Summary

This phase I trial studies the side effects and best dose of donor immune cells (allogenic ex vivo expanded gamma-delta T cells) when given together with dinutuximab, temozolomide, irinotecan and zoledronate in treating children with neuroblastoma that does not respond to treatment (refractory), that has come back (relapsed), or that is growing, spreading, or getting worse (progressive). Donor gamma-delta T cells are immune cells taken from a healthy donor and infused back into the body for treatment. Donor gamma-delta T cells work in the body by activating the body's immune system to create more healthy cells that will directly kill the tumor cells. Dinutuximab is a drug that has been approved by the Food and Drug Administration (FDA) for treating newly diagnosed patients with neuroblastoma who complete other therapy and it has also been used to treat patients with relapsed/ refractory neuroblastoma. It is a monoclonal antibody. Monoclonal antibodies are proteins made in the laboratory (lab), designed to attach to specific targets on cancer cells. Dinutuximab was designed to attach to a target called GD-2 that is common on neuroblastoma cells. When dinutuximab attaches to the GD-2 target on neuroblastoma cells, the gamma-delta T cells can be stimulated to attack and kill the neuroblastoma cells. Temozolomide is a chemotherapy that is commonly given to neuroblastoma patients at relapse. Irinotecan is in a class of antineoplastic medications called topoisomerase I inhibitors. It blocks a certain enzyme needed for cell division and DNA repair and may kill cancer cells. Clinical trials showed that patients had much better tumor responses to dinutuximab given with temozolomide compared to other dinutuximab combinations in the same study, leading to this combination being studies in patients with newly diagnosed high risk neuroblastoma. Zoledronate is a drug given by intravenous (IV) that has been approved by the FDA for the treatment of other cancers. Zoledronate has also been used and safely given to children with solid tumor cancers such as neuroblastoma. Zoledronate has been found in lab tests to make gamma-delta T cells more active in killing neuroblastoma tumor cells. Giving donor gamma-delta T cells dinutuximab, temozolomide, irinotecan and zoledronate may work better in treating children with refractory, recurrent, or progressive neuroblastoma.

Objectives

PRIMARY OBJECTIVES:
I. To determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of allogeneic expanded gamma-delta T cells when delivered with dinutuximab, temozolomide, irinotecan, and zoledronic acid (zoledronate) in children with refractory, recurrent, or progressive neuroblastoma.
II. To define the toxicities of allogeneic expanded gamma-delta T cells when delivered with dinutuximab, temozolomide, irinotecan and zoledronate.

SECONDARY OBJECTIVE:
I. To estimate, within the context of a phase I study, the clinical response rate to this combination regimen in patients with recurrent, refractory, or progressive neuroblastoma.

EXPLORATORY OBJECTIVES:
I. To determine if exhaustion markers (PD1, PDL-1, TIM3, TIGIT, LAG3, CD39) of the expanded product taken before freezing correlate with response and retention of product.
II. To determine if gamma-delta T cell-resident phenotypes correlates with response to therapy.
III. To determine the half-life of allogeneic gamma-delta T cells in the patient when given in this regimen.
IV. To determine effects on the innate immune system following treatment with dinutuximab, temozolomide, irinotecan, zoledronate and allogeneic gamma-delta T cells.

OUTLINE: This is a phase I dose-escalation study of allogeneic expanded gamma-delta T cells followed by a dose-expansion study.

Patients receive temozolomide orally (PO) once daily (QD) and irinotecan intravenously (IV) over 90 minutes on days 1-5, dinutuximab IV over 10 hours on days 2-5, zoledronate IV over at least 15 minutes on day 6, and allogeneic expanded gamma-delta T cells on days 6 and 13 for over 5-15 minutes. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients additionally undergo blood sample collection, multigated acquisition scan (MUGA) or echocardiography, bone marrow aspiration and biopsy, computed tomography (CT) or magnetic resonance imaging (MRI) and Iobenguane (MIBG) positron emission tomography (PET) on study.

After completion of the study treatment, patients are followed for 1 year.

Eligibility

1. Patients must be = 12 months of age at the time of enrollment on the study
2. Patients must have a diagnosis of neuroblastoma either by histologic verification of neuroblastoma and/or demonstration of tumor cells in the bone marrow with increased urinary catecholamines
3. Patients must have high risk neuroblastoma according to Children's Oncology Group (COG) risk classification at the time of study registration. Patients who were initially considered low or intermediate risk, but then reclassified as high risk are also eligible
4. Recurrent/progressive disease after the diagnosis of high risk neuroblastoma at any time prior to study registration – regardless of response to standard of care therapy. Note that this excludes patients initially considered low or intermediate risk that progressed to high risk disease but have not progressed after the diagnosis of high risk neuroblastoma
5. If no prior history of recurrent/progressive disease since the diagnosis of high risk neuroblastoma: * Refractory disease: A best overall response of no response/stable disease since diagnosis of high risk neuroblastoma AND after at least 4 courses of high risk neuroblastoma standard of care induction therapy * Persistent disease: A best overall response of partial response since diagnosis of high risk neuroblastoma AND after at least 4 courses of standard of care induction therapy: ** If a patient with persistent disease has 2 or more metaiodobenzylguanidine (MIBG) avid sites (including all soft tissue and/or bone lesions) OR a Curie Score of >= 2, then no biopsy is required for eligibility ** If a patient with persistent disease has only 1 MIBG avid site (including all soft tissue and/or bone lesions) then biopsy confirmation of neuroblastoma and/or ganglioneuroblastoma (bone marrow, bone, or soft tissue) is required. Bone and/or soft tissue lesions may be biopsied at any time point prior to study registration and subsequent to any prior therapy, bone marrow must be done at the time of study registration
6. MIBG avid tumors: patients must meet one of the following criteria: * Patients with recurrent/progressive or refractory disease: ** Must have at least one MIBG avid bone site. A biopsy is not required regardless of number of MIBG avid sites * Patients with persistent disease: ** If a patient has 2 or more MIBG avid bone lesions, then no biopsy is required ** If a patient has only 1 MIBG avid bone lesion site then biopsy confirmation of neuroblastoma and/or ganglioneuroblastoma in at least one MIBG avid site present at the time of enrollment is required. Bone lesions may be biopsied at any time point prior to enrollment
7. For MIBG non-avid tumors, patients must meet one of the following criteria: * Patients with recurrent/progressive or refractory disease: ** Anatomical imaging done at the time of enrollment consistent with a bone metastasis for at least one fludeoxyglucose (FDG)-avid bone site or biopsy confirmation of neuroblastoma and/or ganglioneuroblastoma at any time prior to enrollment of at least one FDG-PET avid site * Patients with persistent disease: ** Biopsy confirmation of neuroblastoma and/or ganglioneuroblastoma at any time prior to enrollment of at least one FDG-PET avid site
8. Any amount of tumor cells in the bone marrow (including neuroblasts, mature and maturing ganglion cells) done at the time of study enrollment based on routine morphology and/or immunohistochemistry in at least one sample from bilateral aspirates and biopsies
9. At least one soft tissue lesion that meets criteria for a TARGET lesion as defined by: * SIZE: ** Lesion can be accurately measured in at least one dimension with a longest diameter >= 10 mm, or for discrete lymph nodes >= 15mm on short axis. Lesions meeting size criteria will be considered measurable * In addition to SIZE, a lesion needs to meet ONE of the following criteria: ** For MIBG avid tumors: lesion must be MIBG avid and meet one of the following criteria: *** For patients with recurrent/progressive or refractory disease: no biopsy is required *** For patients with persistent disease: **** If a patient has 2 or more MIBG avid soft tissue lesions, then no biopsy is required **** If a patient has only 1 MIBG avid soft tissue lesion sites then biopsy confirmation of neuroblastoma and/or ganglioneuroblastoma in at least one MIBG avid site present at the time of enrollment is required. Soft tissue lesions may be biopsied at any time point prior to enrollment ** For MIBG non-avid tumors: *** A biopsy is required at any time prior to enrollment confirming neuroblastoma and/or ganglioneuroblastoma in at least one soft tissue site (even if FDG-PET avid)
10. Patients must have a Lansky (=< 16 years) or Karnofsky (> 16 years) score of >= 50
11. Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to study registration * Prior dinutuximab therapy is allowed regardless of prior response or progression on dinutuximab * Prior temozolomide therapy is allowed * Prior zoledronate is allowed * Prior dinutuximab/temozolomide chemoimmunotherapy is allowed as long as the patient did not progress on that therapy combination * Prior T cell therapy is excluded
12. Corticosteroid therapy should be utilized only for life threatening conditions
13. Appropriate antibiotics, blood products, anti-emetics, fluids, electrolytes and general supportive care are to be used as necessary for good patient care
14. Absolute neutrophil count (ANC) >= 750/uL (no short-acting hematopoietic growth factors =< 7 days of blood draw documenting eligibility and no long-acting hematopoietic growth factors =< 14 days of blood draw documenting eligibility)
15. Platelet count >= 75,000/ul, transfusion independent (no platelet transfusions or platelet growth factors =< 7 days of blood draw documenting eligibility)
16. Patients must have adequate renal function defined as age-adjusted serum creatinine =< 1.5 upper limit of normal (ULN) for age: * =< 5 years: 0.8 mg/dL * > 5 and =< 10 years: 1.0 mg/dL >10 and =< 15 years: 1.2 mg/dL > 15 years: 1.5 mg/dL
17. Total bilirubin =< 1.5 x ULN for age
18. Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 135 U/L (=< 3 x ULN). Note that for ALT, the upper limit of normal for all sites is defined as 45 unit per liter (U/L); and,
19. Maximum aspartate aminotransferase (AST) < 5 X ULN
20. Normal ejection fraction (>= 55%) documented by either echocardiogram or radionuclide multigated acquisition scan (MUGA) evaluation OR Normal fractional shortening (>= 27%) documented by echocardiogram
21. Normal pulmonary function with no evidence of dyspnea at rest, no exercise intolerance

Treatment Sites in Georgia