Study of MLN8237 in Combination With Irinotecan and Temozolomide

The Aurora A kinase has been shown to play an important role in neuroblastoma growth.
Inhibition of Aurora A kinase activity attenuates the growth of neuroblastoma cells. MLN8237
is a selective small molecule inhibitor of Aurora A kinase that has completed pediatric
single-agent phase I testing, as well as stage 1 phase 2 testing in patients with
Neuroblastoma. MLN8237 showed activity against the NCI-sponsored Pediatric Preclinical
Testing Program neuroblastoma in vivo panel that exceeded the activity level observed with
chemotherapy agents routinely used in the treatment of neuroblastoma. Additional in vitro and
in vivo studies have shown that Aurora A kinase inhibitors result in enhanced cytotoxicity
when used in combination with chemotherapy. Irinotecan and temozolomide is a commonly used
salvage regimen for patients with relapsed or refractory neuroblastoma. This combination has
a modest objective response rate (16%) and is well-tolerated, suggesting that it will provide
a useful platform for the study of novel compounds in combination with chemotherapy.
Preclinical studies demonstrate marked enhancement of anti-neuroblastoma activity with the
addition of MLN8237 to irinotecan and temozolomide. This study therefore evaluates the
tolerability and activity of MLN8237 in combination with irinotecan and temozolomide in
children with refractory or relapsed neuroblastoma. Patients receive irinotecan (50
mg/m2/dose IV) and temozolomide (100 mg/m2/dose orally) once daily for 5 days along with
MLN8237 orally once daily for 7 days. The doses of irinotecan and temozolomide will be fixed
and the dose of MLN8237 will be dose-escalated. In the phase I portion of the study, the
primary aims are to determine the recommended phase II doses of this combination, describe
the toxicity of this combination, and characterize the pharmacokinetic profile of MLN8237 and
irinotecan when used in combination. In the phase II portion of the study, the primary aim is
to determine the objective response rate of this combination in patients with relapsed or
refractory neuroblastoma. With Amendment 5, the tolerability and pharmacokinetics of an
MLN8237 oral solution will be evaluated. Optional correlative studies will evaluate UGT1A1
polymorphisms as predictors of toxicity and archival tumor tissue Aurora A expression as a
predictor of response with this combination.

Criteria that need to be met to participate in this study:

- Patients must be > 12 months and < 30 years of age when registered on study.

- Patients must have relapsed neuroblastoma, refractory neuroblastoma that had less than
a partial response to standard treatment or persistent neuroblastoma that had at least
a partial response to standard treatment. All patients must have at least ONE site of
evaluable disease.

o Patients who have at least a partial response to standard treatment who still have
neuroblastoma that can be seen on CT/MRI or MIBG scans must have a surgical biopsy
done of the tumor to confirm that it is neuroblastoma. Patients with relapsed or
refractory neuroblastoma do not need to have a biopsy done to enter on study.

- Patients must have adequate heart, kidney, liver and bone marrow function. Patients
who have bone marrow disease must still have adequate bone marrow function to enter
the study.

- MLN8237 must be swallowed as whole tablets. Therefore, patients must be able to
swallow pills to be eligible for study. One tablet is the size of small breath mint,
or baby aspirin. Due to the size of MLN8237 tablets, patients must have a body surface
area of at least 0.38 m2 to be eligible for study. A body surface area is a
combination of a patient's height and weight. An example of a child with a BSA of 0.45
is a child that is 25 inches tall and weighs 25 pounds.You can use the link below to
calculate your child's body surface area and determine if they are too small for this
trial.

Patients cannot participate in the study if:

- Patients who have received prior MLN8237 are excluded from all phases of the study.
Patients previously treated with irinotecan and/or temozolomide will be eligible if
they have not had documented progressive disease during treatment with a regimen
containing these agents.

- They have other medical problems that could get much worse if they had this treatment.

- They are on dialysis for bad kidney function.

- They are pregnant or breast feeding.

- They have active infections such as hepatitis or fungal infections.

- They have an allergy to treatment with cefixime and cefpodixime.

- They have brain metastasis at study entry, or have received cranial spinal radiation.

- They have had an allogeneic stem cell transplant (received stem cell from someone
else).

- They can't cooperate with the special precautions that are needed for this trial.