Table 1.

Overview of combination therapy being used in clinical trials for neuroblastoma

Inhibitor	Molecular target	Agent(s) used in combination	Phase	Status	Identifier	Results
Crizotinib	ALK	Topotecan hydrochloride Cyclophosphamide Doxorubicin hydrochloride Vincristine sulfate Dexrazoxane hydrochloride	I	Completed	NCT01606878	• Enrollment of 46 participants, and patients are assigned to experimental part A in which patients receive crizotinib, cyclophosphamide, and topotecan hydrochloride; part B in which patients receive crizotinib, vincristine, dexrazoxane, and doxorubicin, and part C in which patients receive crizotinib, cyclophosphamide, and topotecan hydrochloride) (posted on https://clinicaltrials.gov/) • Eligible age for study - 13 months to 21 years; and all sexes are eligible for study (posted on https://clinicaltrials.gov/) • Outcomes of this trial are divided into (a) primary outcome measures – incidence of adverse events (summary of all toxicities), and maximum tolerated dose of crizotinib; and (b) secondary outcome measures – maximum plasma concentration, peak concentration (Cmax), terminal phase half-life, area under the concentration, plasma clearance, and response rate (posted on https://clinicaltrials.gov/)
Crizotinib	ALK	Standard therapy (busulfan, carboplatin, cisplatin, cyclophosphamide, dexrazoxane, doxorubicin, etoposide, isotretinoin, melphalan, thiotepa, topotecan, vincristine)	III	Recruiting	NCT03126916	• Enrollment of 813 participants, and patients are assigned to the following experimental arms: (1) arm A (chemotherapy, hematopoietic stem cell transplantation (HSCT), external beam radiation therapy (EBRT); (2) arm B (chemotherapy, iobenguane I-131, EBRT, HSCT); (3) arm C (chemotherapy, iobenguane I-131, busulfan/melphalan (BuMel), EBRT, HSCT); arm D (chemotherapy, HSCT, EBRT); arm E (crizotinib, chemotherapy, HSCT, EBRT) (posted on https://clinicaltrials.gov/) • Outcome for this trial is divided into – (a) primary outcome measures: event-free survival (EFS), and (b) secondary outcome measures: incidence of adverse events, EFS, overall survival, response rate (posted on https://clinicaltrials.gov/) • Eligible age for study - 365 days to 30 years, and all sexes are eligible for study (posted on https://clinicaltrials.gov/)
Ceritinib	ALK	Ribociclib	I	Recruiting	NCT02780128	• Event-free survival for patients with both F1174-mutated ALK and amplified MYCN is significantly worse.109 • Relapsed disease has a higher frequency of ALK mutations.124 • Recurrent RAS/MAPK pathway mutations in tumors post- chemotherapy.124 • Exposure of ribociclib is dose-dependent at 350 (recommended phase II dose) and 470 mg/m2 (maximum tolerated dose) (equivalent to 600 (recommended phase II dose) – 900 mg in adults).320
Lorlatinib	ALK	Chemotherapy (cyclophosphamide, topotecan)	I	Recruiting	NCT03107988	• Enrollment of 40 participants, and includes the following experimental arms: (a) experimental cohort A1 (dose finding for lorlatinib); (b) experimental cohort A2 (adult and large BSA); (c) experimental cohort B1(expansion); (d) experimental cohort B2 (combined with chemotherapy) (posted on https://clinicaltrials.gov/) • Outcome measures for this trial: (a) primary outcome measures - RP2D (recommended phase 2 dose) of lorlatinib, toxicities of lorlatinib alone and in combination with cyclophosphamide and topotecan, pharmacokinetics (AUC for lorlatinib and metabolite, clearance for lorlatinib and metabolite, Cmax for lorlatinib and metabolite, Tmax for lorlatinib and metabolite, terminal half-life for lorlatinib and metabolite), and (b) secondary outcome measures - evaluation of overall response, bone response, soft tissue response, and bone marrow response (posted on https://clinicaltrials.gov/) • Eligible age for study – 1 year to 90 years, and all sexes are eligible for study (posted on https://clinicaltrials.gov/)
RG7388 (Idasanutlin)	MDM2	Chemotherapy (cyclophosphamide/topotecan/fludarabine/cytarabine/) or venetoclax	I/II	Recruiting	NCT04029688	• Enrollment of 220 participants, and includes the following experimental arms: (a) dose escalation (idasanutlin single agent), (b) idasanutlin and venetoclax administration, (c) idasanutlin, cyclophosphamide/topotecan administration (posted on https://clinicaltrials.gov/) • Outcome measures for this trial are – (a) primary outcome measures which include number of participants with at least one adverse effect and with dose limiting toxicities, percentage of participants with wild type TP53 achieving objective response, and (b) secondary outcome measures include clinical benefit rate, duration of objective response, progression free survival, and percentage of participants with solid tumors achieving an objective response irrespective of TP53 status (posted on https://clinicaltrials.gov/) • Eligible age for study – up to 30 years (child, adult), and all sexes are eligible for this study (posted on https://clinicaltrials.gov/)
Trametinib	MEK1/2	Dabrafenib (BRAF kinase inhibitor)	I/II	Recruiting	NCT02124772	• Enrollment of 139 participants, and includes the following experimental arms – (a) trametinib dose-escalation; (b) tumor-specific expansion; (c) dose administration of trametinib in this part will be based on trametinib monotherapy RP2D from part a; (d) trametinib and dabrafenib dose administered in this part will be the combination of trametinib and dabrafenib RP2D from part C (posted on https://clinicaltrials.gov/) • Primary outcome measures of this trial – safety assessment of trametinib via evaluating adverse events, ECG, ECHO (echocardiogram), changes in laboratory values, vital signs (posted on https://clinicaltrials.gov/) • Secondary outcome measures of this trial – pharmacokinetic (PK) assessment of trametinib; and safety and tolerability assessment for trametinib for ECG, changes in laboratory values, and vital signs; tumor response for trametinib; effect of age and weight on PK of trametinib; PK and safety assessment of trametinib and dabrafenib when administered in combination (posted on https://clinicaltrials.gov/) • Eligible age for study – 1 month to 17 years (child), and all sexes are eligible for this study (posted on https://clinicaltrials.gov/)
Vorinostat	Histone deacetylase (HDAC)	Isotretinoin	I	Completed	NCT00217412	• Enrollment of 60 participants, and includes the following experimental arms for NB patients: Arm I – patients receive vorinostat, and Arm III – patients receive isotretinoin and vorinostat (posted on https://clinicaltrials.gov/) • Primary outcome measures include maximum tolerated dose and secondary outcome measures include proportion of patients who demonstrate each polymorphism (posted on https://clinicaltrials.gov/) • Eligible age for study – 1 to 21 years, and all sexes are eligible for this study (posted on https://clinicaltrials.gov/)
Vorinostat	Histone deacetylase (HDAC)	Bortezomib	I	Completed	NCT01132911	• Enrollment of 5 participants for this study, and the outcome measures include: (a) primary outcomes – determine the MTD (maximum tolerated dose) and (RP2D) recommended phase 2 dose of combination of bortezomib and vorinostat, and define toxicities and pharmacokinetics; and (b) secondary outcomes – evaluate antitumor activity and determine biological activity of bortezomib via measurement of NFκB activity and endoplasmic reticulum stress response (posted on https://clinicaltrials.gov/) • Eligible age for study – 1 year to 21 years (child, adult) and all sexes are eligible for this study (posted on https://clinicaltrials.gov/)
Vorinostat	Histone deacetylase (HDAC)	131I-MIBG	II	Active, but not recruiting	NCT02035137	• Enrollment of 105 participants for this study, and includes arm A – 131I-MIBG alone; arm B – 131I-MIBG and irinotecan/vincristine; arm C – 131I-MIBG and vorinostat (posted on https://clinicaltrials.gov/) • Primary outcome measures – overall response rate after treatment with the 3 arms mentioned above; and secondary outcome measures – compare toxicity profile associated with delayed engraftment, compare occurrence of toxic death due to treatment regimens, and also compare toxicity profile for grade 3 or greater toxicities associated with treatment regimens (posted on https://clinicaltrials.gov/) • Eligible age for study – 2 years to 30 years, and all sexes are eligible for study (posted on https://clinicaltrials.gov/)
Vorinostat	Histone deacetylase (HDAC)	Dinutuximab/GM-CSF/IL-2 and isotretinoin, and +/−DFMO	II	Recruiting	NCT02559778	• Enrollment of 500 participants for this study, and includes the experimental arm of standard immunotherapy with (arm B) and without (arm A) DFMO (posted on https://clinicaltrials.gov/) • Primary outcome measures – measure the response of treatment based on event-free survival, and determine the feasibility of adding molecular targeted therapy to standard chemotherapy (posted on https://clinicaltrials.gov/) • Secondary outcome measures – number of days that subjects remain alive, overall response rate after induction therapy, number of patients with treatment-related adverse events, and amount of pain medicine required by arm A versus arm B (posted on https://clinicaltrials.gov/) • Eligible age for the study – up to 22 years, and all sexes are eligible for study (posted on https://clinicaltrials.gov/)
Vorinostat	Histone deacetylase (HDAC)	131I-MIBG	I	Completed	NCT01019850	• Enrollment of 27 participants for this study, and experimental arm includes the use of vorinostat, 131I-MIBG, peripheral blood stem cell transfusion (posted on https://clinicaltrials.gov/) • Primary outcome measure – identify all toxicities, and secondary outcome measure includes response evaluation in patients, and determine histone acetylation levels and norepinephrine transported mRNA levels in PBMCs after treatment with vorinostat (posted on https://clinicaltrials.gov/) • Eligible age for study – 2 years to 30 years (adult, child), and all sexes are eligible for study (posted on https://clinicaltrials.gov/)
Vorinostat	Histone deacetylase (HDAC)	Isotretinoin	I	Completed	NCT01208454	• Enrollment of 29 participants for this study, and includes experimental arm of isotretinoin and vorinostat treatment (posted on https://clinicaltrials.gov/) • Primary outcome measure – all toxicities are determined and summarized in terms of type (organ affected or laboratory determination), severity; and also determine the maximum tolerated dose of vorinostat (posted on https://clinicaltrials.gov/) • Secondary outcome measure – assess best response in solid tumors, survival and time-to failure (posted on https://clinicaltrials.gov/) • Eligible age for this study – up to 30 years (adult, child) and all sexes are eligible for the study (posted on https://clinicaltrials.gov/)
Decitabine	DNA methyltransferase (DNMT)	Doxorubicin and cyclophosphamide	I	Completed	NCT00075634	• Enrollment of 21 participants for this study, and experimental arm includes treatment with decitabine, doxorubicin, cyclophosphamide and G-CSF (posted on https://clinicaltrials.gov/) • Primary outcome measure – maximum tolerated dose (MTD) of decitabine and caspase 8 expression in bone marrow or tumor biopsy samples (posted on https://clinicaltrials.gov/) • Secondary outcome measure – objective response rate, and percentage of apoptotic cells determined by TUNEL assay (posted on https://clinicaltrials.gov/) • Eligible age for study – 1 year to 21 years (adult, child), and all sexes are eligible for study (posted on https://clinicaltrials.gov/)
Gemcitabine (pyrimidine nucleoside analog)	DNA	Ribociclib	I	Recruiting	NCT03434262	• Enrollment of 108 participants in this study, and this study includes the following experimental arms – (a) ribociclib and gemcitabine, (b) ribociclib and trametinib, and (c) ribociclib and sonidegib (posted on https://clinicaltrials.gov/) • Primary outcome measure – estimate the RP2D/MTD of each arm, determine the pharmacokinetics of combination treatment (posted on https://clinicaltrials.gov/) • Secondary outcome measure – estimate response rate and duration of objective response of each arm (posted on https://clinicaltrials.gov/) • Eligible age for this trial – 1 year to 39 years (adult, child), and all sexes are eligible for study (posted on https://clinicaltrials.gov/)
Gemcitabine (pyrimidine nucleoside analog)	DNA	Nab-paclitaxel	I	Recruiting	NCT03507491	• Enrollment of 24 participants in this study, and experimental arm includes treatment with gemcitabine and Nab-paclitaxel (posted on https://clinicaltrials.gov/) • Primary outcome measure – determine maximum dose tolerated of nab-paclitaxel, and also toxicity of nab-paclitaxel (posted on https://clinicaltrials.gov/) • Secondary outcome measure – determine the anticancer activity of nab-paclitaxel in combination with gemcitabine, evaluate the change in expression of SPARC (secreted protein acidic and rich in cysteine) in tumor, determine blood concentrations of paclitaxel (posted on https://clinicaltrials.gov/) • Eligible age for study – 6 month to 30 years (adult, child) and all sexes are eligible for study (posted on https://clinicaltrials.gov/)
Etoposide	Topoisomerase	Monoclonal antibody 3F8	II	Completed	NCT00004110	• Child, adult, older adult – all are eligible for this study, and all sexes eligible for this study (posted on https://clinicaltrials.gov/) • Objectives – determine the antitumor effects of monoclonal antibody 3F8, etoposide and isotretinoin; assess PFS (progression-free survival) in patients; and also investigate the effects of oral etoposide on human anti-mouse Ab and anti-idiotype response in patients (posted on https://clinicaltrials.gov/)
131I-MIBG	Norepinephrine receptor	Carboplatin, etoposide, melphalan, and peripheral blood stem cell infusion, and radiotherapy	II	Completed	NCT00253435	• 28.57% is the poor risk patients with serious adverse events (posted on https://clinicaltrials.gov/) • 37.5% is the good risk patients with serious adverse events (posted on https://clinicaltrials.gov/) • Other (not including serious) adverse effects for poor risk patients include febrile neutropenia (73.81%), supraventricular and nodal arrhythmia (26.19%), diarrhea (76.19%), heartburn (7.14%), mucositis/stomatitis (oral cavity) (69.05%) (posted on https://clinicaltrials.gov/) • Other (not including serious) adverse effects for good risk patients include febrile neutropenia (75%), ventricular arrhythmia (12.5%), mucositis/stomatitis (oral cavity) (62.5%), diarrhea (50%) (posted on https://clinicaltrials.gov/)
131I-MIBG	Norepinephrine receptor	Dinutuximab	I	Recruiting	NCT03332667	• Enrollment of 24 participants in this trial, and experimental arm includes treatment with 131I-MIBG and dinutuximab (posted on https://clinicaltrials.gov) • Primary outcome measures of this trial include – determination of MTD and RP2D of 131I-MIBG and dinutuximab, and also define the toxicities of 131I-MIBG in combination with dinutuximab (posted on https://clinicaltrials.gov) • Secondary outcome measures include – evaluation of overall response, bone response, soft tissue response and bone marrow response (posted on https://clinicaltrials.gov) • Eligible age for study – 1 year to 30 years (adult, child), and all sexes are eligible for study (posted on https://clinicaltrials.gov)
131I-MIBG	Norepinephrine receptor	Bevacizumab	I	Completed	NCT00450827	• Enrollment of 25 participants for this clinical trial, and this study includes an experimental arm which involves the use of 131I-3F8 and bevacizumab (posted on https://clinicaltrials.gov) • Primary outcome measure - determine MTD (maximum tolerated dose) and age eligible for this study is 1 year and older (adult, child, older adult), and all sexes are eligible for this study (posted on https://clinicaltrials.gov/)
Dinutuximab (ch14.18)	GD2	131I-MIBG and nivolumab	I	Recruiting	NCT02914405	• Enrollment of 36 participants for this clinical trial study, and the experimental arm includes a constant dose of 131I-MIBG and the doses of ch14.18/CHO and nivolumab are determined by cohort I (nivolumab and no ch14.18/CHO), cohort II (50mg/m2/cycle ch14.18/CHO and 3 mg/kg nivolumab), and cohort III (100mg/m2/cycle ch14.18/CHO and 3 mg/kg nivolumab) (posted on https://clinicaltrials.gov) • Primary outcome measures include – determine the safety and tolerability of 131I-MIBG, ch14.18/CHO and nivolumab in pediatric patients; and secondary outcome measures include – anti-tumor response in patients receiving 131I-MIBG, ch14.18/CHO and nivolumab in paediatric patients; and identify any association between KIR/KIR-ligand genotype, FcγR genotype and response (posted on https://clinicaltrials.gov) • Eligible age for study – 1 year to 18 years (adult, child), and all sexes are eligible for this study (posted on https://clinicaltrials.gov/)
Dinutuximab beta	GD2	Temozolomide and topotecan	II	Recruiting	NCT02308527	• Enrollment of 224 participants in this trial, and the experimental arm includes temozolomide, temozolomide + bevacizumab, temozolomide + irinotecan, bevacizumab + temozolomide + irinotecan, topotecan + temozolomide, bevacizumab + topotecan + temozolomide, temozolomide + dinutuximab beta, dinutuximab beta + temozolomide + topotecan, dinutuximab beta + topotecan + cyclophosphamide (posted on https://clinicaltrials.gov) • Primary outcome measures include – test the effect on bevacizumab addition to the chemotherapy (temozolomide, topotecan-temozolomide or irinotecan-temozolomide) in NB patients, and evaluate the progression-free survival (PFS); and secondary outcome measures – evaluate the toxicity of the different arms (posted on https://clinicaltrials.gov) • Eligible age for study – 1 year to 21 years (adult, child), and all sexes are eligible for study (posted on https://clinicaltrials.gov/)
Dinutuximab and sargramostim (GM-SF)	GD2	Chemotherapy (carboplatin, cisplatin, cyclophosphamide, dexrazoxane, doxorubicin, etoposide, isotretinoin, melphalan, thiotepa, topotecan, vincristine)	II	Recruiting	NCT03786783	• Enrollment of 45 participants in this study, and this study includes experimental arm (chemotherapy, dinutuximab, sargramostim, ASCT, EBRT) (posted on https://clinicaltrials.gov) • Primary outcome measure includes toxicity rate and combined toxic death during treatment (posted on https://clinicaltrials.gov) • Secondary outcome measures for this trial include – determine response rate, event free survival and overall survival (posted on https://clinicaltrials.gov) • Eligible age for study – up to 30 years (adult, child) and all sexes are eligible for study (posted on https://clinicaltrials.gov/)
Dinutuximab	GD2	Immunotherapy (isotretinoin + sargramostim + IL-2)	II	Active, not recruiting	NCT02169609	• Enrollment of 25 participants in this trial study, and this study has primary outcome measures which include – assess the number of participants with serious and non-serious adverse effects, and on the other hand secondary outcome measure includes – estimate the relapse-free survival (posted on https://clinicaltrials.gov) • Eligible age for study – adult, child, older adult, and all sexes are eligible for study (posted on https://clinicaltrials.gov/)
Isotretinoin	Unknown	Dinutuximab, aldesleukin and sargramostim	III	Active, not recruiting	NCT00026312	• Serious side effects of regimen A–RA only: cardiac disorders, eye disorders, nausea, vomiting, small intestinal obstruction, allergic reaction, anaphylaxis, lymphocyte count decreased (posted on https://clinicaltrials.gov). • Serious side effects of regimen B (RA + immunotherapy): anemia, eye disorders, abdominal pain, diarrhea, fever, allergic reaction, anaphylaxis, sepsis, anorexia, hypokalemia, hyponatremia, urticaria, hypotension, respiratory, thoracic and mediastinal disorders and vascular disorders (posted on https://clinicaltrials.gov). • Immunotherapy (isotretinoin, GM-CSF, ch14.18 and IL-2) found superior to standard therapy (isotretinoin) in terms of rates of event-free survival.32
Hu14.18K32A	GD2	Cyclophosphamide and topotecan	II	Active, not recruiting	NCT01857934	• Significant natural killer (NK) cytopenia caused due to chemoimmunotherapy, and complete recovery of NK cells takes place by the 21st day of each therapy cycle and autoHCT.321 • Cytotoxicity of NK cells increased during treatment compared to diagnosis, and such cells conserve their ability to respond to cytokine stimulation.321 • 2 patients groups differ in therapy responses and primary tumor size were identified employing cluster analysis of CD56bright NK cell count and tumor volume.321
Hu3F8	GD2	GM-CSF	I/II	Recruiting	NCT01757626	• Treatment with hu3F8 and GM-CSF was outpatient without unexpected toxic effects and with reversible neuropathic pain.295 • Maximum tolerated dose was not identified.295 • Dose escalation was correlated to augmented serum levels and proceeded through a 9.6 mg/kg/cycle dosage.295 • Out of 31 patients: (i) 5(16%) had stable disease, (ii) 14(45%) had partial response or complete remission, (iii) 1(3%) experienced dose-limiting toxicity (DLT), and (iv) 11 (35%) showed early progressive disease.295
Hu3F8	GD2	Sargramostim	II	Active, not recruiting	NCT00072358	• PRES (posterior reversible encephalopathy syndrome) was diagnosed in 2.3% of patients (5 of 215), including 2 of 55 patients who obtained HD-3F8 and 3 of 160 patients who obtained SD-3F8.322 • PRES occurred in 3 of 26 patients (such patients’ prior treatment included external beam radiotherapy to the brain) compared to 2 of 189 patients (such patients did not receive prior brain irradiation).322 • In 12 of 215 patients (5.6%), hypertension reached grade 3 toxicity, with 7 patients without PRES and 5 patients with PRES.322 • Frequency of all five activation markers (CD11a, CD11b, CD63, CBRM1/5, CD87) was significantly higher in day 4 peripheral blood (PB) samples of cycle 1 of GM-CSF plus anti-GD2 Ab 3F8 as compared to day 0 PB samples.323 • Progression free survival (PFS) is correlated to CBRM1/5-positive granulocytes and increasing CBRM1/5-positive granulocytes as positive prognostic factor for PFS.323
Hu3F8	GD2	Sargramostim	I	Completed	NCT00450307	• Due to drug supply limitations, dose escalation stopped at 160 mg/m2/day, and there were no dose-limiting toxicity (DLT), including absence of hypertension.324 • Human anti-mouse antibody (HAMA) titer was uncommon if the treatment of 3F8 began less than 90 days after high dose alkylator-based therapy.324 • HAMA developed in approx. 40% of patients after one cycle of 3F8 if the initial 3F8 exposure occurred ≥90 days after high-dose alkylator-based therapy.324 • Anti-neuroblastoma activity was observed at all dosages, and mainly in those patients treated for refractory disease in comparison to progressive disease.324
Bevacizumab	VEGF-A	Irinotecan and temozolomide	II	Completed	NCT01114555	• Out of 34 participants, 3 patients (8.8%) have complete response, 18 patients (52.9%) have no response, 12 patients (35.3%) have progressive disease, and 1 patient (2.9%) was not treated (posted on https://clinicaltrials.gov/). • Median overall survival (OS) and progression-free survival were 31.5±5.6 and 7.7±1.7 months, respectively.297 • Grade 4 toxicities include thrombocytopenia and neutropenia; and grade 3 toxicities were transaminitis, hepatic proteinuria, and diarrhea (3%).297
Bevacizumab	VEGF-A	Cyclophosphamide and topotecan	II	Completed	NCT01492673	• All-cause mortality was 77.78% (7/9 – affected/at risk) (posted on https://clinicaltrials.gov/) • Serious adverse effects include febrile neutropenia, lymphocyte count decreased, platelet count decreased, and gastrointestinal disorders (posted on https://clinicaltrials.gov/)
C7R-GD2.CART cells	GD2	Cyclophosphamide and fludarabine	I	Recruiting	NCT03635632	• Enrollment of 94 participants in this clinical trial, and this trial has primary outcome measure which determines MRD (maximum tolerated dose) of C7R-GD2.CART cells; and the secondary outcome measure is to determine the anti-tumor responses (posted on https://clinicaltrials.gov/) • Eligible age for study – 1 year to 74 years (adult, child, older adult), and all sexes are eligible for study (posted on https://clinicaltrials.gov/)
Zoledronic acid	Farnesyl pyrophosphate synthase	Cyclophosphamide	I	Completed	NCT00206388	• Enrollment of 21 participants in this study, and primary outcome measure includes to assess toxicity and determine maximum tolerated dose, and secondary outcome measures focused to investigate anti-tumor activity, and pharmacokinetics in patients (posted on https://clinicaltrials.gov/) • Eligible age for this study – up to 30 years (adult, child) and all sexes are eligible for study (posted on https://clinicaltrials.gov/)
Zoledronic acid	Farnesyl pyrophosphate synthase	IL-2	I	Terminated	NCT01404702	• Enrollment of 4 participants in this study, and primary outcome measure is to evaluate the toxicity and safety of aldesleukin and zoledronic acid (posted on https://clinicaltrials.gov) • Secondary outcome measures include – (1) evaluate the biologic function of autologous activated/expanded gamma delta T cells in NB patients receiving aldesleukin and zoledronic acid; (2) evaluate immune phenotype of in vivo activated/expanded autologous gamma delta T cells; and (3) evaluate tumor response in patients (posted on https://clinicaltrials.gov/)
MLN8237	Aurora A kinase	Irinotecan and temozolomide	I/II	Completed	NCT01601535	• Hematologic toxicities were common events, and patients were treated in phase II and oral solution cohorts.325 • In phase II, four partial responses were observed in 19 patients, and the estimated PFS at 1 year was 34%. The PFS was 20% in the OS group.325 • Alisertib oral solution had significantly higher median Cmax at 45 mg/m2 compared with tablets at 60 mg/m2.325 • Alisertib day 5 trough in the first cycle – associated with first cycle dose-limiting toxicity (DLT).325 • Patients having tumors with amplification of MYCN exhibited lower PFS as compared to patients without MYCN amplification.325
Difluoromethylornithine (DFMO)	Ornithine decarboxylase	Etoposide	I	Completed	NCT01059071	• DFMO dose between 500–1500 mg/m2 orally twice a day exhibits no dose limiting toxicities (DLTs).301 • A minor T-allele at rs2302616 of the ODC gene in the patients had higher baseline urinary polyamine levels, and, the total urinary polyamines are decreased during 1st cycle of DFMO therapy.301 • Patients having increased urinary polyamines exhibited less mean progression-free survival.301 • A minor T allele at rs2302616 of the ODC gene in the patients respond better to DFMO therapy as compared to individuals with major G allele at this locus.301
Difluoromethylornithine	Ornithine decarboxylase	Bortezomib	I/II	Active, not recruiting	NCT02139397	• Enrollment of 16 participants in this study. This study has primary outcome measures which include – determine the tolerability and safety of DFMO in combination with bortezomib and also determine the overall response rate (ORR) (posted on https://clinicaltrials.gov) • Secondary outcome measures include – determine the tolerability and safety of DFMO in combination with bortezomib; evaluate progression-free survival (PFS); correlate PET scan with PFS; and correlate urinary polyamine levels with response and progression of NB disease (posted on https://clinicaltrials.gov/)
Temsirolimus	mTOR	Temozolomide	II	Completed	NCT01767194	• Of the 35 patients, 17 patients were assigned to irinotecan- dinutuximab- temozolomide (arm 2), and 18 were assigned to irinotecan- temsirolimus- temozolomide (arm 1).326 • In arm 1, one patient achieved the partial response, and in arm 2, nine patients had objective responses, including five complete responses and four partial responses.326 • Grade 3 adverse events in arm 1 were neutropenia, anemia, thrombocytopenia, increased alanine aminotransferase, and hypokalaemia.326 • Grade 3 adverse events for arm 2 were pain, hypokalaemia, anemia, fever and infection, hypoxia, neutropenia, and thrombocytopenia.326 • Arm 2 met the protocol criteria for selection as combination therapy for neuroblastoma whereas arm1 did not.326
Temsirolimus	mTOR	Perifosine	I	Completed	NCT01049841	• Enrollment of 23 participants for this study; and the primary outcome measure includes – to determine the MTD of combination of temsirolimus and perifosine in patients (posted on https://clinicaltrials.gov) • Secondary outcome measures include – (1) record the efficacy of perifosine and temsirolimus combination, and (2) determine whether pharmacokinetic serum levels of both temsirolimus and perifosine correlate with toxicity (posted on https://clinicaltrials.gov) • Eligible age for study – up to 21 years (adult, child), and all sexes are eligible for study (posted on https://clinicaltrials.gov/)
Sorafenib	Multikinase inhibitor	Cyclophosphamide and topotecan	I	Active, not recruiting	NCT02298348	• Enrollment of 18 participants in this study; and the primary outcome measures include – (1) determine the MTD (maximum tolerated dose) of sorafenib for pediatric patients, and (2) determine the number and type of toxicities of sorafenib when administered in combination with topotecan and cyclophosphamide (posted on https://clinicaltrials.gov) • Eligible age for study – up to 30 years (adult, child) and all sexes eligible for this study (posted on https://clinicaltrials.gov/)
Nifurtimox	DNA	Cyclophosphamide and topotecan	II	Active, not recruiting	NCT00601003	• Enrollment of 112 participants in this study, and the primary outcome measure includes – assess the efficacy and safety of nifurtimox in combination with topotecan/ cyclophosphamide in NB patients (posted on https://clinicaltrials.gov) • Secondary outcome measures include – (1) assess the correlation between serum nifurtimox levels (in combination with topotecan / cyclophosphamide) with tumor response; (2) biology studies which focus on genome analysis of cells before and after treatment, biomarker development and flow cytometry of tumor in bone marrow (posted on https://clinicaltrials.gov) • Eligible age for study – up to 21 years (adult, child), and all sexes are eligible for this study (posted on https://clinicaltrials.gov/)
Bortezomib	26S proteasome	Irinotecan	I	Completed	NCT00644696	• Enrollment of 18 participants in this study, and the primary outcome measure is to determine the highest dose of IV irinotecan administered along with bortezomib without causing severe side effects (posted on https://clinicaltrials.gov) • Secondary outcome measure includes – measure the NB tumors after treatment with bortezomib and irinotecan to determine any change in tumor size (posted on https://clinicaltrials.gov) • Eligible age for this study include – 1 year to 25 years (adult, child), and all sexes are eligible for the study (posted on https://clinicaltrials.gov/)