ADVL0921, A Phase II Study of MLN8237 (IND# 102984), a Selective Aurora A Kinase Inhibitor in Children with Recurrent/Refractory Solid Tumors and Leukemias
MLn8237 will be administered orally once daily x 7 days, every 21 days. Treatment will be interrupted if there is evidence of progressive disease or drug-related toxicity requiring removal from therapy. Treatment may otherwise continue for 35 cycles or up to a total duration of therapy of 24 months.
Days 1-7 - oral MLn8237 once daily
Days 8-21 - Rest
* Age - Patients must be > 12 months and <= 21 years of age at the time of study enrollment.
* Diagnosis - 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):
a) Neuroblastoma- measurable
b) Neuroblastoma- MIBG evaluable
e) Ewing sarcoma/Peripheral PNET
f) Non-RMS soft tissue sarcoma
h) Malignant germ cell tumor
i) Wilms tumor
j) Acute lymphoblastic leukemia
k) Acute myelogenous leukemia
l) Rhabdoid malignancy
* Disease Status for Solid Tumor Patients - Patients must have radiographically measurable disease (with the exception of neuroblastoma, see Section 220.127.116.11). Measurable disease is defined as the presence of at least one lesion on MRI or 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 PET scans)
- elevated tumor markers in plasma or 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 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 Phabdoid tumors stratum, the patient must have a solid tumor where the institutional pathological evaluation of the tumor at initial diagnosis or relapse has confirmed:
i. Morphology and immunophenotypic panel consistent with rhabdoid tumor (required)
ii. Loss of INI1 confirmed by immunohistochemistry, or
iii. 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.
* Performance Level:
Patients must have a Lansky or Karnofsky performance status score of >= 50, corresponding to 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.
* Prior Therapy - Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to study enrollment.
a. Myelosuppressive chemotherapy:
i. 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).
* 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.
b. Hematopoietic growth factors: 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.
c. Biologic (anti-neoplastic agent): 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.
d. Monoclonal antibodies: At least 3 half-lives must have elapsed since prior therapy that included a monoclonal antibody. (See posting of half-lives for commonly used monoclonal antibodies on the DVL homepage.
e. Radiotherapy: >= 2 weeks must have elapsed since local palliative 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 TBI was received;
>= 6 weeks must have elapsed if other substantial bone marrow irradiation was given.
f. Stem Cell Transplant or Rescue without TBI: No evidence of active graft vs. host disease and >= 3 months must have elapsed since transplant.
* Organ Function Requirements:
Adequate Bone Marrow Function Defined As:
a. For patients with solid tumors without bone marrow involvement:
- Peripheral absolute neutrophil count (ANC) >= 1000/mm3
- Platelet count >= 100,000/mm3 (transfusion independent, defined as not receiving platelet transfusions within a 7 day period prior to enrollment)
- Hemoglobin >= 8.0 g/dL (may receive RBC transfusions).
b. For patients with solid tumors and known bone marrow metastatic disease:
- Peripheral absolute neutrophil count (ANC) >= 750/mm3
- Platelet count >= 50,000/mm3
- 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.
c. Patients with leukemia must not be known to be refractory to red blood cell or platelet transfusions.
Adequate Renal Function Defined As:
Creatinine clearance or radioisotope GFR >= 70 mL/min/1.73 m2 or a serum creatinine based on age/gender as follows: (see table on page 21 of protocol).
Adequate Liver Function Defined As:
- Total bilirubin <= 1.5 x upper limit of normal (ULN) for age
- SGPT (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.
* Informed Consent: All patients and/or their parents or legal guardians must sign a written informed consent.