Study of MLN8237 in Combination With Irinotecan and Temozolomide
Condition: Neuroblastoma
MeSH terms: Neuroblastoma
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): MLN8237; Irinotecan; Temozolomide
Intervention type(s): Drug; Drug; Drug
Intervention description(s): Every course will be 21 days. MLN8237 will be administered orally daily starting on day 1 through day 7.; Irinotecan will be administered intravenously during each course on study day 1 through day 5.; Temozolomide will be administered orally during each course on study day 1 through day 5.
Other intervention name(s): Camptosar; Temodar
Intervention MeSH terms: Irinotecan; Temozolomide
Intervention model: Sequential Assignment
Masking: None (Open Label)
Primary purpose: Treatment