TGFbeta-imprinted Natural Killer Cells in Combination with Irinotecan, Temozolomide, and Dinutuximab for the Treatment of Patients with Relapsed or Refractory Neuroblastoma, Allo-STING Trial

Inclusion Criteria

• Less than 30 years of age when registered on the study
• Patients must have histologic verification of neuroblastoma (NBL) or ganglioneuroblastoma or NBL cells in bone marrow with or without elevated urine catecholamines (> 2 x upper limit of normal [ULN])
• One of the following is required * Recurrent disease or * First episode of progressive disease (new lesion, increase in size, previous negative bone marrow positive) during initial multi-drug, induction myelosuppressive therapy; or * Primary resistant/refractory disease (partial, mixed, stable response criteria met) after completing at least 4 cycles of induction multi-drug induction chemotherapy
• Life expectancy > 2 months
• Disease documentation (ONE of the following required): * Patients must have measurable or evaluable tumor, defined as: ** Measurable tumor on MRI or CT obtained within 4 weeks prior to study entry; Measurable is defined as >= 10mm in at least one dimension AND that has positive uptake on iobenguane sulfate I-123 (I-123) MIBG scan (“MIBG avid”) or demonstrates increased FDG uptake on 18F-FDG PET-CT or PET-MRI (“PET-avid”); or ** Evaluable tumor by I-123 MIBG scan within 4 weeks prior to study entry, defined as positive uptake at a minimum of one site; * Measurable or evaluable disease must represent recurrent disease after therapy completion or progressive disease on therapy or refractory disease during induction; * Patients with refractory disease that are not avid on MIBG scan and do not have increased FDG uptake on PET must have biopsy proven viable NBL; * New soft tissue sites that are MIBG avid or PET avid do not require biopsy as long as initial histologically-confirmed NBL diagnosis prior to current therapy
• Patients must have progressed during or following completion of frontline therapy. Agents considered to be a part of frontline therapy would include chemotherapy, radiation therapy, autologous stem cell transplantation, retinoids, immunotherapy with anti GD2 agents, cellular therapies, or iobenguane I-131 (I-131) MIBG or any combination of these agents defined in published regimens or current cooperative group clinical trials for the successful treatment of neuroblastoma. Therapy may not have been received more recently than the timeframes defined below, and criteria need to be met prior to enrollment: * Myelosuppressive chemotherapy ** At least 14 days since completion of myelosuppressive therapy * Biologic ** At least 7 days since completion of therapy with non-myelosuppressive biologic or retinoid * Radiation ** At least 4 weeks since completion of radiation to any site identified as a target lesion ** Palliative radiation is allowed to sites not used to measure response * Stem cell transplant (SCT) ** At least 6 weeks after autologous stem cell transplant or stem cell infusions as long as hematologic criteria have been met * Iobenguane I-131 (131I)-MIBG therapy ** At least 6 weeks after therapeutic MIBG treatment * Cellular therapies ** At least 6 weeks after any cellular therapy treatment (e.g., prior NK, chimeric antigen receptor T-cell [CAR-T] therapy)
• Subjects who have previously received anti-GD2 monoclonal antibodies for biologic therapy or for tumor imaging are eligible
• Subjects who have received autologous marrow infusions or autologous stem cell infusions that were purged using monoclonal antibody linked to beads are eligible
• Patients must not have progressed during prior treatment with irinotecan and/ or temozolomide
• Peripheral absolute neutrophil count (ANC) >= 500/uL. Patients must not have received long-acting myeloid growth factors (e.g., Neulasta [trademark]) within 14 days or short-acting myeloid growth factors (e.g., Neupogen [trademark]) within 7 days of study entry
• Platelet count >= 50,000/uL (transfusion independent for at least 1 week), use of thrombopoietin (TPO) agonists is not permitted
• Adequate renal function defined as: * Creatinine clearance or estimated radioisotope glomerular filtration rate (GFR) >= 70 ml/min/1.73m^2 or * Serum creatinine < 2 x upper limit of normal (ULN) based on age/gender as follows: ** 1 month to < 6 months: Male 0.4 mg/dL or Female 0.4 mg/dL ** 6 months to < 1 year: Male 0.5 mg/dL or Female 0.5 mg/dL ** 1 to < 2 years: Male 0.6 mg/dL or Female 0.6 mg/dL ** 2 to < 6 years: Male 0.8 mg/dL or Female 0.8 mg/dL ** 6 to <10 years: Male 1 mg/dL or Female 1 mg/dL ** 10 to < 13 years: Male 1.2 mg/dL or Female 1.2 mg/dL ** 13 to < 16 years: Male 1.5 mg/dL or Female 1.4 mg/dL ** > 16 years: Male 1.7 mg/dL or Female 1.4 mg/dL
• Total bilirubin < 1.5 x ULN for age
• Serum glutamic pyruvic transaminase (SGPT) (alanine aminotransferase [ALT]) =< 5 x ULN for age (or =< 225 U/L). For purpose of this study, the ULN for SGPT (ALT) is 45 U/L
• Patients with seizure disorders may be enrolled if seizures are well controlled on anti-convulsants
• Central nervous system (CNS) toxicity =< Grade 2
• Adequate cardiac function as defined as: * Shortening fraction of >= 27% by ECHO OR * Ejection fraction >= 50% by ECHO or gated radionuclide study
• No evidence of dyspnea at rest, no exercise intolerance, no chronic oxygen requirement

Exclusion Criteria

• Female patients of childbearing potential (post-menarche) should have a negative urine or serum pregnancy test within 24 hours prior to starting a new cycle. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. Female patients of childbearing potential (post-menarche) should be willing to use 2 methods of birth control or be surgically sterile or abstain from heterosexual activity from the beginning of the study through 120 days after receiving the last dose of study medication. Patients of childbearing potential are those who have not been surgically sterilized and have reached menarche. Non-pregnant, non-breastfeeding women may be enrolled if they are willing to use 2 methods of birth control or are considered highly unlikely to conceive. Highly unlikely to conceive is defined as 1) surgically sterilized, or 2) premenarchal (a female who has not yet had a menstrual cycle is considered premenarchal) or 3) not heterosexually active for the duration of the study. The 2 birth control methods can be either: two barrier methods or a barrier method plus a hormonal method to prevent pregnancy. Patients should start using birth control from day 1 to 120 days after receiving the last dose of study therapy. The following are considered adequate barrier methods of contraception: diaphragm, condom (by the partner), copper intrauterine device, sponge, or spermicide. Appropriate hormonal contraceptives will include any registered and marketed contraceptive agent that contains an estrogen and/or a progestin agent (including oral, subcutaneous, intrauterine, or intramuscular agents). Patients should be informed that taking the study medication may involve unknown risks to the fetus (unborn baby) if pregnancy were to occur during the study. In order to participate in the study they must adhere to the contraception requirement (described above). If there is any question that a patient will not reliably comply with the requirements for contraception, that patient should not be entered into the study. Male patients should agree to use an adequate method of contraception from the beginning of the study through 120 days after receiving the last dose of study medication
• Patients with elevated catecholamines (i.e., > 2 x ULN) only are NOT eligible for this study
• Patients must not have received 0.5 mg/ kg/ day (prednisone equivalent) doses of systemic steroids for at least 7 days prior to enrollment. Patients with CNS involvement may be eligible if steroids can be tapered off within 7 days prior to start of treatment
• Patients must not have received CYP3A4 inducer or inhibitor for at least 7 days prior to study enrollment
• Patients must not have been diagnosed with any other malignancy
• Patients must not have > Grade 2 diarrhea
• Patients must not have uncontrolled infection
• Patients with history of Grade 4 allergic reactions to anti-GD2 antibodies or reactions that required discontinuation of anti-GD2 therapy are not eligible
• Patients with a significant illness that is not covered by the exclusion criteria or that is expected to interfere with the action of study agents or to increase the severity of the toxicities experienced from the study treatment are not eligible