Irinotecan Hydrochloride and Temozolomide With Temsirolimus or Dinutuximab in Treating Younger Patients With Refractory or Relapsed Neuroblastoma

Official Title

A Phase II Randomized Trial of Irinotecan/Temozolomide With Temsirolimus (NSC# 683864) or Chimeric 14.18 Antibody (ch14.18) (NSC# 764038) in Children With Refractory, Relapsed or Progressive Neuroblastoma

Summary:

This randomized phase II trial studies how well irinotecan hydrochloride and temozolomide with temsirolimus or dinutuximab work in treating younger patients with neuroblastoma that has returned or does not respond to treatment. Drugs used in chemotherapy, such as irinotecan hydrochloride and temozolomide, work in different ways to stop the growth of tumour cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Temsirolimus may stop the growth of tumour cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as dinutuximab, may find tumour cells and help kill them or carry tumour-killing substances to them. It is not yet known whether giving irinotecan hydrochloride and temozolomide together with temsirolimus or dinutuximab is more effective in treating neuroblastoma.

Trial Description

Primary Outcome:

  • Proportion of patients who are responders defined as patients who achieve a >= partial response (PR) per the INRC as their best overall response
Secondary Outcome:
  • Ability to maintain intended treatment with all agents (irinotecan hydrochloride, temozolomide and the experimental agent) without a dose reduction or going off protocol therapy for toxicity
  • Occurrence of unacceptable toxicities, graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0
  • Overall response rate (complete response, PR, stable disease, progressive disease) according to the INRC
  • Overall survival
  • Progression-free survival, defined as a relapse, progressive disease, or death attributable to tumour or treatment
PRIMARY OBJECTIVES:
I. To identify whether temsirolimus or ch14.18 (dinutuximab) is the optimal therapeutic agent to consider for further testing in a future Phase III randomized trial for treatment of newly diagnosed high-risk neuroblastoma. II. To determine the response rate of patients with relapsed, refractory or progressive neuroblastoma following treatment with irinotecan, temozolomide and ch14.18 (dinutuximab) and to compare this with the known response rate of patients treated with irinotecan and temozolomide alone. SECONDARY OBJECTIVES:
I. To compare the response rates (RR) for patients receiving temsirolimus or ch14.18 (dinutuximab) in combination with irinotecan (irinotecan hydrochloride) and temozolomide. II. To compare the progression free survival (PFS) and overall survival (OS) rates for patients receiving temsirolimus or ch14.18 (dinutuximab) in combination with irinotecan and temozolomide. III. To compare the toxicities associated with temsirolimus or ch14.18 (dinutuximab) when combined with irinotecan and temozolomide in patients with refractory, relapsed or progressive neuroblastoma. IV. To compare the ability to maintain intended dose intensity of all agents when temsirolimus or ch14.18 (dinutuximab) is combined with irinotecan and temozolomide in patients with refractory, relapsed or progressive neuroblastoma. V. To determine the concordance between tumour responses as defined by standard International Neuroblastoma Response Criteria (INRC) versus response per the revised INRC. VI. To study the clinical relevance of naturally occurring anti-glycan antibodies in patients receiving ch14.18 (dinutuximab) antibody. VII. To study the clinical relevance of natural killer (NK) receptor natural cytotoxicity triggering receptor 3 (NKp30) isoforms in patients receiving ch14.18 (dinutuximab) antibody or temsirolimus. VIII. To study the association between host factors and response to irinotecan, temozolomide and ch14.18 (dinutuximab). IX. To characterize the tumour immune-microenvironment (gene expression; immune effector cells, activities and signaling molecules; immune target expression) following treatment with irinotecan, temozolomide and ch14.18 (dinutuximab). X. To study the association between changes in the tumour immune-microenvironment (gene expression; immune effector cells, activities and signaling molecules; immune target expression) with response following treatment with irinotecan, temozolomide and ch14.18 (dinutuximab). XI. To study the association between tumour genomic and transcriptomic aberrations as well as levels of circulating ganglioside (GD2) with response to irinotecan, temozolomide and ch14.18 (dinutuximab). OUTLINE:

Patients are randomized to 1 of 2 treatment arms. ARM I (CLOSED TO ACCRUAL 06/17/2016): Patients receive temozolomide orally (PO) on days 1-5, irinotecan hydrochloride intravenously (IV) over 90 minutes on days 1-5, and temsirolimus IV over 30 minutes on days 1 and 8. ARM II: Patients receive temozolomide PO on days 1-5, irinotecan hydrochloride over 90 minutes on days 1-5, dinutuximab IV over 10-20 hours on days 2-5, and sargramostim subcutaneously (SC) or IV over 2 hours on days 6-12. In both arms, treatment repeats every 21 days for up to 17 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up periodically.

View this trial on ClinicalTrials.gov

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