Dinutuximab With Chemotherapy, Surgery and Stem Cell Transplantation for the Treatment of Children With Newly Diagnosed High Risk Neuroblastoma

Neuroblastoma Clinical Trial

Official title: A Phase 3 Study of Dinutuximab Added to Intensive Multimodal Therapy for Children With Newly Diagnosed High-Risk Neuroblastoma

Status Not yet recruiting

Clinical Trial Summary

This phase III trial tests how well adding dinutuximab to induction chemotherapy along with standard of care surgery radiation and stem cell transplantation works for treating children with newly diagnosed high risk neuroblastoma. Dinutuximab is a monoclonal antibody that binds to a molecule called GD2, which is found in greater than normal amounts on some types of cancer cells. This helps cells of the immune system kill the cancer cells. Chemotherapy drugs such as cyclophosphamide, topotecan, cisplatin, etoposide, vincristine, dexrazoxane, doxorubicin, temozolomide, irinotecan and isotretinoin, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing or by stopping them from spreading. During induction, chemotherapy and surgery are used to kill and remove as much tumor as possible. During consolidation, very high doses of chemotherapy are given to kill any remaining cancer cells. This chemotherapy also destroys healthy bone marrow, where blood cells are made. A stem cell transplant is a procedure that helps the body make new healthy blood cells to replace the blood cells that may have been harmed by the cancer and/or chemotherapy. Radiation therapy is also given to the site where the cancer originated (primary site) and to any other areas that are still active at the end of induction.

Clinical Trial Description

PRIMARY OBJECTIVE: I. To determine if the event-free survival (EFS) of patients with newly diagnosed high-risk neuroblastoma assigned to early chemoimmunotherapy during Induction differs from that of patients who are not assigned to treatment that includes early chemoimmunotherapy. SECONDARY OBJECTIVES: I. To determine if early chemoimmunotherapy during Induction therapy improves end of induction (EOI) response rates and overall survival (OS) for patients with newly diagnosed high-risk neuroblastoma. II. To determine response rates, EFS, and OS following an extended induction regimen with chemoimmunotherapy in patients with progressive disease or a poor response to Induction therapy. III. To compare the toxicities experienced by patients treated with chemoimmunotherapy during induction versus those experienced by patients treated with standard induction and to describe toxicities experienced during extended induction. IV. To determine GD2 expression on tumor tissue and tumor cells in bone marrow and assess for associations with response and outcome. EXPLORATORY OBJECTIVES: I. To describe the association between tumor and host factors and outcomes in patients receiving protocol therapy. II. To evaluate circulating biomarkers and markers of minimal residual disease at baseline and during therapy, and assess for associations with response and outcome. III. To compare patterns of failure between patients treated with and without dinutuximab during induction. IV. To determine the effect of telomere maintenance mechanisms on end of Induction response rates, EFS, and OS. V. To explore the impact of high-risk neuroblastoma (HRNBL) and its therapy, including the addition of dinutuximab to Induction chemotherapy, on functional and quality of life outcomes in patients with HRNBL, as measured by caregiver (parent/legal guardian) and patient questionnaires. VI. To describe the adequacy of diagnostic biopsy specimens, including those obtained by percutaneous core needle biopsy. VII. To explore the associations between family-reported adverse social determinants of health and both clinical outcomes and biology. VIII. To develop and validate deep learning predictors of Induction response based on diagnostic MIBG scans. (Imaging Objective) IX. To compare institutional versus central determination of overall response, individual response components (primary tumor, soft tissue and bone metastatic disease, and bone marrow metastatic disease), and poor end of induction response (PEIR) and good end of induction response (GEIR) determination. (Imaging Objective) X. To describe late toxicities (including impaired organ function, neuropsychiatric toxicity, and incidence of secondary malignancy) in patients treated with dinutuximab during Induction or Extended Induction to late toxicities in patients who have not received dinutuximab during these phases of therapy. XI. To evaluate whether reduced dose radiotherapy to the primary site clinical target volume (CTV) in patients with complete response of the primary site at EOI results in comparable local control relative to historical cohorts. XII. To compare post-transplant complications between treatment arms, and assess for associations with outcome. XIII. To assess for associations between EOI response (including good end of Induction response [GEIR] and poor end of Induction response [PEIR]) and individual response components (primary tumor, soft tissue and bone metastatic disease, and bone marrow metastatic disease) with outcome (EFS and OS). XIV. To describe and compare the changes in image-defined risk factors (IDRFs) between patients treated with and without dinutuximab during Induction and associate with surgical outcomes and local failure rates following primary tumor resection. XV. To bank serial samples of blood, bone marrow, and tumor tissue for future research. OUTLINE: Patients receive induction cycle 1. Patients are then randomized to 1 of 2 arms. INDUCTION CYCLE 1: Patients receive cyclophosphamide intravenously (IV) over 30 minutes and topotecan IV over 30 minutes on days 1-5 in the absence of unacceptable toxicity. ARM A: INDUCTION CYCLES 2-4: Patients receive cyclophosphamide IV over 30 minutes and topotecan IV over 30 minutes on days 1-5 of cycle 2 in the absence of unacceptable toxicity. Patients then undergo stem cell harvest via apheresis. Patients then receive cisplatin IV over 4 hours and etoposide IV over 4 hours on days 1-3 of cycle 3 and vincristine IV on day 1 and dexrazoxane IV over 5-15 minutes, doxorubicin over 15 minutes, and cyclophosphamide over 1 hours on days 1-2 of cycle 4 in the absence of unacceptable toxicity. Patients undergo testing to determine response and proceed to surgery followed by induction cycle 5 or extended induction. INDUCTION CYCLE 5: Patients receive cisplatin IV over 4 hours and etoposide IV over 2 hours on days 1-3 in the absence of unacceptable toxicity. Patients with a response to therapy proceed to consolidation. EXTENDED INDUCTION: Patients whose cancer did not respond receive temozolomide orally (PO), via nasogastric tube (NG), or via gastric tube (G-tube) on days 1-5, irinotecan IV over 90 minutes on days 1-5, and dinutuximan IV over 10 hours. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. CONSOLIDATION: Patients receive thiotepa IV over 2 hours on days -7 to -5 and cyclophosphamide IV over 1 hour on days -5 to -2. Patients then receive stem cell infusion IV on day 0. Between 6 and 10 weeks after stem cell infusion patients receive melphalan IV over 30 minutes on days -7 to -5, etoposide IV over 24 hours on days -7 to -4, and carboplatin over 24 hours on days -7 to -4. Patients receive stem cell infusion IV on day 0. Between day +42 and day +80 after second transplant, patients receive radiation daily for 12 treatments in the absence of disease progression or unacceptable toxicity. POST CONSOLIDATION: Patients receive dinutuximab IV over 10 hours on days 4-7 and isotretinoin PO twice daily (BID) on days 11-24 of each cycle. Treatment repeats every 28 days for up to 5 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive isotretinoin PO BID on days 15-28 for 1 additional cycle. Patients undergo bone marrow aspiration and/or biopsy, computed tomography (CT) scan, magnetic resonance imaging (MRI), iodine-123 meta-iodobenzylguanidine (I-MIBG) scan and fluorodeoxyglucose position emission tomography (FDG-PET) scan throughout the study. ARM B: INDUCTION CYCLES 2-4: Patients receive cyclophosphamide IV over 30 minutes, topotecan IV over 30 minutes on days 1-5, and dinutuximab IV over 10 hours on days 2-5 of cycle 2 in the absence of unacceptable toxicity. Patients then undergo stem cell harvest via apheresis. Patients receive cisplatin IV over 4 hours and etoposide IV over 4 hours on days 1-3 and dinutuximab IV on days 2-5 on cycle 3 and vincristine IV on day 1 and dexrazoxane IV over 5-15 minutes, doxorubicin over 15 minutes, and cyclophosphamide over 1 hours on days 1-2, and dinutuximab IV over 10 hours on days 2-5 of cycle 4 in the absence of unacceptable toxicity. Patients then undergo testing to determine response and proceed to surgery followed by induction cycle 5 or extended induction. INDUCTION CYCLE 5: Patients receive cisplatin IV over 4 hours and etoposide IV over 2 hours on days 1-3 and dinutuximab IV on days 2-5 in the absence of unacceptable toxicity. Patients with a response to therapy proceed to consolidation. EXTENDED INDUCTION: Patients receive temozolomide PO, via NG, or via G-tube on days 1-5, irinotecan IV over 90 minutes on days 1-5, and dinutuximan IV over 10 hours. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity CONSOLIDATION: Patients receive thiotepa IV over 2 hours on days -7 to -5 and cyclophosphamide IV over 1 hour on days -5 to -2. Patients then receive stem cell infusion IV on day 0. Between 6 and 10 weeks after stem cell infusion patients receive melphalan IV over 30 minutes on days -7 to -5, etoposide IV over 24 hours on days -7 to -4, and carboplatin over 24 hours on days -7 to -4. Patients receive stem cell infusion IV on day 0. Between day +42 and day +80 after second transplant, patients receive radiation daily for 12 treatments in the absence of disease progression or unacceptable toxicity. POST CONSOLIDATION: Patients receive dinutuximab IV over 10 hours on days 4-7 and isotretinoin PO BID on days 11-24 of each cycle. Treatment repeats every 28 days for up to 5 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive isotretinoin PO BID on days 15-28 for 1 additional cycle. Patients undergo bone marrow aspiration and/or biopsy, CT scan, MRI, I-MIBG scan and FGD-PET scan throughout the study. After completion of study treatment, patients are followed up at 3, 6, 9,12, 15, 18, 24, 30, 36, 42, 48, 54, and 60 months and then periodically for up to 10 years from enrollment. ;

Related Conditions & MeSH terms

• Ganglioneuroblastoma
• Neuroblastoma

• NCT number: NCT06172296
• Study type: Interventional
• Source: National Cancer Institute (NCI)
• Status: Not yet recruiting
• Phase: Phase 3
• Start date: April 15, 2024
• Completion date: December 31, 2029