2004 Sung et al. 2007 n = 20 n = 17 n = 25 Microbiologically documented Infections 4(20%) 9 (53%) 4 (16%) Presence of high fever (≥ 38.5oC) 20(100%) NR 14 (56%) Vomiting NR NR 10 (40%) Oropharyngeal mucositis 20 (100%) 17 (100%) 10 (40%) Diarrhea NR NR 12(48%) Elevation of liver enzyme NR NR 8(32%) Veno -occlusive disease NR NR 2(8%) Hyponatremia NR NR 5(20%) Hypokalemia NR NR 5(20%) Treatment related mortality 2(10%) 2(12%) 4(16%) Intracerebral hemorrhage 1(5%) NR NR Subgaleal hematoma 1(5%) NR NR Hepatotoxicity NR 5(29%) NR Nephrotoxicity NR 2(12%) NR Seizures NR 2(12%) NR Re-MATC H Protocol Page 64 of 106 Version: 20180628 clinical trials including one of our own is included above . Toxicities external to this list will be considered non - overlapping toxicity. 17.2 Immunotherapy Related Dose -limiting Toxicity 17.2.1 PHASE II TOXICITY MONITORING The stopping rules described below for monitoring dose -limiting toxicity and treatment- related mort ality during the Phase II trial are guidelines for determining whether accrual should be formally suspended and the data carefully reviewed. 17.2.2 M ONITORING OF NON-OVERLAPPING VACCINE RELATED TOXICITY Dose -limiting toxicity rates of 5% or less are considered desirable while rates of 20% or greater are considered undesirable. The statistical hypothesis that will be tested will differentiate between a 5% (alternative hypothesis) and 20% (null hypothesis) rate of unacceptable toxicity. Stopping rules based upon boundaries proposed by Pocock will be used to monitor this study. If the following thresholds for DLT ratios are satisfied (≥3/5, ≥4/15, ≥4/25, ≥5/35), then the study will be suspended and the data reviewed carefully. The type I and type II errors associ ated with this testing/monitoring are 0.025 and 0.019, respectively. 17.2.3 M ONITORING OF VACCINE RELATED MORTALITY Accrual will be automatically terminated in the following situations: (1) The occurrence of any vaccine - related death, or (2) The occurrence of any death more than 100 days post -transplant that is not due to tumor progression (or other readily identifiable unrelated cause of death (i.e., motor vehicle accident). A review by the DSMB and IRB along with discussion with the PI will ensue to dete rmine whether accrual to this trial would continue. 17.2.4 MONITORING OF CHEMOTHERAPY -RELATED MORTALITY During the 100 day period post -transplant, there is concern that the administration of vaccines will exacerbate chemotherapy -related mortality. Based upon our experience, a mortality rate of 3 -5% is expected with the administration of HDC followed by transplantation without vaccination. If the true rate of chemotherapy - related mortality with the novel treatment regimen during the 100 day period w as 10% or gr eater the regimen would be considered unacceptable for further clinical development due to excessive toxicity unless significant modifications were made to mitigate the rate of chemotherapy -related mortality. If that percentage were 2.5% or less, the treatment regimen would have an acceptable toxicity mortality rate. Monitoring and decision rules have been developed to differentiate between a 2.5% (alternative hypothesis) and 10% (null hypothesis) rate of chemotherapy -related mortality. Boundaries define d by Pocock will be used to monitor this study. If the following thresholds are satisfied (≥2/5, ≥2/15, ≥2/25, ≥2/35), the study will be terminated due to excessive toxicity. The type I error or probability of concluding that the treatment regimen is saf e from the perspective of chemotherapy -related mortality when it is truly unsafe is 0.05. The type II error rate, or probability of concluding that there is excessive treatment -related mortality when the treatment is safe, is 0.12. These monitoring rules were generated using S+ SeqTrial (S+ SeqTrial 2 User’s Manual, Insightful Corporation, Seattle, WA) using the alternative variance method. 17.3 Management of Toxicities A DLT will be defined as a drug -related Grade IV toxicity or any non -neurologic toxicity ≥ Grade III of any duration. A Grade III neurologic toxicity will only be declared a DLT if not reversible within 48 hours. Only patients receiving at least 3 vaccines without toxicity will be considered as safe for MTD assessment. Patients receiving less than 3 vaccines without toxicity will be replaced for safety assessments. If toxicity is encountered before the 3 rd vaccine, this will still be considered a DLT. Although not considered a DLT, any patient with ≥ Grade II u rticaria will not receive fur ther vaccines and will be withdrawn from the study. Any Grade IV toxicity Re-MATC H Protocol Page 65 of 106 Version: 20180628 or any life -threatening event not attributable to a concomitant medication, co -morbid event, or disease progression, even if reversible, will be considered a DLT. If biopsy cannot be obtained, any new radiographic or clinical changes not attributable to tumor progression that produce a Grade IV or life -threatening toxicity will be considered at DLT. Life -threatening events, as described above, even if considered a Grade III toxicit y, will still be considered a DLT even if reversible and in such cases no further vaccinations will be given. If a Grade III NCI CTC toxicity is seen that is not attributable to a concomitant medication, co -morbid event, or disease progression that has been documented radiographically or clinically, the next immunization for that patient will be withheld for up to 2 months or until the NCI CTC toxicity improves to a Grade II or until the KPS score returns to within 10 points of baseline. Grade III neurologic toxicities will be declared irreversible if they cannot be reversed within 48 hours of their onset. If the event cannot be reversed within 48 hours of its onset, a DLT will be declared for that patient and no further vaccinations or study -related procedures will be performed. If the event is reversed, but Grade III NCI CTC toxicity is again seen with subsequent vaccination s, all further vaccinations and study -related procedures will be withheld and a DLT will be declared. Medical therapy may be used to reverse any toxicity if necessary, but any episode of a toxicity requiring surgical intervention will still be considered a DLT even if reversible by surgery. This study will be halted if a total of 2 patients experience a study -related DLT. Grade III or greater toxicities associated with DC -based immunotherapy have been rare. Adoptive T cell therapy using tumor -infiltrating lymphocytes and high- dose IL -2 in patients with melanoma and treatment with anti-CLTA -4 monoclonal antibody blockade have been the immunotherapy regimens most often associated with treatment related toxicities. To take the most conservative approach to a ssessing possible toxicities associated with this treatment, we will be vigilant for any similar toxicity associated with this therapy, in addition to autoimmune toxicity specific to the CNS. Possible immune -mediated disorders that have been observed in patients who have received immunotherapy in early phase trials have involved the skin (vitiligo and cutaneous leukocytoclastic vasculitis), the thyroid gland (autoimmune thyroiditis), the liver (autoimmune hepatitis) and the pituitary (hypophysitis). Abnorma l lab results, which may be immune -mediated, include elevations of serum lipase and amylase and liver function tests. If a patient has an AE that is thought to be possibly related to autoimmune antibodies (eg, thyroiditis, hepatitis, thrombocytopenia) the PI will send a blood sample for appropriate autoimmune antibody testing. If specific autoantibodies are present, the serum sample taken for storage at baseline will be tested for the presence of those autoantibodies. Further immunotherapy treatment in that patient will be held until the etiology of the event is established. Continuation of DC + xALT therapy in the presence of Grade III or greater immune -mediated events should be done by the PI only after discussion with the patient, medical monitor, and DSM B on a case- by-case basis with consideration to risk -benefit analysis. The IRB will be notified promptly and will review the event and determine whether the problem does or does not represent an unanticipated risk to the study participants. If review dete rmines that unanticipated increased risk did occur a revised consent form stating such a risk will be drafted, approved by the IRB and prior to continued therapy will require the patient to be re- consented with the revised consent. In the case of hypersen sitivity reactions, treatment measures deemed medically appropriate will be initiated and the PI notified of the event. The following treatment recommendations may be applicable and can be adopted at the judgment of the supervising pediatrician: CTCAE (Co mmon Terminology Criteria for Adverse Events) v.4.0 Grade I allergic reaction (transient flushing or rash, drug fever <38°C ; intervention not indicated): -Supervise at the bedside. CTCAE v. 4.0 Grade II allergic reaction (intervention or infusion interruption indicated; responds promptly to symptomatic treatment; prophylactic medications indicated for < 24 hours ): -Interrupt the infusion of xALT and disconnect infusion tubing from patient. Do not inject any remaining DC s. Re-MATC H Protocol Page 66 of 106 Version: 20180628 -Administer IV antihistamines (diphenhydramine 1mg/kg and ranitidine 3 mg/kg). -After recovery of symptoms, resume the infusion at half the initial infusion rate.