5311
	Dallas
	Medical City Dallas Hospital
		Carl Lenarsky	Ph: 972-566-5588
	Simmons Comprehensive Cancer Center at University of Texas Southwestern Medical Center - Dallas
		Naomi J Winick	Ph: 214-648-7097
	Fort Worth
	Cook Children's Medical Center - Fort Worth
		Mary Meaghan P Granger	Ph: 682-885-2103
	Houston
	Dan L. Duncan Cancer Center at Baylor College of Medicine
		Lisa R Bomgaars	Ph: 713-798-1354
			Email: burton@bcm.edu
	San Antonio
	Methodist Children's Hospital of South Texas
		Jaime Estrada	Ph: 210-575-7000
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
	Richmond
	Virginia Commonwealth University Massey Cancer Center
		Kamar Godder	Ph: 804-628-1939
Washington
	Seattle
	Children's Hospital and Regional Medical Center - Seattle
		Julie R Park	Ph: 866-987-2000
	Spokane
	Providence Cancer Center at Sacred Heart Medical Center
		Judy L Felgenhauer	Ph: 800-228-6618
			Email: HopeBeginsHere@providence.org
Wisconsin
	Green Bay
	St. Vincent Hospital Regional Cancer Center
		John R Hill	Ph: 920-433-8889
	Madison
	University of Wisconsin Paul P. Carbone Comprehensive Cancer Center
		Kenneth B De Santes	Ph: 608-262-5223
	Milwaukee
	Midwest Children's Cancer Center at Children's Hospital of Wisconsin
		Michael E Kelly	Ph: 414-805-4380
Canada
Alberta
	Calgary
	Alberta Children's Hospital
		Douglas R Strother	Ph: 403-220-6898
			Email: research4kids@ucalgary.ca
British Columbia
	Vancouver
	Children's and Women's Hospital of British Columbia
		Caron Strahlendorf	Ph: 604-875-2345ext6477
Manitoba
	Winnipeg
	CancerCare Manitoba
		Rochelle A Yanofsky	Ph: 866-561-1026
			Email: CIO_Web@cancercare.mb.ca
Nova Scotia
	Halifax
	IWK Health Centre
		Margaret C Yhap	Ph: 902-470-8394
Ontario
	Kingston
	Cancer Centre of Southeastern Ontario at Kingston General Hospital
		Mariana P Silva	Ph: 613-544-2630
	Toronto
	Hospital for Sick Children
		Ronald M Grant	Ph: 416-813-7654ext2027
			Email: jason.mcguire@sickkids.ca
Quebec
	Montreal
	Hopital Sainte Justine
		Yvan Samson	Ph: 514-345-4931
	Montreal Children's Hospital at McGill University Health Center
		Sharon B Abish	Ph: 514-412-4445
			Email: info@thechildren.com

Link to the current ClinicalTrials.gov record.
NLM Identifer NCT01154816
Information obtained from ClinicalTrials.gov on November 25, 2012

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