Ignite Creation Date:
2024-05-06 @ 9:58 AM
Last Modification Date:
2024-10-26 @ 12:22 PM
Study NCT ID:
NCT03126916
Status:
ACTIVE_NOT_RECRUITING
Last Update Posted:
2024-04-22
First Post:
2017-04-17
Brief Title:
Testing the Addition of 131I-MIBG or Lorlatinib to Intensive Therapy in People With High-Risk Neuroblastoma NBL
Sponsor:
Childrens Oncology Group
Organization:
Childrens Oncology Group
Study Overview
Official Title:
A Phase 3 Study of 131I-Metaiodobenzylguanidine 131I-MIBG or ALK Inhibitor Therapy Added to Intensive Therapy for Children With Newly Diagnosed High-Risk Neuroblastoma NBL
Status:
ACTIVE_NOT_RECRUITING
Status Verified Date:
2024-08
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 studies iobenguane I-131 or lorlatinib and standard therapy in treating younger patients with newly-diagnosed high-risk neuroblastoma or ganglioneuroblastoma Radioactive drugs such as iobenguane I-131 may carry radiation directly to tumor cells and not harm normal cells Lorlatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth Giving iobenguane I-131 or lorlatinib and standard therapy may work better compared to lorlatinib and standard therapy alone in treating younger patients with neuroblastoma or ganglioneuroblastoma
Detailed Description:
PRIMARY OBJECTIVES
I To determine in the context of a randomized trial whether the event-free survival EFS of patients with newly diagnosed high-risk neuroblastoma NBL is improved with the addition of iobenguane I-131 131I-MIBG during induction prior to tandem autologous stem cell transplantation ASCT
II To determine whether the addition of lorlatinib to intensive multimodality therapy for patients with high-risk NBL whose tumors harbor activating point mutations in the ALK gene with a variant allele frequency VAF 5 results in superior EFS compared to a contemporaneously treated cohort of patients with tumors without documented ALK activating mutations
SECONDARY OBJECTIVES
I To describe the toxicities associated with treatment for high-risk NBL with and without the addition of 131I-MIBG or ALK inhibitor therapy
II To estimate EFS and describe toxicity in patients with newly diagnosed high-risk NBL randomized to treatment with an 131I-MIBG-containing induction prior to busulfanmelphalan BuMel ASCT
III To describe the overall survival OS and response rates evaluated per International Neuroblastoma Response Criteria INRC criteria prior to ASCT and prior to post-consolidation therapy for patients with high-risk neuroblastoma treated with or without 131I-MIBG or ALK inhibitor therapy
IV To prospectively evaluate the relationship of response rate per revised International Neuroblastoma Response Criteria INRC to EFS and OS in patients with high-risk NBL treated with and without the addition of 131I-MIBG or ALK inhibitor therapy
EXPLORATORY OBJECTIVES
I To evaluate whole body radiation dose tumor factors and host factors as potential predictors of efficacy andor toxicity associated with 131I-MIBG therapy and transplant conditioning
II To describe end-Induction response EFS and OS according to specific ALK mutations VAF ALK amplification the presence of additional genomic findings or the ALK inhibitor administered
III To characterize changes in tumor markers circulating tumor deoxyribonucleic acid DNA including ALK and other tumor specific genetic aberrations and circulating GD2 over time in response to protocol therapy
IV To correlate results of tumor and host profiling with end-induction response and EFS
V To prospectively evaluate EFS for patients with MIBG non-avid high-risk NBL compared to patients with MIBG-avid high-risk NBL who are randomized to treatment without 131I-MIBG
VI To correlate Curie scores calculated from 131I-MIBG post-treatment scans with end-induction response EFS and OS
VII To describe changes in image defined risk factors IDRFs over the course of induction therapy with correlation to surgical outcomes and local failure rates following primary tumor resection
VIII To define patterns of failure at time of first relapse or progression in patients with high-risk NBL
IX To determine the feasibility of prospectively monitoring adverse events using electronic health records
X To compare local central and computer assisted Curie score assignment at baseline and during therapy in patients with MIBG-avid high-risk NBL
XI To compare late toxicities including impaired organ function and secondary tumor occurrence in patients treated with 131I-MIBG or ALK inhibitor therapy to late toxicities in patients who have not received these therapies
XII To determine the association between household material hardship HMH and clinical outcomes including event free and overall survival and 131I-MIBG receipt
XIII To compare the outcomes EFS OS and toxicity of patients treated with post-consolidation therapy that does not contain aldesleukin to historical outcome data for patients treated with similar induction and consolidation regimens followed by post-consolidation therapy that contained aldesleukin
XIV To characterize and describe longitudinal neuropsychological and behavioral effects of high-risk neuroblastoma therapy
XV To evaluate change in neurobehavioral outcomes over time in patients with neuroblastoma treated with high-risk neuroblastoma therapy plus lorlatinib compared to high-risk therapy alone using parent- or self-report measures of adaptive executive and psychosocial functioning
XVI To characterize the pharmacokinetics and pharmaceutical properties of lorlatinib in children with high-risk neuroblastoma
OUTLINE Patients are randomized or assigned to 1 of 5 arms
All patients receive cyclophosphamide intravenously IV over 15-30 minutes and topotecan hydrochloride IV over 30 minutes on days 1-5 during cycle 1 of induction therapy in the absence of disease progression or unacceptable toxicity Patients not assigned to an Arm by the end of cycle 1 may receive an addition cycle of cyclophosphamide and topotecan
ARM A
INDUCTION THERAPY Patients receive cyclophosphamide IV over 15-30 minutes and topotecan hydrochloride IV over 30 minutes on days 1-5 of cycle 2 and cisplatin IV over 4 hours and etoposide phosphate IV over 2 hours on days 1-3 of cycles 3 and 5 Patients also receive vincristine sulfate IV over 1 minute on day 1 and dexrazoxane hydrochloride IV over 5-15 minutes doxorubicin hydrochloride IV over 1-15 minutes and cyclophosphamide IV over 1-6 hours on days 1-2 of cycle 4 in the absence of disease progression or unacceptable toxicity
CONSOLIDATION THERAPY
HSCT1 Patients receive thiotepa IV over 2 hours on days -7 to -5 and cyclophosphamide IV over 1 hour on days -5 to -2 in the absence of disease progression or unacceptable toxicity
HSCT2 Patients receive melphalan hydrochloride IV over 30 minutes on days -7 to -5 and etoposide phosphate IV over 24 hours and carboplatin IV over 24 hours on days -7 to -4 in the absence of disease progression or unacceptable toxicity
POST-CONSOLIDATION THERAPY Patients receive sargramostim subcutaneously SC on days 1-14 dinutuximab IV over 10 hours on days 4-7 of cycles 1-5 and isotretinoin orally PO twice daily BID on days 11-24 of cycles 1-5 and days 15-28 during cycle 6 in the absence of disease progression or unacceptable toxicity
Patients undergo echocardiography or multigated acquisition MUGA scan magnetic resonance imaging MRI or computed tomography CT scan receive 123I-MIBG and undergo MIBG imaging bone marrow aspiration and biopsy and blood sample collection throughout the study
ARM B
INDUCTION THERAPY Patients receive cyclophosphamide topotecan hydrochloride cisplatin and etoposide phosphate as in Arm A iobenguane I-131 IV over 15-2 hours on day 1 beginning 3 weeks after the start of cycle 3 and vincristine sulfate dexrazoxane hydrochloride doxorubicin hydrochloride and cyclophosphamide as in Arm A beginning no sooner than 35 days after the infusion of iobenguane I-131
CONSOLIDATION THERAPY
HSCT1 Patients receive thiotepa and cyclophosphamide as in Arm A
HSCT2 Patients receive melphalan etoposide phosphate and carboplatin as in Arm A
POST-CONSOLIDATION THERAPY Patients receive sargramostim dinutuximab and isotretinoin as in Arm A-D
Patients undergo echocardiography or MUGA scan MRI or CT scan receive 123I-MIGB and undergo MIBG imaging bone marrow aspiration and biopsy and blood sample collection throughout the study
ARM C CLOSED TO ACCRUAL AS OF DECEMBER 17 2020
INDUCTION THERAPY Patients receive cyclophosphamide topotecan hydrochloride cisplatin etoposide phosphate iobenguane I-131 vincristine sulfate dexrazoxane hydrochloride doxorubicin hydrochloride and cyclophosphamide as in Arm B
CONSOLIDATION THERAPY Patients receive busulfan IV over 3 hours on days -6 to -3 and melphalan hydrochloride IV over 30 minutes on day -1 in the absence of disease progression or unacceptable toxicity
POST-CONSOLIDATION THERAPY Patients receive sargramostim dinutuximab and isotretinoin as in Arm A
Patients undergo echocardiography or MUGA scan MRI or CT scan receive 123I-MIGB and undergo MIBG imaging bone marrow aspiration and biopsy and blood sample collection throughout the study
ARM D Patients receive treatment identical to Arm A
Patients undergo echocardiography or MUGA scan MRI or CT scan receive 123I-MIGB and undergo MIBG imaging bone marrow aspiration and biopsy and blood sample collection throughout the study and may undergo fludeoxyglucose- positron emission tomography PET scan on study
ARM E
INDUCTION THERAPY Patients receive cyclophosphamide topotecan hydrochloride cisplatin etoposide phosphate vincristine sulfate dexrazoxane hydrochloride doxorubicin hydrochloride and cyclophosphamide as in Arm A Patients also receive lorlatinib PO once daily QD starting cycle 2 prior to HSCT 1 in the absence of disease progression or unacceptable toxicity
CONSOLIDATION THERAPY
HSCT1 Patients receive thiotepa and cyclophosphamide as in Arm A Patients also receive lorlatinib PO QD until day -8 of HSCT2 in the absence of disease progression or unacceptable toxicity
HSCT2 Patients receive melphalan hydrochloride etoposide phosphate carboplatin as in Arm A Lorlatinib is restarted when patient has reached at least day 14 post-HSCT2 and is able to tolerate enteral medications provided there is no evidence of disease progression or unacceptable toxicity
RADIATION THERAPY Patients receive lorlatinib PO QD concurrently with radiation therapy in the absence of disease progression or unacceptable toxicity
POST-CONSOLIDATION THERAPY Patients receive sargramostim and dinutuximab as in Arm A-D Patients also receive isotretinoin PO BID on days 11-24 of cycles 1-5 and days 15-28 of cycle 6 and lorlatinib PO QD on days 15-28 of cycles 2-5 and days 1-28 of cycle 6 in the absence of disease progression or unacceptable toxicity
CONTINUATION THERAPY Patients receive lorlatinib PO QD on days 1-28 Cycles repeat every 28 days for 18 months in the absence of disease progression or unacceptable toxicity
Patients undergo echocardiography or MUGA scan MRI or CT scan receive 123I-MIGB and undergo MIBG imaging bone marrow aspiration and biopsy and blood sample collection throughout the study and may undergo MRI and PET scan on study
After completion of study therapy patients in Arms A-D are followed up every 3 months for 18 months and then every 6 months for 42 months patients in Arm E are followed up every 3 months for 6 months and then every 6 months for 42 months
I To determine in the context of a randomized trial whether the event-free survival EFS of patients with newly diagnosed high-risk neuroblastoma NBL is improved with the addition of iobenguane I-131 131I-MIBG during induction prior to tandem autologous stem cell transplantation ASCT
II To determine whether the addition of lorlatinib to intensive multimodality therapy for patients with high-risk NBL whose tumors harbor activating point mutations in the ALK gene with a variant allele frequency VAF 5 results in superior EFS compared to a contemporaneously treated cohort of patients with tumors without documented ALK activating mutations
SECONDARY OBJECTIVES
I To describe the toxicities associated with treatment for high-risk NBL with and without the addition of 131I-MIBG or ALK inhibitor therapy
II To estimate EFS and describe toxicity in patients with newly diagnosed high-risk NBL randomized to treatment with an 131I-MIBG-containing induction prior to busulfanmelphalan BuMel ASCT
III To describe the overall survival OS and response rates evaluated per International Neuroblastoma Response Criteria INRC criteria prior to ASCT and prior to post-consolidation therapy for patients with high-risk neuroblastoma treated with or without 131I-MIBG or ALK inhibitor therapy
IV To prospectively evaluate the relationship of response rate per revised International Neuroblastoma Response Criteria INRC to EFS and OS in patients with high-risk NBL treated with and without the addition of 131I-MIBG or ALK inhibitor therapy
EXPLORATORY OBJECTIVES
I To evaluate whole body radiation dose tumor factors and host factors as potential predictors of efficacy andor toxicity associated with 131I-MIBG therapy and transplant conditioning
II To describe end-Induction response EFS and OS according to specific ALK mutations VAF ALK amplification the presence of additional genomic findings or the ALK inhibitor administered
III To characterize changes in tumor markers circulating tumor deoxyribonucleic acid DNA including ALK and other tumor specific genetic aberrations and circulating GD2 over time in response to protocol therapy
IV To correlate results of tumor and host profiling with end-induction response and EFS
V To prospectively evaluate EFS for patients with MIBG non-avid high-risk NBL compared to patients with MIBG-avid high-risk NBL who are randomized to treatment without 131I-MIBG
VI To correlate Curie scores calculated from 131I-MIBG post-treatment scans with end-induction response EFS and OS
VII To describe changes in image defined risk factors IDRFs over the course of induction therapy with correlation to surgical outcomes and local failure rates following primary tumor resection
VIII To define patterns of failure at time of first relapse or progression in patients with high-risk NBL
IX To determine the feasibility of prospectively monitoring adverse events using electronic health records
X To compare local central and computer assisted Curie score assignment at baseline and during therapy in patients with MIBG-avid high-risk NBL
XI To compare late toxicities including impaired organ function and secondary tumor occurrence in patients treated with 131I-MIBG or ALK inhibitor therapy to late toxicities in patients who have not received these therapies
XII To determine the association between household material hardship HMH and clinical outcomes including event free and overall survival and 131I-MIBG receipt
XIII To compare the outcomes EFS OS and toxicity of patients treated with post-consolidation therapy that does not contain aldesleukin to historical outcome data for patients treated with similar induction and consolidation regimens followed by post-consolidation therapy that contained aldesleukin
XIV To characterize and describe longitudinal neuropsychological and behavioral effects of high-risk neuroblastoma therapy
XV To evaluate change in neurobehavioral outcomes over time in patients with neuroblastoma treated with high-risk neuroblastoma therapy plus lorlatinib compared to high-risk therapy alone using parent- or self-report measures of adaptive executive and psychosocial functioning
XVI To characterize the pharmacokinetics and pharmaceutical properties of lorlatinib in children with high-risk neuroblastoma
OUTLINE Patients are randomized or assigned to 1 of 5 arms
All patients receive cyclophosphamide intravenously IV over 15-30 minutes and topotecan hydrochloride IV over 30 minutes on days 1-5 during cycle 1 of induction therapy in the absence of disease progression or unacceptable toxicity Patients not assigned to an Arm by the end of cycle 1 may receive an addition cycle of cyclophosphamide and topotecan
ARM A
INDUCTION THERAPY Patients receive cyclophosphamide IV over 15-30 minutes and topotecan hydrochloride IV over 30 minutes on days 1-5 of cycle 2 and cisplatin IV over 4 hours and etoposide phosphate IV over 2 hours on days 1-3 of cycles 3 and 5 Patients also receive vincristine sulfate IV over 1 minute on day 1 and dexrazoxane hydrochloride IV over 5-15 minutes doxorubicin hydrochloride IV over 1-15 minutes and cyclophosphamide IV over 1-6 hours on days 1-2 of cycle 4 in the absence of disease progression or unacceptable toxicity
CONSOLIDATION THERAPY
HSCT1 Patients receive thiotepa IV over 2 hours on days -7 to -5 and cyclophosphamide IV over 1 hour on days -5 to -2 in the absence of disease progression or unacceptable toxicity
HSCT2 Patients receive melphalan hydrochloride IV over 30 minutes on days -7 to -5 and etoposide phosphate IV over 24 hours and carboplatin IV over 24 hours on days -7 to -4 in the absence of disease progression or unacceptable toxicity
POST-CONSOLIDATION THERAPY Patients receive sargramostim subcutaneously SC on days 1-14 dinutuximab IV over 10 hours on days 4-7 of cycles 1-5 and isotretinoin orally PO twice daily BID on days 11-24 of cycles 1-5 and days 15-28 during cycle 6 in the absence of disease progression or unacceptable toxicity
Patients undergo echocardiography or multigated acquisition MUGA scan magnetic resonance imaging MRI or computed tomography CT scan receive 123I-MIBG and undergo MIBG imaging bone marrow aspiration and biopsy and blood sample collection throughout the study
ARM B
INDUCTION THERAPY Patients receive cyclophosphamide topotecan hydrochloride cisplatin and etoposide phosphate as in Arm A iobenguane I-131 IV over 15-2 hours on day 1 beginning 3 weeks after the start of cycle 3 and vincristine sulfate dexrazoxane hydrochloride doxorubicin hydrochloride and cyclophosphamide as in Arm A beginning no sooner than 35 days after the infusion of iobenguane I-131
CONSOLIDATION THERAPY
HSCT1 Patients receive thiotepa and cyclophosphamide as in Arm A
HSCT2 Patients receive melphalan etoposide phosphate and carboplatin as in Arm A
POST-CONSOLIDATION THERAPY Patients receive sargramostim dinutuximab and isotretinoin as in Arm A-D
Patients undergo echocardiography or MUGA scan MRI or CT scan receive 123I-MIGB and undergo MIBG imaging bone marrow aspiration and biopsy and blood sample collection throughout the study
ARM C CLOSED TO ACCRUAL AS OF DECEMBER 17 2020
INDUCTION THERAPY Patients receive cyclophosphamide topotecan hydrochloride cisplatin etoposide phosphate iobenguane I-131 vincristine sulfate dexrazoxane hydrochloride doxorubicin hydrochloride and cyclophosphamide as in Arm B
CONSOLIDATION THERAPY Patients receive busulfan IV over 3 hours on days -6 to -3 and melphalan hydrochloride IV over 30 minutes on day -1 in the absence of disease progression or unacceptable toxicity
POST-CONSOLIDATION THERAPY Patients receive sargramostim dinutuximab and isotretinoin as in Arm A
Patients undergo echocardiography or MUGA scan MRI or CT scan receive 123I-MIGB and undergo MIBG imaging bone marrow aspiration and biopsy and blood sample collection throughout the study
ARM D Patients receive treatment identical to Arm A
Patients undergo echocardiography or MUGA scan MRI or CT scan receive 123I-MIGB and undergo MIBG imaging bone marrow aspiration and biopsy and blood sample collection throughout the study and may undergo fludeoxyglucose- positron emission tomography PET scan on study
ARM E
INDUCTION THERAPY Patients receive cyclophosphamide topotecan hydrochloride cisplatin etoposide phosphate vincristine sulfate dexrazoxane hydrochloride doxorubicin hydrochloride and cyclophosphamide as in Arm A Patients also receive lorlatinib PO once daily QD starting cycle 2 prior to HSCT 1 in the absence of disease progression or unacceptable toxicity
CONSOLIDATION THERAPY
HSCT1 Patients receive thiotepa and cyclophosphamide as in Arm A Patients also receive lorlatinib PO QD until day -8 of HSCT2 in the absence of disease progression or unacceptable toxicity
HSCT2 Patients receive melphalan hydrochloride etoposide phosphate carboplatin as in Arm A Lorlatinib is restarted when patient has reached at least day 14 post-HSCT2 and is able to tolerate enteral medications provided there is no evidence of disease progression or unacceptable toxicity
RADIATION THERAPY Patients receive lorlatinib PO QD concurrently with radiation therapy in the absence of disease progression or unacceptable toxicity
POST-CONSOLIDATION THERAPY Patients receive sargramostim and dinutuximab as in Arm A-D Patients also receive isotretinoin PO BID on days 11-24 of cycles 1-5 and days 15-28 of cycle 6 and lorlatinib PO QD on days 15-28 of cycles 2-5 and days 1-28 of cycle 6 in the absence of disease progression or unacceptable toxicity
CONTINUATION THERAPY Patients receive lorlatinib PO QD on days 1-28 Cycles repeat every 28 days for 18 months in the absence of disease progression or unacceptable toxicity
Patients undergo echocardiography or MUGA scan MRI or CT scan receive 123I-MIGB and undergo MIBG imaging bone marrow aspiration and biopsy and blood sample collection throughout the study and may undergo MRI and PET scan on study
After completion of study therapy patients in Arms A-D are followed up every 3 months for 18 months and then every 6 months for 42 months patients in Arm E are followed up every 3 months for 6 months and then every 6 months for 42 months
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?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| U10CA180886 | NIH | CTEP | httpsreporternihgovquickSearchU10CA180886 |
| NCI-2016-01734 | REGISTRY | None | None |
| ANBL1531 | OTHER | None | None |
| ANBL1531 | OTHER | None | None |