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.

Study Overview

• Status: Completed
• Conditions: Neuroblastoma
• Intervention / Treatment: Drug: MLN8237; Drug: Irinotecan; Drug: 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.

• Study Type: Interventional
• Enrollment (Actual): 54
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 1X8
      • Hospital for Sick Children
• United States
  • California
    • Los Angeles, California, United States, 90027-0700
      • Children's Hospital Los Angeles
    • Palo Alto, California, United States, 94304
      • Lucile Packard Children's Hospital at Stanford University Medical Center
    • San Francisco, California, United States, 94115
      • UCSF Helen Diller Family Comprehensive Cancer Center
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Children Hospital of Colorado
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Children's Healthcare of Atlanta
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago Comer Children's Hospital
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Childrens Hospital Boston, Dana-Farber Cancer Institute.
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Comprehensive Cancer Center
  • Ohio
    • Cincinnati, Ohio, United States, 45229-3039
      • Cincinnati Children's Hospital Medical Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104-4318
      • Children's Hospital of Philadelphia
  • Texas
    • Fort Worth, Texas, United States, 76104
      • Cook Children's Medical Center - Fort Worth
  • Washington
    • Seattle, Washington, United States, 98105
      • Children's Hospital and Regional Medical Center - Seattle

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 26 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment; 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.	Drug: MLN8237; Every course will be 21 days. MLN8237 will be administered orally daily starting on day 1 through day 7.; Drug: Irinotecan; Irinotecan will be administered intravenously during each course on study day 1 through day 5.; Other Names: Camptosar; Drug: Temozolomide; Temozolomide will be administered orally during each course on study day 1 through day 5.; Other Names: Temodar

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Tolerated Dose (MTD) When Given Together With Fixed Doses of Irinotecan and Temozolomide in Children and Young Adults With Relapsed or Refractory Neuroblastoma	The MTD was the highest dose level tested at which fewer than two of six patients had first course DLT. Hematologic DLT was defined as grade 4 neutropenia for more than 7 days, need for platelet transfusion for a platelet count of less than 20,000/mL twice within a 7-day period, or greater than 14-day delay in the start of a subsequent course because of neutropenia or thrombocytopenia. Nonhematologic DLT was defined as any nonhematologic toxicity that delayed the start of a subsequent cycle by more than 14 days or any grade ≥3 toxicity with the exception of the following grade 3 toxicities: nausea, vomiting, anorexia, or dehydration resolving to grade ≤ 2 within 72 hours; increase in hepatic transaminase or electrolyte abnormality resolving to grade ≤ 1 within 7 days; diarrhea persisting for less than 72 hours; fever; infection; or febrile neutropenia. DLT definitions included only toxicities deemed at least possibly related to therapy.	21 days, from study day 1
Dose Limiting Toxicity (DLT) Data Associated With the Determination of the Recommended Phase 2 Dose	The MTD was the highest dose level tested at which fewer than two of six patients had first course DLT. Hematologic DLT was defined as grade 4 neutropenia for more than 7 days, need for platelet transfusion for a platelet count of less than 20,000/mL twice within a 7-day period, or greater than 14-day delay in the start of a subsequent course because of neutropenia or thrombocytopenia. Nonhematologic DLT was defined as any nonhematologic toxicity that delayed the start of a subsequent cycle by more than 14 days or any grade ≥3 toxicity with the exception of the following grade 3 toxicities: nausea, vomiting, anorexia, or dehydration resolving to grade ≤ 2 within 72 hours; increase in hepatic transaminase or electrolyte abnormality resolving to grade ≤ 1 within 7 days; diarrhea persisting for less than 72 hours; fever; infection; or febrile neutropenia. DLT definitions included only toxicities deemed at least possibly related to therapy.	21 days, from study day 1
Pharmacokinetics When Given Together With Fixed Doses of Irinotecan and Temozolomide in Children and Young Adults With Relapsed or Refractory Neuroblastoma: Alisertib Day 4 Trough, Day 5 Trough and Cmax	Outcomes included Alisertib, irinotecan, APC, SN-38, and SN-38G. APC, SN-38, and SN-38G are metabolites of irinotecan.	1st week of cycle 1
Pharmacokinetics When Given Together With Fixed Doses of Irinotecan and Temozolomide in Children and Young Adults With Relapsed or Refractory Neuroblastoma: Alisertib Tmax and Half-life	Outcomes included Alisertib, irinotecan, APC, SN-38, and SN-38G. APC, SN-38, and SN-38G are metabolites of irinotecan.	1st week of cycle 1
Pharmacokinetics When Given Together With Fixed Doses of Irinotecan and Temozolomide in Children and Young Adults With Relapsed or Refractory Neuroblastoma: Alisertib AUC	Outcomes included Alisertib, irinotecan, APC, SN-38, and SN-38G. APC, SN-38, and SN-38G are metabolites of irinotecan.	1st week of cycle 1
Pharmacokinetics When Given Together With Fixed Doses of Irinotecan and Temozolomide in Children and Young Adults With Relapsed or Refractory Neuroblastoma: Irinotecan Cmax, APC Cmax, SN-38 Cmax, and SN-38G Cmax	Outcomes included Alisertib, irinotecan, APC, SN-38, and SN-38G. APC, SN-38, and SN-38G are metabolites of irinotecan.	1st week of cycle 1
Pharmacokinetics When Given Together With Fixed Doses of Irinotecan and Temozolomide in Children and Young Adults With Relapsed or Refractory Neuroblastoma: Irinotecan AUC, APC AUC, SN-38 AUC, and SN-38G AUC	Outcomes included Alisertib, irinotecan, APC, SN-38, and SN-38G. APC, SN-38, and SN-38G are metabolites of irinotecan.	1st week of cycle 1
Pharmacokinetics When Given Together With Fixed Doses of Irinotecan and Temozolomide in Children and Young Adults With Relapsed or Refractory Neuroblastoma: Irinotecan Clearance	Outcomes included Alisertib, irinotecan, APC, SN-38, and SN-38G. APC, SN-38, and SN-38G are metabolites of irinotecan.	1st week of cycle 1
Response Rate for Patients With Relapsed or Refractory Neuroblastoma Treated With MLN8237, Irinotecan, and Temozolomide at the Identified MTD	Response was graded according to version 1.2 of the NANT response criteria that classifies patients as having one of the following overall response categories based upon underlying response at soft tissue sites, MIBG positive sites, and bone marrow disease: complete response (CR); CR with minimal residual disease (CR-MRD); partial response (PR); minor response (MR); stable disease (SD); and progressive disease (PD). These criteria utilize RECIST criteria for measurable tumors, Curie score for MIBG scan response, and bone marrow (BM) morphology. BM response was graded as CR (required two time points to confirm), CR unconfirmed (one time point only), CR-MRD (bone marrow involvement < 5% at study entry with negative follow-up biopsies), SD, or PD. Patients with at least SD or better underwent central review of MIBG scans, CT scans, and bone marrow pathology slides. Overall responses of CR, CR-MRD, or PR were considered objective responses.	Cycles repeated every 21 days for up to 34 cycles.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Aurora A Expression	To explore whether MYCN status and markers of expression of Aurora A in archival tumor tissue are associated with the antitumor activity of the combination of MLN8237, irinotecan, and temozolomide	From date of study enrollment to the date of progression or withdrawal from the study, up to 34 cycles (about 2 years).
UGT1A1 Genotype	To explore whether UGT1A1 genotype is associated with toxicity in children with refractory neuroblastoma treated with the combination of MLN8237, irinotecan, and temozolomide	Day 7 of cycle 1
AURKA Genotype	To explore whether AURKA genotype is associated with antitumor activity in children with refractory neuroblastoma treated with the combination of MLN8237, irinotecan, and temozolomide.	Day 7 of cycle 1
One Year Progression Free Survival Rate	To determine the progression free survival rates for patients with relapsed or refractory neuroblastoma treated with MLN8237, irinotecan, and temozolomide at the identified MTD	1 Years after completion of study

Collaborators and Investigators

• Sponsor: New Approaches to Neuroblastoma Therapy Consortium

Publications and helpful links

General Publications

• DuBois SG, Mosse YP, Fox E, Kudgus RA, Reid JM, McGovern R, Groshen S, Bagatell R, Maris JM, Twist CJ, Goldsmith K, Granger MM, Weiss B, Park JR, Macy ME, Cohn SL, Yanik G, Wagner LM, Hawkins R, Courtier J, Lai H, Goodarzian F, Shimada H, Boucher N, Czarnecki S, Luo C, Tsao-Wei D, Matthay KK, Marachelian A. Phase II Trial of Alisertib in Combination with Irinotecan and Temozolomide for Patients with Relapsed or Refractory Neuroblastoma. Clin Cancer Res. 2018 Dec 15;24(24):6142-6149. doi: 10.1158/1078-0432.CCR-18-1381. Epub 2018 Aug 9.

Study record dates

Study Major Dates

• Study Start: May 1, 2012
• Primary Completion (Actual): July 25, 2018
• Study Completion (Actual): July 25, 2018

Study Registration Dates

• First Submitted: May 11, 2012
• First Submitted That Met QC Criteria: May 16, 2012
• First Posted (Estimate): May 18, 2012

Study Record Updates

• Last Update Posted (Actual): July 31, 2019
• Last Update Submitted That Met QC Criteria: July 10, 2019
• Last Verified: July 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroectodermal Tumors, Primitive; Neuroectodermal Tumors, Primitive, Peripheral; Neuroblastoma; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Topoisomerase Inhibitors; Topoisomerase I Inhibitors; Temozolomide; Irinotecan
• Other Study ID Numbers: N2009-03