Alisertib in Treating Young Patients With Recurrent or Refractory Solid Tumors or Leukemia

Recurrent Childhood Acute Lymphoblastic Leukemia Clinical Trial

Official title:

A Phase II Study of MLN8237, a Selective Aurora A Kinase Inhibitor in Children With Recurrent/Refractory Solid Tumors and Leukemias

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01154816
• Other study ID #: ADVL0921
• Secondary ID: NCI-2011-02051CD
• Status: Completed
• Phase: Phase 2
• Start date: February 2011
• Est. completion date: June 30, 2019

Study information

• Verified date: September 2017
• Source: Children's Oncology Group
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

Description:

PRIMARY OBJECTIVE:

I. To determine the objective response rate to MLN8237 (alisertib) in children with relapsed or refractory solid tumors and leukemias, administered once daily for 7 days every 21 days.

SECONDARY OBJECTIVES:

I. To further define and describe the toxicities of MLN8237 administered on this schedule.

II. To further characterize the pharmacokinetics of MLN8237 in children with refractory cancer.

III. To evaluate aurora A kinase expression using immunohistochemistry in solid tumors and leukemic blasts from tissue obtained at diagnosis and, if available, at relapse.

IV. To explore the relationship between polymorphic variations in the UDP-glucuronosyltransferase gene UGT1A1 and exposure to MLN8237, and to assess 2 common polymorphic variants in the aurora A kinase gene, Phe31Ile and Val57Ile.

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

ARM I (NEUROBLASTOMA- MEASURABLE): Patients receive alisertib orally (PO) once daily (QD) on days 1-7. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity.

ARM II (NEUROBLASTOMA-MIBG EVALUABLE): Patients receive alisertib PO QD on days 1-7. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity.

ARM III (RHABDOMYOSARCOMA): Patients receive alisertib PO QD on days 1-7. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity.

ARM IV (OSTEOSARCOMA): Patients receive alisertib PO QD on days 1-7. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity.

ARM V (EWING SARCOMA/ PERIPHERAL PNET): Patients receive alisertib PO QD on days 1-7. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity.

ARM VI (NON-RMS SOFT TISSUE SARCOMA): Patients receive alisertib PO QD on days 1-7. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity.

ARM VII (HEPATOBLASTOMA): Patients receive alisertib PO QD on days 1-7. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity.

ARM VIII (MALIGNANT GERM CELL TUMOR): Patients receive alisertib PO QD on days 1-7. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity.

ARM IX (WILMS TUMOR): Patients receive alisertib PO QD on days 1-7. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity.

ARM X (ACUTE LYMPHOBLASTIC LEUKEMIA): Patients receive alisertib PO QD on days 1-7. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity.

ARM XI (ACUTE MYELOGENOUS LEUKEMIA): Patients receive alisertib PO QD on days 1-7. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity.

ARM XII (RHABDOID MALIGNANCY): Patients receive alisertib PO QD 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 118
• Est. completion date: June 30, 2019
• Est. primary completion date: December 31, 2015
• Accepts healthy volunteers: No
• Gender: All
• Age group: 1 Year to 21 Years

Eligibility

Inclusion Criteria:

• Patients must have had histologic verification of malignancy at original diagnosis or at relapse, to include any of the following malignancies (no other histology is eligible):

• Neuroblastoma- measurable

• Neuroblastoma- MIBG evaluable

• Rhabdomyosarcoma

• Osteosarcoma

• Ewing sarcoma/Peripheral PNET

• Non-RMS soft tissue sarcoma

• Hepatoblastoma

• Malignant germ cell tumor

• Wilms tumor

• Acute lymphoblastic leukemia

• Acute myelogenous leukemia

• Rhabdoid malignancy

• Disease status for solid tumor patients:

• Patients must have radiographically measurable disease (with the exception of neuroblastoma)

• Measurable disease is defined as the presence of at least one lesion on magnetic resonance imaging (MRI) or computed tomography (CT) scan that can be accurately measured with the longest diameter a minimum of 20 mm in at least one dimension; for spiral CT, measurable disease is defined as a minimum diameter of 10 mm in at least one dimension

• Note: The following do not 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 positron emission tomography [PET] scans)

• Elevated tumor markers in plasma or cerebrospinal fluid (CSF)

• Previously irradiated lesions that have not demonstrated clear progression post radiation

• Patients with neuroblastoma who do not have measurable disease but have MIBG+ evaluable disease are eligible

• Disease status for leukemia patients:

• Patients with leukemia must be recurrent or refractory to at least two prior induction or treatment regimens, in addition to the following criteria:

• Acute lymphoid leukemia:

• 25% blasts in the bone marrow (M3 bone marrow), excluding patients with known central nervous system (CNS) disease

• Acute myeloid leukemia according to FAB classification

• = 5 % blasts in the bone marrow (M2/M3 bone marrow); excluding patients with known CNS disease

• Rhabdoid tumors:

• To be eligible for enrollment in the rhabdoid tumors stratum, the patient must have a solid tumor where the institutional pathological evaluation of the tumor at initial diagnosis or relapse has confirmed:

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

• Loss of SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily b, member 1 (INI1) confirmed by immunohistochemistry, or

• Molecular confirmation of tumor-specific bi-allelic INI1 loss/mutation if INI1 immunohistochemistry is not available; note that molecular confirmation of tumor-specific bi-allelic INI1 loss/mutation is encouraged in cases where INI1 immunohistochemistry is equivocal

• Patients must have a Lansky or Karnofsky performance status score of = 50, corresponding to Eastern Cooperative Oncology Group (ECOG) categories 0, 1 or 2; use Karnofsky for patients > 16 years of age and Lansky for patients = 16 years of age; Note: Patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score

• Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to study enrollment

• Myelosuppressive chemotherapy:

• Solid tumors:

• Patients with solid tumors must not have received myelosuppressive chemotherapy within 3 weeks of enrollment onto this study (6 weeks if prior nitrosourea)

• Leukemia:

• Patients with leukemia who relapse while receiving standard maintenance therapy will not be required to have a waiting period before enrollment onto this study

• Patients who relapse while they are not receiving standard maintenance therapy must have completely recovered from all acute toxic effects of chemotherapy, immunotherapy or radiotherapy prior to study enrollment; at least 14 days must have elapsed since the completion of cytotoxic therapy, with the exception of hydroxyurea

• Note: cytoreduction with hydroxyurea can be initiated and continued for up to 24 hours prior to the start of MLN8237

• At least 7 days must have elapsed since the completion of therapy with a growth factor; at least 14 days must have elapsed after receiving pegfilgrastim

• At least 7 days must have elapsed since completion of therapy with a biologic agent; for agents that have known adverse events occurring beyond 7 days after administration, this period prior to enrollment must be extended beyond the time during which adverse events are known to occur

• At least 3 half-lives must have elapsed since prior therapy that included a monoclonal antibody

• = 2 weeks must have elapsed since local palliative radiation therapy (XRT) (small port); = 6 weeks must have elapsed since treatment with therapeutic doses of MIBG; = 6 months must have elapsed if prior craniospinal XRT was received, if = 50% of the pelvis was irradiated, or if total body irradiation (TBI) was received; = 6 weeks must have elapsed if other substantial bone marrow irradiation was given

• No evidence of active graft vs. host disease and = 3 months must have elapsed since transplant

• For patients with solid tumors without bone marrow involvement:

• Peripheral absolute neutrophil count (ANC) >= 1000/mm^3

• Platelet count >= 100,000/mm^3 (transfusion independent, defined as not receiving platelet transfusions within a 7 day period prior to enrollment)

• Hemoglobin > 8.0 g/dL (may receive red blood cell [RBC] transfusions)

• For patients with solid tumors and known bone marrow metastatic disease:

• Peripheral absolute neutrophil count (ANC) = 750/mm^3

• Platelet count = 50,000/mm^3

• Hemoglobin = 8.0 g/dL

• Transfusions are permitted to meet both the platelet and hemoglobin criteria; patients must not be known to be refractory to red blood cell or platelet transfusions

• Patients with leukemia must not be known to be refractory to red blood cell or platelet transfusions

• Creatinine clearance or radioisotope glomerular filtration rate (GFR) 70 mL/min/1.73 m^2 or a serum creatinine based on age/gender as follows:

• 1 to < 2 years: 0.6

• 2 to < 6 years: 0.8

• 6 to < 10 years: 1

• 10 to < 13 years: 1.2

• 13 to < 16 years: 1.5 (male), 1.4 (female)

• >= 16 years: 1.7 (male), 1.4 (female)

• Total bilirubin =< 1.5 x upper limit of normal (ULN) for age

• Serum glutamic pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) = 5.0 x ULN for age (= 225 U/L); for the purpose of this study, the ULN for SGPT is 45 U/L

• Serum albumin = 2 g/dL

• All patients and/or their parents or legal guardians must sign a written informed consent

Exclusion Criteria:

• Patients who are pregnant or breast-feeding are not eligible for this study; negative pregnancy tests must be obtained in girls who are post-menarchal; males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method for the duration of study therapy; breastfeeding women are excluded

• Growth factors that support platelet or white cell number or function must not have been administered within the 7 days prior to enrollment (14 days if pegfilgrastim)

• Patients requiring corticosteroids who have not been on a stable or decreasing dose of corticosteroid for the 7 days prior to enrollment are not eligible

• Patients who are currently receiving another investigational drug are not eligible

• Patients who are currently receiving other anti-cancer agents are not eligible

• Use of daily benzodiazepine therapy excludes a patient from being eligible because of the potential benzodiazepine-like effects of MLN8237

• Patients who are currently receiving digoxin, cyclosporine, tacrolimus, or sirolimus are not eligible

• Patients who are unable to swallow tablets are not eligible

• Patients who have an uncontrolled infection are not eligible

• Leukemia patients with CNS disease are not eligible

• Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are not eligible

Related Conditions & MeSH terms

• Hepatoblastoma
• Kidney Neoplasms
• Leukemia
• Neoplasms
• Neuroblastoma
• Neuroectodermal Tumors
• Neuroectodermal Tumors, Primitive
• Neuroectodermal Tumors, Primitive, Peripheral
• Osteosarcoma
• Precursor Cell Lymphoblastic Leukemia-Lymphoma
• Previously Treated Childhood Rhabdomyosarcoma
• Recurrent Childhood Acute Lymphoblastic Leukemia
• Recurrent Childhood Acute Myeloid Leukemia
• Recurrent Childhood Kidney Neoplasm
• Recurrent Childhood Malignant Germ Cell Tumor
• Recurrent Childhood Rhabdomyosarcoma
• Recurrent Childhood Soft Tissue Sarcoma
• Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor
• Recurrent Neuroblastoma
• Recurrent Osteosarcoma
• Rhabdomyosarcoma
• Sarcoma
• Sarcoma, Ewing

Intervention

Drug:
• Alisertib
Given orally

Other:
• Laboratory Biomarker Analysis
Correlative studies
• Pharmacological Study
Correlative studies

Locations

Country	Name	City	State
Canada	Alberta Children's Hospital	Calgary	Alberta
Canada	IWK Health Centre	Halifax	Nova Scotia
Canada	Cancer Centre of Southeastern Ontario at Kingston General Hospital	Kingston	Ontario
Canada	Centre Hospitalier Universitaire Sainte-Justine	Montreal	Quebec
Canada	The Montreal Children's Hospital of the MUHC	Montreal	Quebec
Canada	Hospital for Sick Children	Toronto	Ontario
Canada	British Columbia Children's Hospital	Vancouver	British Columbia
Canada	CancerCare Manitoba	Winnipeg	Manitoba
United States	University of New Mexico Cancer Center	Albuquerque	New Mexico
United States	Children's Healthcare of Atlanta - Egleston	Atlanta	Georgia
United States	Johns Hopkins University/Sidney Kimmel Cancer Center	Baltimore	Maryland
United States	Sinai Hospital of Baltimore	Baltimore	Maryland
United States	Children's Hospital of Alabama	Birmingham	Alabama
United States	University of Alabama at Birmingham Cancer Center	Birmingham	Alabama
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	Montefiore Medical Center - Moses Campus	Bronx	New York
United States	Roswell Park Cancer Institute	Buffalo	New York
United States	University of Vermont College of Medicine	Burlington	Vermont
United States	UNC Lineberger Comprehensive Cancer Center	Chapel Hill	North Carolina
United States	Carolinas Medical Center/Levine Cancer Institute	Charlotte	North Carolina
United States	Novant Health Presbyterian Medical Center	Charlotte	North Carolina
United States	Lurie Children's Hospital-Chicago	Chicago	Illinois
United States	University of Chicago Comprehensive Cancer Center	Chicago	Illinois
United States	University of Illinois	Chicago	Illinois
United States	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio
United States	Rainbow Babies and Childrens Hospital	Cleveland	Ohio
United States	Palmetto Health Richland	Columbia	South Carolina
United States	Nationwide Children's Hospital	Columbus	Ohio
United States	Driscoll Children's Hospital	Corpus Christi	Texas
United States	Medical City Dallas Hospital	Dallas	Texas
United States	UT Southwestern/Simmons Cancer Center-Dallas	Dallas	Texas
United States	Dayton Children's Hospital	Dayton	Ohio
United States	Wayne State University/Karmanos Cancer Institute	Detroit	Michigan
United States	Southern California Permanente Medical Group	Downey	California
United States	Lee Memorial Health System	Fort Myers	Florida
United States	Cook Children's Medical Center	Fort Worth	Texas
United States	Saint Vincent Hospital	Green Bay	Wisconsin
United States	Hackensack University Medical Center	Hackensack	New Jersey
United States	Connecticut Children's Medical Center	Hartford	Connecticut
United States	Penn State Hershey Children's Hospital	Hershey	Pennsylvania
United States	University of Hawaii Cancer Center	Honolulu	Hawaii
United States	Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center	Houston	Texas
United States	Indiana University/Melvin and Bren Simon Cancer Center	Indianapolis	Indiana
United States	Riley Hospital for Children	Indianapolis	Indiana
United States	University of Iowa/Holden Comprehensive Cancer Center	Iowa City	Iowa
United States	University of Mississippi Medical Center	Jackson	Mississippi
United States	Nemours Children's Clinic-Jacksonville	Jacksonville	Florida
United States	The Childrens Mercy Hospital	Kansas City	Missouri
United States	East Tennessee Childrens Hospital	Knoxville	Tennessee
United States	University of Kentucky/Markey Cancer Center	Lexington	Kentucky
United States	University of Arkansas for Medical Sciences	Little Rock	Arkansas
United States	Miller Children's and Women's Hospital Long Beach	Long Beach	California
United States	Cedars-Sinai Medical Center	Los Angeles	California
United States	Children's Hospital Los Angeles	Los Angeles	California
United States	Children's Hospital Central California	Madera	California
United States	University of Wisconsin Hospital and Clinics	Madison	Wisconsin
United States	St. Jude Children's Research Hospital	Memphis	Tennessee
United States	University of Miami Miller School of Medicine-Sylvester Cancer Center	Miami	Florida
United States	Children¿s Hospital of Wisconsin	Milwaukee	Wisconsin
United States	Winthrop University Hospital	Mineola	New York
United States	Children's Hospitals and Clinics of Minnesota - Minneapolis	Minneapolis	Minnesota
United States	University of Minnesota/Masonic Cancer Center	Minneapolis	Minnesota
United States	Vanderbilt University/Ingram Cancer Center	Nashville	Tennessee
United States	Rutgers Cancer Institute of New Jersey-Robert Wood Johnson University Hospital	New Brunswick	New Jersey
United States	Yale University	New Haven	Connecticut
United States	Tulane University Health Sciences Center	New Orleans	Louisiana
United States	Columbia University/Herbert Irving Cancer Center	New York	New York
United States	Childrens Hospital-King's Daughters	Norfolk	Virginia
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	Children's Hospital and Medical Center of Omaha	Omaha	Nebraska
United States	Children's Hospital of Orange County	Orange	California
United States	Florida Hospital Orlando	Orlando	Florida
United States	Nemours Children's Clinic - Orlando	Orlando	Florida
United States	UF Cancer Center at Orlando Health	Orlando	Florida
United States	Lucile Packard Children's Hospital Stanford University	Palo Alto	California
United States	Nemours Children's Clinic - Pensacola	Pensacola	Florida
United States	Saint Jude Midwest Affiliate	Peoria	Illinois
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Childrens Oncology Group	Philadelphia	Pennsylvania
United States	Saint Christopher's Hospital for Children	Philadelphia	Pennsylvania
United States	Children's Hospital of Pittsburgh of UPMC	Pittsburgh	Pennsylvania
United States	Legacy Emanuel Children's Hospital	Portland	Oregon
United States	Legacy Emanuel Hospital and Health Center	Portland	Oregon
United States	Oregon Health and Science University	Portland	Oregon
United States	Virginia Commonwealth University/Massey Cancer Center	Richmond	Virginia
United States	Carilion Clinic Children's Hospital	Roanoke	Virginia
United States	Mayo Clinic	Rochester	Minnesota
United States	Mercy Hospital Saint Louis	Saint Louis	Missouri
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	All Children's Hospital	Saint Petersburg	Florida
United States	Methodist Children's Hospital of South Texas	San Antonio	Texas
United States	Rady Children's Hospital - San Diego	San Diego	California
United States	UCSF Medical Center-Parnassus	San Francisco	California
United States	Seattle Children's Hospital	Seattle	Washington
United States	Providence Sacred Heart Medical Center and Children's Hospital	Spokane	Washington
United States	Southern Illinois University School of Medicine	Springfield	Illinois
United States	Overlook Hospital	Summit	New Jersey
United States	State University of New York Upstate Medical University	Syracuse	New York
United States	Saint Joseph's Hospital/Children's Hospital-Tampa	Tampa	Florida
United States	Mercy Children's Hospital	Toledo	Ohio
United States	Natalie Warren Bryant Cancer Center at Saint Francis	Tulsa	Oklahoma
United States	New York Medical College	Valhalla	New York
United States	Children's National Medical Center	Washington	District of Columbia
United States	Alfred I duPont Hospital for Children	Wilmington	Delaware
United States	Wake Forest University Health Sciences	Winston-Salem	North Carolina

Sponsors (2)

Lead Sponsor	Collaborator
Children's Oncology Group	National Cancer Institute (NCI)

Countries where clinical trial is conducted

United States,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants With Overall Response	For patients with recurrent solid tumors a patient who experienced a complete or partial response according to RECIST version 1.1 criteria is considered a responder. For patients with recurrent acute lymphoblastic leukemia a patient who experiences a bone marrow evaluation with < 5% blast cells on morphological evaluation of bone marrow will be considered a responder. For patients with recurrent acute myelogenous leukemia a patient who experiences a complete remission or complete remission with partial recovery of platelet count according to the AML International Working Group Criteria will be considered a responder.	From first dose of alisertib through 6 cycles of protocol therapy or until removal from protocol therapy whichever occurred first.
Secondary	Number of Patients Cycles With Grade 3 or Higher Adverse Event	The number of patient-cycles in which the adverse event considered grade 3 or higher AE according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 considered by the treating physician to be possibly, probably or definitely related to alisertib.	Up to 24 months
Secondary	Serum Concentration of Alisertib Prior to the First Day of Administration	Serum concentration of alisertib prior to the first day of administration in nanograms/milliliter.	day 1 of protocol therapy
Secondary	Serum Concentration of Alisertib on the First Day of Administration One Hour After Administration	Serum concentration of alisertib on the first day of administration one hour after administration in nanograms/milliliter.	day 1 of protocol therapy
Secondary	Serum Concentration of Alisertib on the First Day of Administration Three Hours After Administration	Serum concentration of alisertib on the first day of administration three hours after administration in nanograms/milliliter.	day 1 of protocol therapy
Secondary	Serum Concentration of Alisertib on the First Day of Administration Six Hours After Administration	Serum concentration of alisertib on the first day of administration six hours after administration in nanograms/milliliter.	day 1 of protocol therapy
Secondary	Serum Concentration of Alisertib on the Fourth Day of Administration Prior to the Administration of the Day 4 Dose	Serum concentration of alisertib on the fourth day of administration prior to the administration of the day 4 dose in nanograms/milliliter.	day 4 of protocol therapy
Secondary	Serum Concentration of Alisertib on the Seventh Day of Administration Prior to the Administration of the Day 7 Dose.	Serum concentration of alisertib on the seventh day of administration prior to the administration of the day 7 dose in nanograms/milliliter.	day 7 of protocol therapy