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 or osteosarcoma 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 or osteosarcoma.

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 or osteosarcoma.
II. To define the toxicities of allogeneic expanded gamma-delta T cells when delivered with dinutuximab, temozolomide, irinotecan and zoledronate.

SECONDARY OBJECTIVE:
I. To preliminarily define the antitumor activity of allogeneic expanded gamma-delta T cells when delivered with dinutuximab, temozolomide, irinotecan, and zoledronate within the confines of a phase I study

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, computed tomography (CT) or magnetic resonance imaging (MRI), and may undergo bone marrow aspiration and biopsy, 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. Histological confirmation of neuroblastoma or ganglioneuroblastoma at initial diagnosis. Bone marrow samples with positive catecholamines are acceptable as confirmation of neuroblastoma OR histological confirmation of osteosarcoma at diagnosis
3. High-risk neuroblastoma with refractory, relapsed or progressive disease, defined as: * First or greater relapse of neuroblastoma following completion of aggressive multi-drug frontline therapy * First episode of progressive neuroblastoma during aggressive multi-drug frontline therapy * Persistent/refractory neuroblastoma as defined by less than a complete response by the revised International Neuroblastoma Response Criteria (INRC) at the conclusion of at least 4 cycles of aggressive multidrug induction chemotherapy on or according to a high-risk neuroblastoma protocol (such as A3973 or ANBL0532) * Note that this excludes patients initially considered low or intermediate risk neuroblastoma that progressed to high risk disease but the patient has not progressed after the diagnosis of high risk neuroblastoma. OR Relapsed or refractory osteosarcoma that is not responsive to standard treatment
4. Patient must have measurable or evaluable disease per Revised INRC for subjects with neuroblastoma or measurable or evaluable disease by Response Evaluation Criteria In Solid Tumors Criteria (RECIST) v1.1 criteria for subjects with osteosarcoma
5. Patients must have a Lansky (=< 16 years) or Karnofsky (> 16 years) score of >= 50
6. 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 * Prior T cell therapy is excluded
7. Patients must not have received the therapies indicated below within the specified restricted time period prior to study registration: * Myelosuppressive chemotherapy =< 14 days. This includes cytotoxic agents given on a low dose metronomic regimen as well as retinoids * Biologic antineoplastic =< 7 days. This includes cytotoxic agents given on a low dose metronomic regimen as well as retinoids * Monoclonal antibodies =< 7 days or 3 half-lives whichever is longer, but no longer than 30 days (with recovery of any associated toxicities) * Cellular therapy (e.g., natural killer [NK] cells, dendritic cells, etc.) =< 21 days and with recovery of all associated toxicities * Small port radiation =< 7 days * Large field radiation therapy =< 12 weeks i.e., total body irradiation, craniospinal, whole abdominal, total lung, > 50% marrow space * Other substantial bone marrow radiation =< 6 weeks * Iobenguane I-131 (131I-MIBG) therapy =< 6 weeks * Autologous stem cell infusion following myeloablative therapy =< 6 weeks. Patients who have received an autologous stem cell infusion to support non-myeloablative therapy (such as 131I-MIBG) are eligible at any time as long as they meet the other criteria for eligibility * Any other investigational agents (covered under another investigational new drug [IND]) =< 14 days
8. Patients must not have received the concomitant medications indicated below within the specified time period prior to study registration or planned treatment start date on this study as follows: * Other anti-cancer agents or radiotherapy at time of study registration or while on study * Systemic corticosteroids at pharmacologic doses 7 days ** Inhaled steroids are permitted to treat asthma ** =< 2mg/kg of hydrocortisone or equivalent is permitted as blood product premedication to avoid allergic reactions ** Physiologic dosing is permitted for patients with known adrenal insufficiency * Intravenous immunoglobulin therapy (IVIG) 14 days before planned treatment start date
9. Immunosuppressive drugs (other than corticosteroids used to treat side effects of protocol therapy) are not allowed during protocol therapy. Dexamethasone should be avoided as an anti-nausea/antiemetic therapy
10. Corticosteroid therapy should be utilized only for life threatening conditions
11. No other cancer chemotherapy, immunomodulating agents, or biologics can be used during protocol therapy
12. External beam radiation therapy can NOT be used during protocol therapy
13. Appropriate antibiotics, blood products, anti-emetics, fluids, electrolytes and general supportive care are to be used as necessary for good patient care
14. IVIG should not be given while patient is receiving protocol therapy
15. 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)
16. Platelet count >= 75,000/ul, transfusion independent (no platelet transfusions or platelet growth factors =< 7 days of blood draw documenting eligibility)
17. 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
18. Total bilirubin =< 1.5 x ULN for age
19. 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,
20. Maximum aspartate aminotransferase (AST) < 5 X ULN
21. Normal ejection fraction (>= 55%) documented by either echocardiogram or radionuclide multigated acquisition scan (MUGA) evaluation OR Normal fractional shortening (>= 27%) documented by echocardiogram
22. Normal pulmonary function with no evidence of dyspnea at rest, no exercise intolerance

Treatment Sites in Georgia