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Study of MLN8237 in Combination With Irinotecan and Temozolomide

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ClinicalTrials.gov Identifier: NCT01601535
Recruitment Status : Completed
First Posted : May 18, 2012
Last Update Posted : April 26, 2019
Sponsor:
Information provided by (Responsible Party):
New Approaches to Neuroblastoma Therapy Consortium

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.


Condition or disease Intervention/treatment Phase
Neuroblastoma Drug: MLN8237 Drug: Irinotecan Drug: Temozolomide Phase 1 Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 44 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I/II Study of MLN8237 in Combination With Irinotecan and Temozolomide for Patients With Relapsed or Refractory Neuroblastoma
Study Start Date : May 2012
Actual Primary Completion Date : July 25, 2018
Actual Study Completion Date : July 25, 2018


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 Name: Camptosar

Drug: Temozolomide
Temozolomide will be administered orally during each course on study day 1 through day 5.
Other Name: Temodar




Primary Outcome Measures :
  1. Toxicity [ Time Frame: 21 days, from study day 1 ]
    1. To estimate the maximum tolerated dose (MTD), toxicities and pharmacokinetics of MLN8237 when given together with fixed doses of irinotecan and temozolomide in children and young adults with relapsed or refractory neuroblastoma.
    2. To determine the response rate for patients with relapsed or refractory neuroblastoma treated with MLN8237, irinotecan, and temozolomide at the identified MTD


Secondary Outcome Measures :
  1. Aurora A Expression [ Time Frame: From date of study enrollment to the date of progression or withdrawl from the study ]
    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

  2. UGT1A1 genotype [ Time Frame: Day 7 of cycle 1 ]
    To explore whether UGT1A1 genotype is associated with toxicity in children with refractory neuroblastoma treated with the combination of MLN8237, irinotecan, and temozolomide

  3. AURKA genotype [ Time Frame: Day 7 of cycle 1 ]
    To explore whether AURKA genotype is associated with antitumor activity in children with refractory neuroblastoma treated with the combination of MLN8237, irinotecan, and temozolomide.

  4. Progression Free Survival [ Time Frame: 2 Years after completion of study ]
    To determine the progression free survival rates for patients with relapsed or refractory neuroblastoma treated with MLN8237, irinotecan, and temozolomide at the identified MTD



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   12 Months to 30 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01601535


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

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Responsible Party: New Approaches to Neuroblastoma Therapy Consortium
ClinicalTrials.gov Identifier: NCT01601535     History of Changes
Other Study ID Numbers: N2009-03
First Posted: May 18, 2012    Key Record Dates
Last Update Posted: April 26, 2019
Last Verified: April 2019

Additional relevant MeSH terms:
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Neuroblastoma
Neuroectodermal Tumors, Primitive, Peripheral
Neuroectodermal Tumors, Primitive
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Irinotecan
Temozolomide
Topoisomerase I Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents