Study of MLN8237 in Combination With Irinotecan and Temozolomide

NCT ID: NCT01601535

Last Updated: 2019-07-31

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 54 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2012-05-31
• Study Completion Date: 2018-07-25

Brief 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.

Conditions

Neuroblastoma

Study Design

• Intervention Model: SEQUENTIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

MLN8237

Intervention Type: DRUG

Every course will be 21 days. MLN8237 will be administered orally daily starting on day 1 through day 7.

Irinotecan

Intervention Type: DRUG

Irinotecan will be administered intravenously during each course on study day 1 through day 5.

Temozolomide

Intervention Type: DRUG

Temozolomide will be administered orally during each course on study day 1 through day 5.

Interventions

MLN8237

Every course will be 21 days. MLN8237 will be administered orally daily starting on day 1 through day 7.

Intervention Type: DRUG

Irinotecan

Irinotecan will be administered intravenously during each course on study day 1 through day 5.

Intervention Type: DRUG

Temozolomide

Temozolomide will be administered orally during each course on study day 1 through day 5.

Intervention Type: DRUG

Other Intervention Names

Camptosar; Temodar

Eligibility Criteria

Inclusion Criteria

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.

• Minimum Eligible Age: 12 Months
• Maximum Eligible Age: 30 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

New Approaches to Neuroblastoma Therapy Consortium

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Steven DuBois, MD

Role: STUDY_CHAIR

Dana-Farber Cancer Institute

Locations

Children's Hospital Los Angeles

Los Angeles, California, United States

Lucile Packard Children's Hospital at Stanford University Medical Center

Palo Alto, California, United States

UCSF Helen Diller Family Comprehensive Cancer Center

San Francisco, California, United States

Children Hospital of Colorado

Aurora, Colorado, United States

Children's Healthcare of Atlanta

Atlanta, Georgia, United States

University of Chicago Comer Children's Hospital

Chicago, Illinois, United States

Childrens Hospital Boston, Dana-Farber Cancer Institute.

Boston, Massachusetts, United States

University of Michigan Comprehensive Cancer Center

Ann Arbor, Michigan, United States

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, United States

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States

Cook Children's Medical Center - Fort Worth

Fort Worth, Texas, United States

Children's Hospital and Regional Medical Center - Seattle

Seattle, Washington, United States

Hospital for Sick Children

Toronto, Ontario, Canada

Countries

United States; Canada

References

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.

Reference Type: DERIVED

PMID: 30093449 (View on PubMed)

Provided Documents

Document Type: Study Protocol, Statistical Analysis Plan, and Informed Consent Form

View Document

Other Identifiers

N2009-03

Identifier Type: -

Identifier Source: org_study_id