RecruitingPhase 1NCT05400603

Allogeneic Expanded Gamma Delta T Cells With GD2 Chemoimmunotherapy in Relapsed /Refractory Neuroblastoma or Refractory/ Relapsed Osteosarcoma

A Phase I Study of Allogeneic Ex Vivo Expanded Gamma Delta (γδ) T Cells in Combination With Dinutuximab, Temozolomide, Irinotecan, and Zoledronate in Children With Refractory/ Relapsed, or Progressive Neuroblastoma or Refractory/ Relapsed Osteosarcoma

Sponsor

Emory University

Enrollment

24 participants

Start Date

Nov 6, 2023

Study Type

INTERVENTIONAL

Conditions

Neuroblastoma Refractory Osteosarcoma Refractory Neuroblastoma Relapsed Neuroblastoma Relapsed Osteosarcoma

Summary

The goal of this clinical trial is to determine the maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) of allogeneic expanded γδ T cells when delivered with Dinutuximab, temozolomide, irinotecan, and zoledronate in children with refractory or recurrent neuroblastoma or refractory/ relapsed osteosarcoma as well as to define the toxicities of allogeneic expanded γδ T cells when delivered with Dinutuximab, temozolomide, irinotecan, and zoledronate

Eligibility

Min Age: 12 Months

Inclusion Criteria25

Patients must be ≥ 12 months of age at the time of enrollment in the study.
Diagnosis: 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
Response to prior therapy:
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) after 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.
Relapsed or refractory osteosarcoma that is not responsive to standard treatment
Disease Status
Patients 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 (RECIST) v1.1 for subjects with Osteosarcoma
Performance Level:Patients must have a Lansky (≤16 years) or Karnofsky (\>16 years) score of ≥50
Prior Therapy
Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy before 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/irinotecan chemoimmunotherapy is allowed
Prior T cell therapy is excluded
Organ Function Requirements:
Hematologic Functions : Absolute Neutrofil count ≥750/uL and platelet count ≥ 75,000/µl, transfusion independent .
Renal Function: Patients must have adequate renal function defined as age-adjusted serum creatinine ≤1.5 ULN for age.
Liver Function: Total bilirubin ≤ 1.5 x ULN for age and serum glutamic-pyruvic transaminase (SGPT) (ALT) ≤ 135 U/L (≤ 3x ULN).
Cardiac Function: Normal ejection fraction (≥ 55%) documented by either echocardiogram or radionuclide multigated acquisition scan (MUGA) evaluation OR Normal fractional shortening (≥ 27%) documented by echocardiogram
Pulmonary Function: Normal pulmonary function with no evidence of dyspnea at rest, no exercise intolerance.

Exclusion Criteria13

Prior T cell therapy
Pregnancy, breast feeding, or unwillingness to use effective contraception during the study will not be entered on this study.
Patients who, in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study.
Patients with known active Central Nervous System (CNS) disease (excluding skull disease with intracranial extension). Patients with a history of CNS disease are required to have a brain CT and/ or MRI at study registration.
Patients with prior allogeneic stem cell transplant
Patients who are on hemodialysis
Patients with an active or uncontrolled infection. Patients on prolonged antifungal therapy are still eligible if they are culture negative, afebrile, and meet other organ function criteria
Known history of human immunodeficiency virus (HIV) infection, hepatitis B, or hepatitis C. Testing is not required in the absence of clinical findings or suspicion.
Patients with disease of any major organ system that would compromise their ability to withstand therapy.
Patients who have had to permanently discontinue Dinutuximab due to toxicity
Patients with serious, uncontrolled cardiac arrhythmias
Patients with a history of myocarditis
Patients who have received any live vaccines within 30 days before enrollment

Interventions

COMBINATION_PRODUCTEx Vivo Expanded Allogeneic γδ T Cells in Combination with Dinutuximab, Temozolomide, Irinotecan and Zoledronate

The cell dose will be based on the subject's body weight. Subjects will receive a single infusion of third party, ex vivo expanded, frozen then thawed γδ T cell product at a dose of 3 x 106 cells/kg on Day 6 and then if they meet criteria for subsequent γδ T cell dose will receive a second dose of 3 x 106 cells/kg on Day 13. The dose will be escalated to 1 x 10\^7 and then 3 x 10\^7 cells/kg. In absence of any dose limiting toxicity, 3 x 10\^7 cells/kg will be accepted as the maximal dose. Dinutuximab (17.5 mg/m2), temozolomide (100 mg/m2),irinotecan (50 mg/m2) and zoledronic acid (0.0125 mg/kg/dose) will be consistent across all dose levels. Max γδ T cell dose will not exceed Level 3 dosing at 50 kg: 1.5×10⁹ total γδ T cells.