Study of MLN8237 in Combination With Irinotecan and Temozolomide

Phase I/II Study of MLN8237 in Combination With Irinotecan and Temozolomide for Patients With Relapsed or Refractory Neuroblastoma

The goal of the first part of this clinical trial (Phase I portion) is to study the side effects, drug breakdown (pharmacokinetics), and dosing of the drug MLN8237 when added to standard chemotherapy drugs, irinotecan and temozolomide.

The goal of the second part of this clinical trial (Phase II portion) is to learn how many children and young adults show improvements in their neuroblastoma when treated with the combination of MLN8237, 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.