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A Phase II Study of MLN8237 (IND# 102984), a Selective Aurora A Kinase Inhibitor in Children With Recurrent/Refractory Solid Tumors and Leukemias


Phase 2
1 Year
21 Years
Open (Enrolling)
Both
Childhood Hepatoblastoma, Previously Treated Childhood Rhabdomyosarcoma, Recurrent Childhood Acute Lymphoblastic Leukemia, Recurrent Childhood Acute Myeloid Leukemia, 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, Recurrent Wilms Tumor and Other Childhood Kidney Tumors

Thank you

Trial Information

A Phase II Study of MLN8237 (IND# 102984), a Selective Aurora A Kinase Inhibitor in Children With Recurrent/Refractory Solid Tumors and Leukemias


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).

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.

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.


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

Type of Study:

Interventional

Study Design:

Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Objective response rate

Outcome Description:

Response rates will be calculated as the percent of evaluable patients who are responders, and confidence intervals will be constructed accounting for the two-stage design.

Outcome Time Frame:

Up to 5 years

Safety Issue:

No

Principal Investigator

Yael Mosse

Investigator Role:

Principal Investigator

Investigator Affiliation:

Children's Oncology Group

Authority:

United States: Institutional Review Board

Study ID:

ADVL0921

NCT ID:

NCT01154816

Start Date:

February 2011

Completion Date:

Related Keywords:

  • Childhood Hepatoblastoma
  • Previously Treated Childhood Rhabdomyosarcoma
  • Recurrent Childhood Acute Lymphoblastic Leukemia
  • Recurrent Childhood Acute Myeloid Leukemia
  • 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
  • Recurrent Wilms Tumor and Other Childhood Kidney Tumors
  • Kidney Neoplasms
  • Leukemia
  • Leukemia, Lymphoid
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid
  • Wilms Tumor
  • Neuroblastoma
  • Osteosarcoma
  • Rhabdomyosarcoma
  • Neoplasms, Germ Cell and Embryonal
  • Neuroectodermal Tumors
  • Neuroectodermal Tumors, Primitive
  • Hepatoblastoma
  • Rhabdomyosarcoma, Embryonal
  • Sarcoma
  • Sarcoma, Ewing's
  • Neuroectodermal Tumors, Primitive, Peripheral

Name

Location

Baylor College of MedicineHouston, Texas  77030
Johns Hopkins UniversityBaltimore, Maryland  21205
Roswell Park Cancer InstituteBuffalo, New York  14263
Mayo ClinicRochester, Minnesota  55905
Children's Hospital of PhiladelphiaPhiladelphia, Pennsylvania  19104
University of Iowa Hospitals and ClinicsIowa City, Iowa  52242
University of Mississippi Medical CenterJackson, Mississippi  39216-4505
Washington University School of MedicineSaint Louis, Missouri  63110
Medical City Dallas HospitalDallas, Texas  75230
Midwest Children's Cancer CenterMilwaukee, Wisconsin  53226
Sinai Hospital of BaltimoreBaltimore, Maryland  21225
Vanderbilt-Ingram Cancer CenterNashville, Tennessee  37232-6838
Morristown Memorial HospitalMorristown, New Jersey  07962-1956
New York Medical CollegeValhalla, New York  10595
Dana-Farber Cancer InstituteBoston, Massachusetts  02115
Cedars-Sinai Medical CenterLos Angeles, California  90048
University of Arkansas for Medical SciencesLittle Rock, Arkansas  72205
Hackensack University Medical CenterHackensack, New Jersey  07601
Children's Hospital Los AngelesLos Angeles, California  90027-0700
Children's National Medical CenterWashington, District of Columbia  20010-2970
All Children's HospitalSt. Petersburg, Florida  33701
Saint Jude Midwest AffiliatePeoria, Illinois  61637
Carolinas Medical CenterCharlotte, North Carolina  28232-2861
University of Oklahoma Health Sciences CenterOklahoma City, Oklahoma  73104
Legacy Emanuel Hospital and Health CenterPortland, Oregon  97227
St. Jude Children's Research HospitalMemphis, Tennessee  38105-2794
Driscoll Children's HospitalCorpus Christi, Texas  78466
Southern California Permanente Medical GroupDowney, California  90242
Children's Hospital Central CaliforniaMadera, California  93638-8762
University of Wisconsin Hospital and ClinicsMadison, Wisconsin  53792-0001
Overlook HospitalSummit, New Jersey  07902-0220
Winthrop University HospitalMineola, New York  11501
Cincinnati Children's Hospital Medical CenterCincinnati, Ohio  45229-3039
Methodist Children's Hospital of South TexasSan Antonio, Texas  78229-3993
Montefiore Medical CenterBronx, New York  10467-2490
Rady Children's Hospital - San DiegoSan Diego, California  92123-4282
Children's Hospitals and Clinics of Minnesota - MinneapolisMinneapolis, Minnesota  55404
University of New Mexico Cancer CenterAlbuquerque, New Mexico  87131-5636
Nationwide Children's HospitalColumbus, Ohio  43205-2696
Children's Hospital of Pittsburgh of UPMCPittsburgh, Pennsylvania  15213
Children's Hospital and Research Center at OaklandOakland, California  94609-1809
Presbyterian HospitalCharlotte, North Carolina  28233-3549
Lee Memorial Health SystemFort Myers, Florida  33902
University of Alabama at BirminghamBirmingham, Alabama  35294-3300
Children's Hospital of AlabamaBirmingham, Alabama  35233
Connecticut Children's Medical CenterHartford, Connecticut  06106
University of North CarolinaChapel Hill, North Carolina  27599
Nemours Children's Clinic - PensacolaPensacola, Florida  32504
Yale UniversityNew Haven, Connecticut  06520
Wayne State UniversityDetroit, Michigan  48202
Mercy Children's HospitalToledo, Ohio  43608
Legacy Emanuel Children's HospitalPortland, Oregon  97227
University Of VermontBurlington,, Vermont  05403
University of Texas Southwestern Medical CenterDallas, Texas  
University of KentuckyLexington, Kentucky  40536-0098
Oregon Health and Science UniversityPortland, Oregon  97201
Tulane University Health Sciences CenterNew Orleans, Louisiana  70112
Virginia Commonwealth UniversityRichmond, Virginia  
Florida HospitalOrlando, Florida  32803
University of Chicago Comprehensive Cancer CenterChicago, Illinois  60637-1470
Seattle Children's HospitalSeattle, Washington  98105
Wake Forest University Health SciencesWinston-Salem, North Carolina  27157
Childrens Memorial HospitalChicago, Illinois  60614
M D Anderson Cancer Center- OrlandoOrlando, Florida  32806
University of HawaiiHonolulu, Hawaii  96813
Saint John's Mercy Medical CenterSaint Louis, Missouri  63141
Columbia University Medical CenterNew York, New York  10032
State University of New York Upstate Medical UniversitySyracuse, New York  13210
Natalie W Bryant Cancer CenterTulsa, Oklahoma  74136
Saint Vincent HospitalGreen Bay, Wisconsin  54301
University of IllinoisChicago, Illinois  60612
Cook Children's Medical CenterFort Worth, Texas  76104
The Children's Medical Center of DaytonDayton, Ohio  45404
University of Miami Miller School of Medicine-Sylvester Cancer CenterMiami, Florida  33136
University of Minnesota Medical Center-FairviewMinneapolis, Minnesota  55455
Children's Oncology GroupArcadia, California  91006-3776
Southern Illinois UniversitySpringfield, Illinois  62702
Riley Hospital for ChildrenIndianapolis, Indiana  46202
UMDNJ - Robert Wood Johnson University HospitalNew Brunswick, New Jersey  08903
Miller Children's HospitalLong Beach, California  90806
Childrens Hospital of Orange CountyOrange, California  92868-3874
Alfred I duPont Hospital for ChildrenWilmington, Delaware  19803
Nemours Children's Clinic - JacksonvilleJacksonville, Florida  32207-8426
Nemours Childrens Clinic - OrlandoOrlando, Florida  32806
Saint Joseph Children's Hospital of TampaTampa, Florida  33607
Children's Healthcare of Atlanta - EglestonAtlanta, Georgia  30322
The Childrens Mercy HospitalKansas City, Missouri  64108
Rainbow Babies and Childrens HospitalCleveland, Ohio  44106
Penn State Hershey Children's HospitalHershey, Pennsylvania  17033
Palmetto Health RichlandColumbia, South Carolina  29203
East Tennessee Childrens HospitalKnoxville, Tennessee  37916
Children's Hospital and Medical Center of OmahaOmaha, Nebraska  68114
Childrens Hospital-King's DaughtersNorfolk, Virginia  23507
Lucile Packard Children's Hospital Stanford UniversityPalo Alto, California  94304
University of California San Francisco Medical Center-ParnassusSan Francisco, California  94143
Saint Christopher's Hospital for ChildrenPhiladelphia, Pennsylvania  19134
Carilion Clinic Children's HospitalRoanoke, Virginia  24014
Providence Sacred Heart Medical Center and Children's HospitalSpokane, Washington  99204