- 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).
- 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.
- Diagnosis of 1 of the following:
- Histologically confirmed malignant solid tumor at original diagnosis or relapse
- Rhabdomyosarcoma (RMS)
- Ewing sarcoma/peripheral primitive neuroectodermal tumor
- Non-RMS soft tissue sarcoma
- 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)
- 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)
Last updated: 10/24/2012