Allogeneic Expanded Gamma Delta T Cells With GD2 Chemoimmunotherapy in Relapsed or Refractory Neuroblastoma (Aflac-NBL-2002)

A Phase I Study of Allogeneic Ex Vivo Expanded Gamma Delta (γδ) T Cells (IND # 28460) in Combination With Dinutuximab, Temozolomide, Irinotecan, and Zoledronate in Children With Refractory, Relapsed, or Progressive Neuroblastoma

High risk neuroblastoma is an aggressive and often lethal pediatric solid tumor. Survival remains less than 50% and those patients who do survive suffer many treatment-related acute and chronic toxicities. Chemoimmunotherapy using a combination of an anti-GD2 monoclonal antibody (dinutuximab) and different chemotherapy agents in the relapsed/refractory (r/r) neuroblastoma population, has demonstrated the most robust response rates to date, shifting the clinical practice to administer chemoimmunotherapy as a standard treatment for patients with r/r neuroblastoma.

The goal of this study is to improve upon GD2 chemoimmunotherapy regimens for neuroblastoma by delivering standard drugs like temozolomide, irinotecan, and dinutuximab in combination with a novel cell-based immunotherapy called gamma delta (γδ) T cells in addition to zoledronate that enhances γδ T cell activation and potency. γδ T cells are an innovative approach to cell therapy for neuroblastoma as they are major histocompatibility complex (MHC) independent and directly cytotoxic to tumor cells without the need for engineering them to recognize the tumor. The study team has developed a Good Manufacturing Practice (GMP)-compliant manufacturing strategy to expand safe γδ T cells from healthy donors for this trial.

This is a Phase 1 study to determine the safety, recommended phase 2 dose, and preliminary efficacy of allogeneic (third party), ex vivo expanded γδ T cells in combination with dinutuximab, temozolomide, irinotecan and zoledronate in children with refractory, relapsed, or progressive neuroblastoma.

Study Overview

• Status: Recruiting
• Conditions: Neuroblastoma; Refractory Neuroblastoma; Relapsed Neuroblastoma
• Intervention / Treatment: Combination product: Ex Vivo Expanded Allogeneic γδ T Cells in Combination with Dinutuximab, Temozolomide, Irinotecan and Zoledronate

Detailed Description

High risk neuroblastoma is an aggressive and lethal pediatric solid tumor. Survival remains less than 50% and those patients who do survive suffer many treatment-related acute and chronic toxicities, stressing a critical need for novel tumor-targeting therapies.

γδ T cells are an innovative approach to cell therapy for neuroblastoma as they are MHC independent and directly cytolytic to tumor cells. We have developed a GMP-compliant manufacturing strategy to expand γδ T cells from normal donor and neuroblastoma patient apheresis products for this trial.

This is a Phase 1 study to determine the safety, recommended phase 2 cell therapy dose, and preliminary efficacy of allogenic (third party) ex vivo expanded gamma delta (γδ) T cells in combination with dinutuximab, temozolomide, irinotecan and zoledronate in children with refractory, relapsed, or progressive neuroblastoma.

The purpose of this study is to help doctors and scientists learn if γδ T cells will aid in clinical and disease response in this population and to determine the maximum tolerated dose (MTD).

This is a single-site non-randomized clinical trial, that will take place at Children's Healthcare of Atlanta (CHOA) at Egleston.

Third party γδ T cells will be prepared from healthy donors and expanded under GMP conditions at Expression Therapeutics, LLC. γδ T cells will be expanded, cryopreserved as numerous aliquots, and transported to The Children's Healthcare of Atlanta, Egleston Campus. At the appropriate time, an aliquot of γδ T cells appropriate for the size of the subject will be thawed and infused into the patient according to institutional protocol.

Subjects will receive a single infusion of third party, ex vivo expanded, frozen then thawed γδ T cell product on Day 6 and then if they meet criteria for subsequent γδ T cell dose will receive a second dose on Day 13. The γδ T cell dose will be infused after the dinutuximab, temozolomide, irinotecan and zoledronate schedule is complete. There will be no intra-patient dose escalation. The entry dose level is Dose Level 1, with escalation up to Dose Level 3 following standard 3+3 rules for γδ T cell dose escalation design.

If a subject does not want to enter into the clinical trial, they may choose an alternative therapy for r/r neuroblastoma that their physician deems appropriate. There will be no compensation for participation in this study.

A minimum of 6 and a maximum of 24 patients with refractory, relapsed, or progressive neuroblastoma will be recruited through a variety of strategies, including: face to face encounters between participants and study staff during clinical encounters at Children's Healthcare of Atlanta, Institutional Review Board approved advertisement flyer, and potential subjects will be referred to the investigators for information about the potential benefits and side effects of the treatment regimen. An approved informed consent statement will be read and signed by the legal guardian, and an investigator. Written assent will be obtained from children ages 11 to 17, using an approved assent statement, along with use of the informed consent by their parent or guardian. Verbal assent will be obtained from children ages 6-10 years.

Leftover blood samples collected may be stored for future research by the sponsor of this study. This research will advance scientific knowledge and clinical data in the neuroblastoma field and knowledge of γδ T cells. Cell therapy has been a promising treatment for neuroblastoma, so with this advancement in T cell therapy, we can potentially advance patient outcomes.

• Study Type: Interventional
• Enrollment (Estimated): 24
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Kelly Goldsmith, MD; Phone Number: (404) 727-2655; Email: kgoldsm@emory.edu; mpactcto@choa.org

Study Locations

• United States
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Recruiting
      • Children's Healthcare of Atlanta
      • Contact: Kelly Goldsmith, MD; Email: kgoldsm@emory.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 16 years (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients must be ≥ 12 months of age at the time of enrollment on the study.
• 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.
• 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.

• Patients must have at least ONE of the following:

  • Recurrent/progressive disease after the diagnosis of high risk neuroblastoma at any time prior to study registration - regardless of response to frontline 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.

  • 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 induction therapy.
    • Persistent disease: A best overall response of partial response since diagnosis of high risk neuroblastoma AND after at least 4 courses of 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.

• Sites of disease: Patients must have at least ONE of the following:

  • Bone sites
  • Bone Marrow sites
  • Soft Tissues sites
• Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to study registration.

• 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 Criteria:

• 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 prior to enrollment

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Dose Escalation Phase I cohort; Subjects will be assigned a cell therapy dose level at time of registration. The entry dose level is Dose Level 1, with escalation up to Dose Level 3 following a 3 + 3 dose escalation design. If there is no evidence of progression, patients may receive up to a maximum of 4 courses. Each course includes two administrations of γδ T cells, administered one week apart. Toxicity, for deciding dose escalation and defining the MTD, will be evaluated during Course 1. Disease response assessment will be done after Courses 2 and 4. Dinutuximab (17.5 mg/m2), temozolomide (100 mg/m2), irinotecan (50 mg/m2) and zoledronate (0.0125 mg/kg/dose) will be consistent across all dose levels.The same donor for γδ T cell will be used for both cell therapy product infusions per course. Treatment of the first two subjects in each dose escalation cohort will be staggered. The second subject will not be enrolled until the first subject completes the DLT observation interval (minimum of 21 days).

Combination product: Ex 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Tolerated Dose/Recommended Phase 2 Dose of gamma delta T cells	The descriptions and grading scales found in the revised National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for adverse event (AE) reporting. The MTD/RP2D is defined as the maximum dose at which fewer than one-third of patients experience dose limiting toxicity course	21 Days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Describe Non-Hematological Toxicities	Proportion of patients with any Grade 3 or greater non-hematological toxicities on any course	all toxicities from enrollment through 30 days following end of protocol therapy
Describe Hematological Toxicities	Proportion of patients with any Grade 3 or greater hematological toxicities on any course	all toxicities from enrollment through 30 days following end of protocol therapy
Overall Response	Proportion of patients evaluable for response with a best overall response of CR/PR	From Day 1 of protocol therapy through 30 days following end of protocol therapy

Collaborators and Investigators

• Sponsor: Emory University
• Investigators: Principal Investigator: Kelly Goldsmith, MD, Associate Profesor

Study record dates

Study Major Dates

• Study Start (Estimated): November 1, 2023
• Primary Completion (Estimated): December 1, 2025
• Study Completion (Estimated): December 1, 2025

Study Registration Dates

• First Submitted: May 25, 2022
• First Submitted That Met QC Criteria: May 31, 2022
• First Posted (Actual): June 1, 2022

Study Record Updates

• Last Update Posted (Actual): October 25, 2023
• Last Update Submitted That Met QC Criteria: October 24, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: Temozolomide; Irinotecan; GD2; Zoledronate; Dinutuximab; Gamma Delta T Cells; chemoimmunotherapy
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroectodermal Tumors, Primitive; Neuroectodermal Tumors, Primitive, Peripheral; Neuroblastoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Topoisomerase Inhibitors; Bone Density Conservation Agents; Topoisomerase I Inhibitors; Temozolomide; Irinotecan; Zoledronic Acid; Dinutuximab
• Other Study ID Numbers: STUDY00003123

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Toxicity/Response data, correlative study data
• IPD Sharing Time Frame: Data will be come available once approved by the study Data Safety Monitoring Committee and made public through manuscript. No end date.

IPD Sharing Access Criteria

With the scientific public and community through presentation of results at national/international meetings and through manuscript submissions.

All trial endpoints in the clinical study by peer reviewed manuscript submission, national meeting abstract submission/presentations.

• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No