ANBL1821: Study of Eflornithine with Chemo-Immunotherapy for Children with Advanced Neuroblastoma

Brief Summary

This study is designed to compare response rates and progression free survival for patients treated with dinutuximab, irinotecan and temozolomide alone compared to dinutuximab, irinotecan and temozolomide with difluoromethylornithine (DFMO, eflornithine).

The combination of dinutuximab, irinotecan, and temozolomide has shown promising activity in patients with refractory, relapsed, and progressive neuroblastoma. However, the overall objective response rate on a Phase II trial of the regimen was less than 50%. This study proposes the addition of eflornithine to the chemo-immunotherapy backbone.

ODC1 (ornithine decarboxylase 1) is a downstream transcriptional target of MYCN and a key enzyme in the polyamine synthesis pathway. Eflornithine is an irreversible inhibitor of ODC1 and depletes essential polyamines necessary for tumor survival. Eflornithine has been studied alone and in combination with chemotherapy in patients with relapsed and refractory neuroblastoma and has shown no significant toxicity. Additionally, preclinical data supports a role for eflornithine in regulating the tumor microenvironment to reinstate anti-tumor immune responses.

Primary Objective

• To determine whether eflornithine, in combination with dinutuximab, irinotecan and temozolomide, results in an improved response rate in patients with newly diagnosed high-risk neuroblastoma, compared to a regimen of dinutuximab, irinotecan and temozolomide without eflornithine

Eligibility Criteria

Inclusion criteria include:

• At least 1 year old
• Diagnosis of neuroblastoma, ganglioneuroblastoma or demonstration of neuroblastoma cells in the bone marrow with elevated urinary catecholamines
• Active disease with one of the following:
  • First episode of recurrent disease following completion of aggressive multi-drug frontline therapy
  • First episode of progressive disease during aggressive multi-drug frontline therapy
  • Primary resistant/refractory disease detected at conclusion of at least 4 cycles of aggressive multi-drug induction chemotherapy on or according to a high-risk neuroblastoma protocol
• Documentation of disease with at least one of the following:
  • Measurable tumor on MRI or CT scan
  • MIBG-avid lesion detected on MIBG scan with positive uptake at one site or more
  • Biopsy to document presence of viable neuroblastoma for patients with resistant/refractory soft tissue disease that is not MIBG avid or does not demonstrate increased FDG uptake on PET scan
  • More than 5% disease involvement in at least one sample from bilateral bone marrow biopsies in patients with bone marrow disease

Exclusion Criteria include:

• Pregnant or breastfeeding
• Elevated catecholamines only
• Prior treatment with irinotecan and temozolomide
• Prior anti-GD2 monoclonal antibodies in combination with chemotherapy

Study Sites

St. Jude Children’s Research Hospital, Memphis, Tennessee
Collaborating sites in the U.S.

About this study

Neuroblastoma develops in nerve cells that are outside of the brain. At this time, there is no single standard treatment for patients with neuroblastoma that has come back after treatment (relapsed) or not responded to treatment (refractory).

In this study, you will receive therapy composed of one of the following combinations of drugs: (1) irinotecan, temozolomide, dinutuximab and sargramostim or (2) irinotecan, temozolomide, dinutuximab and sargramostim with eflornithine.

Eflornithine (DFMO) is an investigational drug that is not yet approved by the U.S. Food and Drug Administration (FDA) for use in cancer patients. It has been approved by the FDA for treatment of an infection called trypanosomiasis. Eflornithine blocks the production of certain chemicals that are important in the growth of cancer cells. This drug has been used in adults with cancer. It has also been tested both alone and in combination with chemotherapy in children with cancer, including children with neuroblastoma.

Purpose of this clinical trial

The main purpose of this study is to find out the good and bad effects of eflornithine combined with irinotecan, temozolomide, and dinutuximab in children and young adults with relapsed or refractory neuroblastoma.

Eligibility overview

• At least 1 year old
• Diagnosis of relapsed, refractory or progressive neuroblastoma