Testing the Addition of 131I-MIBG or Lorlatinib to Intensive Therapy in People With High-Risk Neuroblastoma (NBL)

Study Overview
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Brief Summary
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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
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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 busulfan/melphalan (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 and/or 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: HSCT#1: 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. HSCT#2: 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. ARM B: INDUCTION THERAPY: Patients receive cyclophosphamide, topotecan hydrochloride, cisplatin, and etoposide phosphate as in Arm A, iobenguane I-131 IV over 1.5-2 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: HSCT#1: Patients receive thiotepa and cyclophosphamide as in Arm A. HSCT#2: 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. 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. ARM D: Patients receive treatment identical to Arm A. 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: HSCT#1: Patients receive thiotepa and cyclophosphamide as in Arm A. Patients also receive lorlatinib PO QD until day -8 of HSCT#2 in the absence of disease progression or unacceptable toxicity. HSCT#2: Patients receive melphalan hydrochloride, etoposide phosphate, carboplatin as in Arm A. Lorlatinib is restarted when patient has reached at least day +14 post-HSCT#2 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 1-28 of cycles 1-6 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. 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.

Official Title
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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)

Conditions
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Ganglioneuroblastoma, Neuroblastoma

Intervention / Treatment
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* Procedure: Autologous Hematopoietic Stem Cell Transplantation
* Drug: Busulfan
* Drug: Carboplatin
* Drug: Cisplatin
* Drug: Cyclophosphamide
* Drug: Dexrazoxane Hydrochloride
* Biological: Dinutuximab
* Drug: Doxorubicin Hydrochloride
* Drug: Etoposide Phosphate
* Radiation: External Beam Radiation Therapy
* Radiation: Iobenguane I-131
* Drug: Isotretinoin
* Drug: Lorlatinib
* Drug: Melphalan Hydrochloride
* Biological: Sargramostim
* Procedure: Therapeutic Conventional Surgery
* Drug: Thiotepa
* Drug: Topotecan Hydrochloride
* Drug: Vincristine Sulfate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must be enrolled on ANBL00B1 (NCT00904241) or APEC14B1 (NCT02402244) prior to enrollment on ANBL1531 (NCT03126916) Patient must be >= 365 days and =< 30 years of age at diagnosis Patients must have a diagnosis of neuroblastoma or ganglioneuroblastoma (nodular) verified by tumor pathology analysis or demonstration of clumps of tumor cells in bone marrow with elevated urinary catecholamine metabolites; the following disease groups are eligible: Patients with International Neuroblastoma Risk Group (INRG) stage M disease are eligible if found to have either of the following features: MYCN amplification (> 4-fold increase in MYCN signals as compared to reference signals), regardless of additional biologic features; OR Age > 547 days regardless of biologic features Patients with INRG stage MS disease with MYCN amplification Patients with INRG stage L2 disease with MYCN amplification Patients > 547 days of age initially diagnosed with INRG stage L1, L2 or MS disease who progressed to stage M without prior chemotherapy may enroll within 4 weeks of progression to stage M Patients >= 365 days of age initially diagnosed with MYCN amplified INRG stage L1 disease who progress to stage M without systemic therapy may enroll within 4 weeks of progression to stage M Patients initially recognized to have high-risk disease must have had no prior systemic therapy (other than topotecan/cyclophosphamide initiated on an emergent basis and within allowed timing); patients observed or treated with a single cycle of chemotherapy per a low or intermediate risk neuroblastoma regimen (e.g., as per ANBL0531, ANBL1232 or similar) for what initially appeared to be non-high risk disease but subsequently found to meet the criteria will also be eligible; patients who receive localized emergency radiation to sites of life-threatening or function-threatening disease prior to or immediately after establishment of the definitive diagnosis will be eligible Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 or a serum creatinine based on age/sex as follows: 1 to < 2 years: male = 0.6; female = 0.6 2 to < 6 years: male = 0.8; female = 0.8 6 to < 10 years: male = 1; female = 1 10 to < 13 years: male = 1.2; female = 1.2 13 to < 16 years: male = 1.5; female = 1.4 >= 16 years: male = 1.7; female = 1.4 Total bilirubin =< 1.5 x upper limit of normal (ULN) for age, and Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) < 10 x ULN; for the purposes of this study, ULN for SGPT (ALT) is 45 Shortening fraction of >= 27% by echocardiogram, or ejection fraction of > 50% by echocardiogram or radionuclide angiogram No known contraindication to peripheral blood stem cell (PBSC) collection; examples of contraindications might be a weight or size less than the collecting institution finds feasible, or a physical condition that would limit the ability of the child to undergo apheresis catheter placement (if necessary) and/or the apheresis procedure Exclusion Criteria: Patients with INRG stage L2 tumors without amplification of MYCN regardless of tumor histology (may meet criteria for high risk classification but are not eligible for this trial) Patients with bone marrow failure syndromes Patients for whom targeted radiopharmaceutical therapy would be contraindicated due to underlying medical disorders Female patients who are pregnant since fetal toxicities and teratogenic effects have been noted for several of the study drugs; a pregnancy test is required for female patients of childbearing potential Lactating females who plan to breastfeed their infants Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their study participation

Ages Eligible for Study
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Minimum Age: 365 Days
Maximum Age: 30 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A (chemotherapy, HSCT, EBRT)<br>See Arm A in detailed description. | Procedure: Autologous Hematopoietic Stem Cell Transplantation<br>* Undergo autologous HSCT<br>* Other names: Stem Cell Transplantation, Autologous;Drug: Carboplatin<br>* Given IV<br>* Other names: Ribocarbo;Drug: Cisplatin<br>* Given IV<br>* Other names: Platosin;Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR-138719;Drug: Dexrazoxane Hydrochloride<br>* Given IV<br>* Other names: Zinecard;Biological: Dinutuximab<br>* Given IV<br>* Other names: Unituxin;Drug: Doxorubicin Hydrochloride<br>* Given IV<br>* Other names: Rubex;Drug: Etoposide Phosphate<br>* Given IV<br>* Other names: Etopophos;Radiation: External Beam Radiation Therapy<br>* Undergo EBRT<br>* Other names: Teletherapy Radiation;Drug: Isotretinoin<br>* Given PO<br>* Other names: ZENATANE;Biological: Sargramostim<br>* Given SC<br>* Other names: Sargramostatin;Procedure: Therapeutic Conventional Surgery<br>* Undergo standard of care surgery<br>Drug: Thiotepa<br>* Given IV<br>* Other names: WR 45312;Drug: Topotecan Hydrochloride<br>* Given IV<br>* Other names: topotecan hydrochloride (oral);Drug: Vincristine Sulfate<br>* Given IV<br>* Other names: Vincristine, sulfate;|
| Experimental: Arm B (Iobenguane I-131, chemotherapy, HSCT, EBRT)<br>See Arm B in detailed description. | Procedure: Autologous Hematopoietic Stem Cell Transplantation<br>* Undergo autologous HSCT<br>* Other names: Stem Cell Transplantation, Autologous;Drug: Carboplatin<br>* Given IV<br>* Other names: Ribocarbo;Drug: Cisplatin<br>* Given IV<br>* Other names: Platosin;Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR-138719;Drug: Dexrazoxane Hydrochloride<br>* Given IV<br>* Other names: Zinecard;Biological: Dinutuximab<br>* Given IV<br>* Other names: Unituxin;Drug: Doxorubicin Hydrochloride<br>* Given IV<br>* Other names: Rubex;Drug: Etoposide Phosphate<br>* Given IV<br>* Other names: Etopophos;Radiation: External Beam Radiation Therapy<br>* Undergo EBRT<br>* Other names: Teletherapy Radiation;Radiation: Iobenguane I-131<br>* Given IV<br>* Other names: MIBG I-131;Drug: Isotretinoin<br>* Given PO<br>* Other names: ZENATANE;Biological: Sargramostim<br>* Given SC<br>* Other names: Sargramostatin;Procedure: Therapeutic Conventional Surgery<br>* Undergo standard of care surgery<br>Drug: Thiotepa<br>* Given IV<br>* Other names: WR 45312;Drug: Topotecan Hydrochloride<br>* Given IV<br>* Other names: topotecan hydrochloride (oral);Drug: Vincristine Sulfate<br>* Given IV<br>* Other names: Vincristine, sulfate;|
| Experimental: Arm C (Iobenguane I-131, chemotherapy, BuMel, HSCT, EBRT)<br>See Arm C in detailed description. Closed to accrual as of 12/17/20. | Procedure: Autologous Hematopoietic Stem Cell Transplantation<br>* Undergo autologous HSCT<br>* Other names: Stem Cell Transplantation, Autologous;Drug: Busulfan<br>* Given IV<br>* Other names: WR-19508;Drug: Cisplatin<br>* Given IV<br>* Other names: Platosin;Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR-138719;Drug: Dexrazoxane Hydrochloride<br>* Given IV<br>* Other names: Zinecard;Biological: Dinutuximab<br>* Given IV<br>* Other names: Unituxin;Drug: Doxorubicin Hydrochloride<br>* Given IV<br>* Other names: Rubex;Drug: Etoposide Phosphate<br>* Given IV<br>* Other names: Etopophos;Radiation: External Beam Radiation Therapy<br>* Undergo EBRT<br>* Other names: Teletherapy Radiation;Radiation: Iobenguane I-131<br>* Given IV<br>* Other names: MIBG I-131;Drug: Isotretinoin<br>* Given PO<br>* Other names: ZENATANE;Drug: Melphalan Hydrochloride<br>* Given IV<br>* Other names: Evomela;Biological: Sargramostim<br>* Given SC<br>* Other names: Sargramostatin;Procedure: Therapeutic Conventional Surgery<br>* Undergo standard of care surgery<br>Drug: Thiotepa<br>* Given IV<br>* Other names: WR 45312;Drug: Topotecan Hydrochloride<br>* Given IV<br>* Other names: topotecan hydrochloride (oral);Drug: Vincristine Sulfate<br>* Given IV<br>* Other names: Vincristine, sulfate;|
| Experimental: Arm D (chemotherapy, HSCT, EBRT)<br>See Arm D in detailed description. | Procedure: Autologous Hematopoietic Stem Cell Transplantation<br>* Undergo autologous HSCT<br>* Other names: Stem Cell Transplantation, Autologous;Drug: Carboplatin<br>* Given IV<br>* Other names: Ribocarbo;Drug: Cisplatin<br>* Given IV<br>* Other names: Platosin;Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR-138719;Drug: Dexrazoxane Hydrochloride<br>* Given IV<br>* Other names: Zinecard;Biological: Dinutuximab<br>* Given IV<br>* Other names: Unituxin;Drug: Doxorubicin Hydrochloride<br>* Given IV<br>* Other names: Rubex;Drug: Etoposide Phosphate<br>* Given IV<br>* Other names: Etopophos;Radiation: External Beam Radiation Therapy<br>* Undergo EBRT<br>* Other names: Teletherapy Radiation;Drug: Isotretinoin<br>* Given PO<br>* Other names: ZENATANE;Biological: Sargramostim<br>* Given SC<br>* Other names: Sargramostatin;Procedure: Therapeutic Conventional Surgery<br>* Undergo standard of care surgery<br>Drug: Thiotepa<br>* Given IV<br>* Other names: WR 45312;Drug: Topotecan Hydrochloride<br>* Given IV<br>* Other names: topotecan hydrochloride (oral);Drug: Vincristine Sulfate<br>* Given IV<br>* Other names: Vincristine, sulfate;|
| Experimental: Arm E (lorlatinib, chemotherapy, HSCT, EBRT)<br>See Arm E in detailed description. | Procedure: Autologous Hematopoietic Stem Cell Transplantation<br>* Undergo autologous HSCT<br>* Other names: Stem Cell Transplantation, Autologous;Drug: Carboplatin<br>* Given IV<br>* Other names: Ribocarbo;Drug: Cisplatin<br>* Given IV<br>* Other names: Platosin;Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR-138719;Drug: Dexrazoxane Hydrochloride<br>* Given IV<br>* Other names: Zinecard;Biological: Dinutuximab<br>* Given IV<br>* Other names: Unituxin;Drug: Doxorubicin Hydrochloride<br>* Given IV<br>* Other names: Rubex;Drug: Etoposide Phosphate<br>* Given IV<br>* Other names: Etopophos;Radiation: External Beam Radiation Therapy<br>* Undergo EBRT<br>* Other names: Teletherapy Radiation;Drug: Isotretinoin<br>* Given PO<br>* Other names: ZENATANE;Drug: Lorlatinib<br>* Given PO<br>* Other names: PF-06463922;Biological: Sargramostim<br>* Given SC<br>* Other names: Sargramostatin;Procedure: Therapeutic Conventional Surgery<br>* Undergo standard of care surgery<br>Drug: Thiotepa<br>* Given IV<br>* Other names: WR 45312;Drug: Topotecan Hydrochloride<br>* Given IV<br>* Other names: topotecan hydrochloride (oral);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event free survival (EFS) (Arm A, B, D, and E) | EFS time is calculated from date of randomization or assignment to first episode of disease relapse or progression, second malignancy, or death, or until last contact if no event has occurred. | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events | The proportion of patients with at least one Grade 3 or higher toxicity during protocol therapy, graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0, will be reported. | Up to 18 months for Arms A-D and 28 months for Arm E | 
| EFS (Arm C) | EFS time is calculated from date of randomization to first episode of disease relapse or progression, second malignancy, or death, or until last contact if no event has occurred. | 3 years | 
| Overall survival (OS) | OS time is calculated from date of randomization or assignment until death, or until last contact if patient is alive. | 3 years | 
| Response rate | The response rate will be calculated among all evaluable patients at end-Induction. Responders are defined as patients who achieve a >= partial response (PR) per the revised International Neuroblastoma Response Criteria (INRC). | Up to 6 months |