Ignite Creation Date:
2024-05-06 @ 7:53 PM
Last Modification Date:
2024-10-26 @ 3:16 PM
Study NCT ID:
NCT06172296
Status:
RECRUITING
Last Update Posted:
2024-07-15
First Post:
2023-12-13
Brief Title:
Dinutuximab With Chemotherapy Surgery and Stem Cell Transplantation for the Treatment of Children With Newly Diagnosed High Risk Neuroblastoma
Sponsor:
National Cancer Institute NCI
Organization:
National Cancer Institute NCI
Study Overview
Official Title:
A Phase 3 Study of Dinutuximab Added to Intensive Multimodal Therapy for Children With Newly Diagnosed High-Risk Neuroblastoma
Status:
RECRUITING
Status Verified Date:
2024-06
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
No
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
This phase III trial tests how well the addition of dinutuximab to Induction chemotherapy along with standard of care surgical resection of the primary tumor radiation stem cell transplantation and immunotherapy 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 on the surface of neuroblastoma cells but is not present on many healthy or normal cells in the body When dinutuximab binds to the neuroblastoma cells it helps signal the immune system to kill the tumor cells This helps the cells of the immune system kill the cancer cells this is a type of immunotherapy When chemotherapy and immunotherapy are given together during the same treatment cycle it is called chemoimmunotherapy This clinical trial randomly assigns patients to receive either standard chemotherapy and surgery or chemoimmunotherapy chemotherapy plus dinutuximab and surgery during Induction therapy Chemotherapy drugs administered during Induction include cyclophosphamide topotecan cisplatin etoposide vincristine and doxorubicin These drugs 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 Upon completion of 5 cycles of Induction therapy a disease evaluation is completed to determine how well the treatment worked If the tumor responds to therapy patients receive a tandem transplantation with stem cell rescue If the tumor has little improvement or worsens patients receive chemoimmunotherapy on Extended Induction During Extended Induction dinutuximab is given with irinotecan temozolomide Patients with a good response to therapy move on to Consolidation therapy when very high doses of chemotherapy are given at two separate points to kill any remaining cancer cells Following transplant radiation therapy is given to the site where the cancer originated primary site and to any other areas that are still active at the end of Induction The final stage of therapy is Post-Consolidation During Post-Consolidation dinutuximab is given with isotretinoin with the goal of maintaining the response achieved with the previous therapy Adding dinutuximab to Induction chemotherapy along with standard of care surgical resection of the primary tumor radiation stem cell transplantation and immunotherapy may be better at treating children with newly diagnosed high-risk neuroblastoma
Detailed 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 parentlegal 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 and are then randomized to 1 of 2 treatment 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 2-5 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 2 hours on days 1-3 of cycles 3 and 5 and vincristine IV on day 1 doxorubicin IV over 15 minutes and cyclophosphamide IV over 1 hour on days 1-2 of cycle 4 in the absence of unacceptable toxicity Patients undergo primary tumor resection after Induction cycle 4 or 5 Following Induction cycle 5 patients undergo testing to determine response to Induction therapy Patients with a good tumor response proceed to Consolidation while patients with a poor tumor response proceed to Extended Induction
EXTENDED INDUCTION Patients with a poor tumor response or progression during Induction 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 dinutuximab IV over 10 hours Treatment repeats every 21 days for up to a maximum of 6 cycles in the absence of disease progression or unacceptable toxicity If at any time during Extended Induction testing shows a good tumor response patients proceed to Consolidation If after 6 cycles of Extended Induction or if at any time progression is noted patients are removed from the study
CONSOLIDATION Patients undergo two autologous hematopoietic stem cell transplantations HSCTs during Consolidation Patients receive thiotepa IV over 2 hours on days -7 to -5 and cyclophosphamide IV over 1 hour on days -5 to -2 during HSCT 1 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 during HSCT 2 Patients receive stem cell infusion IV on day 0 Between day 42 and day 80 after HSCT 2 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 cycles 1-5 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 cycle 6
Patients undergo bone marrow aspiration andor biopsy computed tomography CT scan magnetic resonance imaging MRI iodine-123 meta-iodobenzylguanidine I-MIBG scan and possible fluorodeoxyglucose position emission tomography FDG-PET scan throughout the study
ARM B
INDUCTION CYCLES 2-5 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 2 hours on days 1-3 and dinutuximab IV over 10 hours on days 2-5 of cycles 3 and 5 and vincristine IV on day 1 doxorubicin IV over 15 minutes and cyclophosphamide IV over 1 hour on days 1-2 and dinutuximab IV over 10 hours on days 2-5 of cycle 4 in the absence of unacceptable toxicity Patients undergo primary tumor resection after Induction cycle 4 or 5 Following Induction cycle 5 patients undergo testing to determine response to Induction therapy Patients with a good tumor response proceed to Consolidation while patients with a poor tumor response proceed to Extended Induction
EXTENDED INDUCTION Patients with a poor tumor response or progression during Induction receive temozolomide PO via NG tube or via G-tube on days 1-5 irinotecan IV over 90 minutes on days 1-5 and dinutuximab IV over 10 hours Treatment repeats every 21 days for up to a maximum of 6 cycles in the absence of disease progression or unacceptable toxicity If at any time during Extended Induction testing shows a good tumor response patients proceed to Consolidation If after 6 cycles of Extended Induction or if at any time progression is noted patients are removed from the study
CONSOLIDATION Patients undergo two autologous HSCTs during Consolidation Patients receive thiotepa IV over 2 hours on days -7 to -5 and cyclophosphamide IV over 1 hour on days -5 to -2 during HSCT 1 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 during HSCT 2 Patients receive stem cell infusion IV on day 0 Between day 42 and day 80 after HSCT 2 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 cycles 1-5 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 cycle 6
Patients undergo bone marrow aspiration andor biopsy CT scan MRI I-MIBG scan and possible FGD-PET scan throughout the study
After completion of study treatment patients are followed up at 3 6 912 15 18 24 30 36 42 48 54 and 60 months and then periodically for up to 10 years from enrollment
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 parentlegal 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 and are then randomized to 1 of 2 treatment 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 2-5 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 2 hours on days 1-3 of cycles 3 and 5 and vincristine IV on day 1 doxorubicin IV over 15 minutes and cyclophosphamide IV over 1 hour on days 1-2 of cycle 4 in the absence of unacceptable toxicity Patients undergo primary tumor resection after Induction cycle 4 or 5 Following Induction cycle 5 patients undergo testing to determine response to Induction therapy Patients with a good tumor response proceed to Consolidation while patients with a poor tumor response proceed to Extended Induction
EXTENDED INDUCTION Patients with a poor tumor response or progression during Induction 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 dinutuximab IV over 10 hours Treatment repeats every 21 days for up to a maximum of 6 cycles in the absence of disease progression or unacceptable toxicity If at any time during Extended Induction testing shows a good tumor response patients proceed to Consolidation If after 6 cycles of Extended Induction or if at any time progression is noted patients are removed from the study
CONSOLIDATION Patients undergo two autologous hematopoietic stem cell transplantations HSCTs during Consolidation Patients receive thiotepa IV over 2 hours on days -7 to -5 and cyclophosphamide IV over 1 hour on days -5 to -2 during HSCT 1 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 during HSCT 2 Patients receive stem cell infusion IV on day 0 Between day 42 and day 80 after HSCT 2 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 cycles 1-5 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 cycle 6
Patients undergo bone marrow aspiration andor biopsy computed tomography CT scan magnetic resonance imaging MRI iodine-123 meta-iodobenzylguanidine I-MIBG scan and possible fluorodeoxyglucose position emission tomography FDG-PET scan throughout the study
ARM B
INDUCTION CYCLES 2-5 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 2 hours on days 1-3 and dinutuximab IV over 10 hours on days 2-5 of cycles 3 and 5 and vincristine IV on day 1 doxorubicin IV over 15 minutes and cyclophosphamide IV over 1 hour on days 1-2 and dinutuximab IV over 10 hours on days 2-5 of cycle 4 in the absence of unacceptable toxicity Patients undergo primary tumor resection after Induction cycle 4 or 5 Following Induction cycle 5 patients undergo testing to determine response to Induction therapy Patients with a good tumor response proceed to Consolidation while patients with a poor tumor response proceed to Extended Induction
EXTENDED INDUCTION Patients with a poor tumor response or progression during Induction receive temozolomide PO via NG tube or via G-tube on days 1-5 irinotecan IV over 90 minutes on days 1-5 and dinutuximab IV over 10 hours Treatment repeats every 21 days for up to a maximum of 6 cycles in the absence of disease progression or unacceptable toxicity If at any time during Extended Induction testing shows a good tumor response patients proceed to Consolidation If after 6 cycles of Extended Induction or if at any time progression is noted patients are removed from the study
CONSOLIDATION Patients undergo two autologous HSCTs during Consolidation Patients receive thiotepa IV over 2 hours on days -7 to -5 and cyclophosphamide IV over 1 hour on days -5 to -2 during HSCT 1 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 during HSCT 2 Patients receive stem cell infusion IV on day 0 Between day 42 and day 80 after HSCT 2 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 cycles 1-5 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 cycle 6
Patients undergo bone marrow aspiration andor biopsy CT scan MRI I-MIBG scan and possible FGD-PET scan throughout the study
After completion of study treatment patients are followed up at 3 6 912 15 18 24 30 36 42 48 54 and 60 months and then periodically for up to 10 years from enrollment
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
True
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
True
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| NCI-2023-08530 | REGISTRY | None | None |
| ANBL2131 | OTHER | None | None |
| ANBL2131 | OTHER | None | None |
| U10CA180886 | NIH | CTEP | httpsreporternihgovquickSearchU10CA180886 |