NANT 2021-01 Phase II STING (Sequential Temozolomide, Irinotecan, NK Cells and GD2 mAb) Trial

Inclusion Criteria:

• Patients must be ≥ 1 year and ≤31 years of age at the time of enrollment on thestudy.

• Patients must have a diagnosis of neuroblastoma either by histologic verification ofneuroblastoma and/or demonstration of tumor cells in the bone marrow with increasedurinary catecholamines.

• Patients must have high-risk neuroblastoma according to COG risk classification atthe time of study registration. Patients whose disease was initially considered lowor intermediate risk but then reclassified as high-risk neuroblastoma prior toenrollment also meet this criteria.

• Patients must have at least ONE of the following:

1. Recurrent/progressive disease after the diagnosis of high risk neuroblastoma atany time prior to enrollment - regardless of response to frontline therapy. (Note that this excludes patients initially considered low or intermediate riskthat progressed to high risk disease but have not progressed after thediagnosis of high risk neuroblastoma).

2. If no prior history of recurrent/progressive disease since the diagnosis ofhigh-risk neuroblastoma,

2a) Refractory disease: A best overall response of no response/stable disease sincediagnosis of high-risk neuroblastoma AND after at least 4 courses of inductiontherapy.

2b) Persistent disease: A best overall response of partial response since diagnosisof high-risk neuroblastoma AND after at least 4 courses of induction therapy

• Patients must have at least ONE of the following (lesions may have received priorradiation therapy as long as they meet the other criteria listed below) based oninstitutional assessment:

1. Bone Sites

1. a) MIBG avid tumors: patients must meet one of the following criteria: a. Patients with recurrent/progressive or refractory disease: i. Must have atleast one MIBG avid bone site on planar imaging OR ii. Must have > 2 avid bonelesions on SPECT. iii. A biopsy is not required unless the above imagingcriteria are not met. b. Patients with persistent disease: i. If a patient has 3 or more MIBG avid sites by planar or SPECT imaging (including soft tissueand/or bone), then no biopsy is required. ii. If a patient has only 1 or 2 MIBG avid sites by planar or SPECT imaging (including soft tissue and/or bone) then biopsy confirmation of neuroblastomaand/or ganglioneuroblastoma in at least one MIBG avid site present at the timeof enrollment is required. Bone lesions may be biopsied at any time point priorto enrollment.

1b) For MIBG non-avid tumors, patients must have biopsy confirmation ofneuroblastoma and/or ganglioneuroblastoma from a lesion at any time prior toenrollment of at least one site (with or without FDG-PET uptake).

2. Bone Marrow Any amount of tumor cells in the bone marrow (includingneuroblasts, mature and maturing ganglion cells) done at the time of studyenrollment based on routine morphology and/or immunohistochemistry in at leastone sample from bilateral aspirates and biopsies.

3. Soft Tissue Sites

3a) At least one soft tissue lesion that meets criteria for a TARGET lesion asdefined by:

1. SIZE: Lesion can be accurately measured in at least one dimension with alongest diameter ≥ 10 mm, or for discrete lymph nodes ≥ 15mm on short axis.Lesions meeting size criteria will be considered measurable.

2. In addition to size, a lesion needs to meet ONE of the following criteriaexcept for patients with parenchymal CNS lesions which will only need to meetsize criteria:

3. For MIBG avid tumors: lesion must be MIBG avid and meet one of thefollowing criteria:

4. For patients with recurrent/progressive or refractory disease: i. No biopsy is required

5. For patients with persistent disease: i. If a patient has 3 or more MIBG avid sites by planar or SPECT imaging (including soft tissue and/or bone), then no biopsy is required. ii. If a patient has only 1 or 2 MIBG avid sites by planar or SPECT imaging (including soft tissue and/or bone), then biopsy confirmation of neuroblastomaand/or ganglioneuroblastoma in at least one MIBG avid site present at the timeof enrollment is required. Soft tissue lesions may be biopsied at any timepoint prior to enrollment. b. For MIBG non-avid tumors, patient must have biopsy confirmation ofneuroblastoma and/or ganglioneuroblastoma at any time prior to enrollment fromsoft tissue lesion (with or without FDG uptake) present at time of enrollment.

3b) At least one non-target soft tissue lesion that is not measurable, but had abiopsy positive for neuroblastoma and/or ganglioneuroblastoma at any time prior toenrollment OR is MIBG avid on planar imaging.

• Patients must have a Lansky (≤ 16 years) or Karnofsky (> 16 years) score of ≥ 50 (Appendix I).

Note: Patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.

• Patients must have fully recovered from the acute toxic effects of all priorchemotherapy, immunotherapy, or radiotherapy prior to study registration.

• Patients must not have received the therapies indicated below after diseaseevaluation or within the specified time period prior to registration on this studyas follows:

1. Myelosuppressive chemotherapy: must not have received within 2 weeks prior toregistration.

2. Biologic anti-neoplastics- agents not known to be associated with reducedplatelet or ANC counts (including retinoids): must not have received within 7days prior to registration.

3. Monoclonal antibodies: must not have received last dose within 14 days ofregistration and resolution of all toxicities.

4. Cellular Therapy (e.g. modified T cells, NK cells, dentritic cells etc.): mustnot have received within 3 weeks and resolution of all toxicities.

5. Radiation: must not have received small port radiation within 7 days prior toregistration, large field radiation within 12 weeks, and 131I-MIBG therapy orother radiopharmaceutical within 6 weeks.

6. Hematopoietic Stem Cell Transplant- none following myeloblative therapy within 6 weeks

7. Any other investigational agents (covered under another IND within 14 days

8. Strong inducers or inhibitors of CYP3A4

• Hematologic Function:

NOTE: No short acting hematopoietic growth factors within 7 days of blood draw documenting eligibility and no long-acting hematopoietic growth factors within 14 days of blood draw documenting eligibility

1. Absolute Neutrophil count ≥750/µL

2. Platelet count ≥ 75,000/µL, transfusion independent (no platelet transfusions within 7 days of blood draw documenting eligibility)

Patients with known bone marrow metastatic disease will be eligible for study as long as they meet hematologic function criteria above.

• Renal Function Patients must have adequate renal function defined as age-adjustedserum creatinine ≤1.5 ULN for age

• Liver Function

1. Total bilirubin ≤ 1.5 x ULN for age; and,

2. SGPT (ALT) ≤ 135 U/L (≤ 3x ULN). Note that for ALT, the upper limit of normalfor all sites is defined as 45 U/L.

• Cardiac Function

1. Normal ejection fraction (≥ 55%) documented by either echocardiogram OR

2. Normal fractional shortening (≥ 27%) documented by echocardiogram

• Pulmonary Function No evidence of dyspnea at rest

• Reproductive Function All females ≥ Tanner stage 2 and post-menarchal ofchildbearing potential must have a negative beta-HCG within 7 days prior to studyregistration. Males and females of reproductive age and childbearing potential mustcommit to using effective contraception for the duration of their participation.

• Central Nervous System (CNS) Patients with a history of intraparenchymal orleptomeningeal based CNS disease must have no clinical or radiological evidence ofactive CNS disease at the time of study enrollment.

Patients with skull-based tumors with direct intracranial extension are eligible as long as there are no neurologic signs or symptoms related to the lesion.

Exclusion Criteria:

• Patients who are pregnant, breast feeding, or unwilling to use effectivecontraception during the study

• Patients who, in the opinion of the investigator, may not be able to comply with thesafety monitoring requirements of the study.

• Patients with disease of any major organ system that would compromise their abilityto withstand therapy.

• Patients with > Grade 2 diarrhea.

• Patients who have undergone a prior allogeneic stem cell or solid organ transplant.

• Patients who are on hemodialysis.

• Patients with an active or uncontrolled infection. Patients on prolonged antifungaltherapy are still eligible if they are culture negative, afebrile, and meet otherorgan function criteria.

• Patients with known history of human immunodeficiency virus (HIV) infection,hepatitis B, or hepatitis C. Testing is not required in the absence of clinicalfindings or suspicion.

• Patients must not have been diagnosed with any other malignancy.

• Patients with history of Grade 4 Allergic reactions to anti-GD2 antibody therapy orreactions that caused permanent discontinuation of therapy.

• Patients with history of progressive disease while receiving therapy per ANBL1221.

• Patient declines participation in the NANT biology study and the site has not beengranted a waiver from participation.

• Systemic Steroids and Immunosuppressive Medications

• Patients who have received pharmacologic doses of systemic steroids 7 days prior tostudy registration or likely to require them after study registration.

Note: Exceptions are the following:

1. Patients known to require 2 mg/kg or less of hydrocortisone (or an equivalent doseof an alternative corticosteroid) as premedication for blood product administration.

2. The use of conventional doses of inhaled steroids for the treatment of asthma

3. The use of physiologic doses of steroids for patients with known adrenalinsufficiency.

• Patients on any other immunosuppressive medications (e.g., cyclosporine,tacrolimus) at the time of study registration.