NANT 2015-02

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What is this Study About

This study involves the use of an experimental drug called lorlatinib. Lorlatinib works by inhibiting the Anaplastic Lymphoma Kinase (ALK) oncogene. Lorlatinib has demonstrated an ability to target ALK mutations in the laboratory which other drugs have been ineffective at targeting. Neuroblastoma is a cancer that may benefit from a therapy which utilizes lorlatinib because ALK mutations can often be found in neuroblastoma patients.

Lorlatinib has not been approved by the United States Food and Drug Administration (FDA). Lorlatinib has been used only in a small number of adults and has an adult dose identified but there is still more information to learn about it. Lorlatinib has not previously been used in children and adolescents.

This study is a phase 1 study because the goal is to find the highest dose of lorlatinib that can be safely given in children and adolescents. Once we have found out the highest dose of lorlatinib that can be given safely, we will treat more children and adolescents with neuroblastoma with this lorlatinib dose and in combination with chemotherapy (cyclophosphamide and topotecan).

Why is this Study Being Done

• To find the highest safe dose of lorlatinib that can be given to children and adolescents with refractory or relapsed neuroblastoma without causing severe side effects.

• To learn about the side effects of  lorlatinib given in children and adolescents

• To measure the levels of lorlatinib in the blood at different dose levels.

• To determine the response of neuroblastoma tumors treated with lorlatinib.

Other Thing We are Trying to Do in this Study

• • To look at genetic changes in tumor DNA found in the blood during treatment with lorlatinib.

  • To look at genetic changes in tumor tissue to see if they affect response to lorlatinib.

  • To describe the amount of neuroblastoma tumor found in the blood and bone marrow using a sensitive new test.

Criteria that Need to be Met to Participate in this Study

• • Patients are required to have an activating ALK aberration in their tumor detected by a certified assay

  • Patients must have high risk neuroblastoma with either recurrent/progressive,  refractory, or persistent disease.

  • Patients must have evidence of active neuroblastoma

  • Patients must have adequate organ function

  • Patients must not have been previously treated with lorlatinib.

Criteria That Would Make Patients Ineligible to Participate in this Study

• Patients who have received prior allogeneic stem cell transplant.

• Patients with an active or uncontrolled infection.

• Known history of human immunodeficiency virus (HIV) infection, hepatitis B, or hepatitis C.

Study Schedule

There are 4 cohorts in this study:

Cohort A1 (dose escalation cohort), lorlatinib will be given orally once daily continuously for 28 days. The dose level of lorlatinib will be assigned at the time of study registration.

Cohort B1 (limited expansion cohort) will start when A1 is complete and the dose level identified.

Cohort A2 is for adult (18 years and older) and larger adolescents. Lorlatinib will be given at the adult recommended phase 2 dose orally once daily continuously for 28 days.

Cohort B2 (combination with conventional chemotherapy), lorlatinib will be given orally once daily continuously for 28 days at the dose level defined by cohort A1. This will be given together with cyclophosphamide and topotecan.

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