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Anti-GD2 CAR T Cells in Pediatric Patients Affected by High Risk and/or Relapsed/Refractory Neuroblastoma or Other GD2-positive Solid Tumors

Primary Purpose

Neuroblastoma, Neuroblastoma Recurrent, GD2-positive Solid Tumors

Status
Recruiting
Phase
Phase 1
Locations
Italy
Study Type
Interventional
Intervention
GD2-CART01
Sponsored by
Bambino Gesù Hospital and Research Institute
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Neuroblastoma focused on measuring Neuroblastoma, GD2 CAR T cell, CAR T, GD2-positive solid tumors, Osteosarcoma, Ewing Sarcoma, GD2-positive sarcoma

Eligibility Criteria

12 Months - 25 Years (Child, Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Phase I The patient must meet the following eligibility inclusion criteria to be enrolled to receive treatment in the Phase I study.

  1. Diagnosis of NBL that have been treated with frontline therapy and is judged to be incurable, based upon the following criteria:

    1. Relapse after first-line treatment, proved by a positive 123-I-mMIBG-scan
    2. Persistence/progression of disease after the initiation of the upfront treatment
  2. Patients must have measurable or evaluable disease at the time of treatment enrollment, as shown by bone marrow biopsy/aspirate, US or CT/MRI scan or by 123-I-mMIBG scan.
  3. Recover from the toxic effect of previous chemotherapies: grade 4 and or 3 non-hematologic toxicities must have resolved to grade ≤2; if some effects of the therapies have become chronic (i.e. treatment associated thrombocytopenia), the patient must be clinically stable, according to the opinion of the treating physicians, and meet all other eligibility criteria.
  4. Age: 12 months -18 years.
  5. Voluntary informed consent is given. For subjects < 18 years old their legal guardian must give informed consent. Pediatric subjects will be included in age appropriate discussion and verbal assent will be obtained for those greater than or equal to 12 years of age, when appropriate.
  6. Clinical performance status: Patients > 16 years of age: Karnofsky greater than or equal to 60%; Patients less than or equal to 16 years of age: Lansky scale greater than or equal to 60%.
  7. Patients of child-bearing or child-fathering potential must be willing to practice birth control from the time of enrollment on this study and for four months after receiving the preparative regimen.
  8. Females of child-bearing potential must have a negative pregnancy test because of the potentially dangerous effects on the fetus.

Phase II

The patient must meet the following eligibility inclusion criteria to be enrolled to receive treatment in the Phase II study.

  1. Diagnosis of NBL that have been treated with frontline therapy and is judged to be incurable, based upon the following criteria:

    1. Relapse after first-line treatment, proved by a positive MIBG-scan
    2. Persistence/progression of disease after the initiation of the upfront treatment

    OR

  2. Diagnosis of extremely High Risk NBL at high risk of relapse, defined by stage III/IV and Myc-N amplification, at the end of the first-line treatment according to the Standard of Care, even if NED.

    OR

  3. Diagnosis of GD2+ tumors other than Neuroblastoma, considered incurable with conventional treatments by the treating physician.
  4. Patients with relapsed/refractory disease must have measurable or evaluable disease at the time of treatment enrollment, as shown by bone marrow biopsy/aspirate, US or CT/MRI scan or by MIBG-scan.
  5. Recover from the toxic effect of previous chemotherapies: grade 4 and or 3 non-hematologic toxicities must have resolved to grade ≤2; if some effects of the therapies have become chronic (i.e. treatment associated thrombocytopenia), the patient must be clinically stable, according to the opinion of the treating physicians, and meet all other eligibility criteria.
  6. Age: 12 months - 18 years.
  7. Voluntary informed consent is given. For subjects < 18 years old their legal guardian must give informed consent. Pediatric subjects will be included in age appropriate discussion and verbal assent will be obtained for those greater than or equal to 12 years of age, when appropriate.
  8. Clinical performance status: Patients > 16 years of age: Karnofsky greater than or equal to 60%; Patients less than or equal to 16 years of age: Lansky scale greater than or equal to 60%.
  9. Patients of child-bearing or child-fathering potential must be willing to practice birth control from the time of enrollment on this study and for four months after receiving the preparative regimen.
  10. Females of child-bearing potential must have a negative pregnancy test because of the potentially dangerous effects on the fetus

Exclusion Criteria:

  1. Pregnant or lactating women
  2. Severe, uncontrolled active intercurrent infections
  3. Active hepatitis B or hepatitis C infection
  4. HIV infection
  5. Rapidly progressive disease with life-expectancy < 6 weeks
  6. History of grade 3 or 4 hypersensitivity to murine protein-containing products
  7. Hepatic function: Inadequate liver function defined as total bilirubin > 4x upper limit of normal (ULN) or transaminase (ALT and AST) > 6 x ULN based on age and laboratory specific normal ranges
  8. Renal function: serum creatinine > 3x ULN for age.
  9. Blood oxygen saturation < 90%.
  10. Cardiac function: Left ventricular ejection fraction lower than 45% by ECHO.
  11. Marrow function: ANC lower than 500/mm3 and/or platelets lower than 20.000 (not reached by transfusion).
  12. Congestive heart failure, cardiac arrhythmia, psychiatric illness, or social situations that would limit compliance with study requirements or in the opinion of the PI would pose an unacceptable risk to the subject.
  13. Untreated CNS metastasis; patients with previous CNS tumor involvement that has been treated and is stable for at least 6 weeks following completion of therapy are eligible.
  14. Concurrent or recent prior therapies, before infusion:

    1. Systemic steroids (at a dose equivalent to or greater 2 mg/kg prednisone) in the 2 weeks before infusion. Recent or current use of inhaled/topical/non-absorbable steroids is not exclusionary.
    2. Systemic chemotherapy in the 2 weeks preceding infusion.
    3. Immunosuppressive agents less than or equal to 30 days.
    4. Radiation therapy must have been completed at least 3 weeks prior to enrollment.
    5. I131-MIBG therapy must have been completes at least 6 weeks prior to enrollment
    6. Anti-GD2 murine monoclonal antibody (ch14.18 antibody) in the 2 weeks preceding infusion
    7. Other anti-neoplastic investigational agents currently or within 30 days prior to start of protocol therapy;
    8. Exceptions:
    9. Subjects receiving steroid therapy at physiologic replacement doses only are allowed provided there has been no increase in dose for at least 2 weeks prior to starting apheresis
  15. Patient-derived GD2-CART01 production failure.

Sites / Locations

  • Ospedale Pediatrico Bambino GesùRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

GD2-CART01

Arm Description

After a lymphodepleting regimen the patients will receive 1.0 to 10.0 x 10⁶/kg GD2 Chimeric Antigen Receptor (CAR) positive T cells.

Outcomes

Primary Outcome Measures

Phase I - Identification of the dose limiting toxicity (DLT)
Toxicity will be assessed according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) scale, version 4 and the number of patients experiencing DLT will be evaluated
Phase II - Antitumor effect
Assessment of Best Overall Response (BOR)

Secondary Outcome Measures

In vivo persistence/expansion of infused CAR T cell
Detection of infused CAR T cell in the peripheral and bone marrow blood
Serum cytokine profiling
Assessment of the seric cytokines profile
Time To Progression (TTP)
Event-Free Survival (EFS)
Overall Survival (OS)
Disease outcome according to INRC vs irRC
Tumor response assessment through the two different criteria
Elimination of CAR T cell through iC9 in case of toxicity
Assessment of the kinetic of CAR T cell elimination after infusion of the dimerizer

Full Information

First Posted
December 6, 2017
Last Updated
March 9, 2022
Sponsor
Bambino Gesù Hospital and Research Institute
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1. Study Identification

Unique Protocol Identification Number
NCT03373097
Brief Title
Anti-GD2 CAR T Cells in Pediatric Patients Affected by High Risk and/or Relapsed/Refractory Neuroblastoma or Other GD2-positive Solid Tumors
Official Title
Phase I/II Study of Anti-GD2 Chimeric Antigen Receptor-Expressing T Cells in Pediatric Patients Affected by High Risk and/or Relapsed/Refractory Neuroblastoma or Other GD2-positive Solid Tumors
Study Type
Interventional

2. Study Status

Record Verification Date
March 2022
Overall Recruitment Status
Recruiting
Study Start Date
January 5, 2018 (Actual)
Primary Completion Date
December 2024 (Anticipated)
Study Completion Date
December 2027 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Bambino Gesù Hospital and Research Institute

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The purpose of this study is to test the safety and efficacy of GD2-CART01, a CAR T cell treatment targeting GD2 in paediatric or young adult patients with High Risk and/or relapsed/refractory Neuroblastoma. A small exploratory cohort of patients with GD2-positive tumors other than Neuroblastoma has also been included.
Detailed Description
The study will consist of 2 phases, a Phase I or dose escalation phase and a Phase II or expansion phase. Paediatric or young adult patients with relapsed High Risk and/or relapsed/refractory Neuroblastoma will be enrolled in the study. After completion of the phase I portion of the study, a small cohort of patients with GD2-positive tumors other than Neuroblastoma has also been included. Eligible patients will undergo leukapheresis in order to harvest T cells, which will be manufactured to obtain the autologous CAR T product GD2-CART01, a GD2-targeting CAR T product. Briefly, the patients will be treated with a lymphodepleting regimen containing conventional chemotherapic agents and subsequently will receive a single infusion of GD2-CART01. Moreover, the product contains a suicide gene safety switch (namely inducible Caspase 9): in case of relevant toxicities, the patient will receive the dimerizing agent in order to activate the apoptotic pathway in the infused T cells. After infusion of CAR T cells, the patients will enter a 5-year active follow-up period.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Neuroblastoma, Neuroblastoma Recurrent, GD2-positive Solid Tumors, Osteosarcoma, Ewing Sarcoma, Sarcoma
Keywords
Neuroblastoma, GD2 CAR T cell, CAR T, GD2-positive solid tumors, Osteosarcoma, Ewing Sarcoma, GD2-positive sarcoma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
42 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
GD2-CART01
Arm Type
Experimental
Arm Description
After a lymphodepleting regimen the patients will receive 1.0 to 10.0 x 10⁶/kg GD2 Chimeric Antigen Receptor (CAR) positive T cells.
Intervention Type
Biological
Intervention Name(s)
GD2-CART01
Intervention Description
Following a lymphodepleting treatment with conventional chemotherapy, patients will be treated with 1.0 to 10.0 x 10⁶/kg GD2 Chimeric Antigen Receptor (CAR) positive T cells as a single dose.
Primary Outcome Measure Information:
Title
Phase I - Identification of the dose limiting toxicity (DLT)
Description
Toxicity will be assessed according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) scale, version 4 and the number of patients experiencing DLT will be evaluated
Time Frame
4 weeks after T cell infusion
Title
Phase II - Antitumor effect
Description
Assessment of Best Overall Response (BOR)
Time Frame
Up to 6 months after T cell infusion
Secondary Outcome Measure Information:
Title
In vivo persistence/expansion of infused CAR T cell
Description
Detection of infused CAR T cell in the peripheral and bone marrow blood
Time Frame
UP to 5 years
Title
Serum cytokine profiling
Description
Assessment of the seric cytokines profile
Time Frame
First 2 weeks after T cell infusion
Title
Time To Progression (TTP)
Time Frame
Up 5 years after T cell infusion
Title
Event-Free Survival (EFS)
Time Frame
Up 5 years after T cell infusion
Title
Overall Survival (OS)
Time Frame
Up 5 years after T cell infusion
Title
Disease outcome according to INRC vs irRC
Description
Tumor response assessment through the two different criteria
Time Frame
Up to 5 years
Title
Elimination of CAR T cell through iC9 in case of toxicity
Description
Assessment of the kinetic of CAR T cell elimination after infusion of the dimerizer
Time Frame
Up to 15 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
12 Months
Maximum Age & Unit of Time
25 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Phase I The patient must meet the following eligibility inclusion criteria to be enrolled to receive treatment in the Phase I study. Diagnosis of NBL that have been treated with frontline therapy and is judged to be incurable, based upon the following criteria: Relapse after first-line treatment, proved by a positive 123-I-mMIBG-scan Persistence/progression of disease after the initiation of the upfront treatment Patients must have measurable or evaluable disease at the time of treatment enrollment, as shown by bone marrow biopsy/aspirate, US or CT/MRI scan or by 123-I-mMIBG scan. Recover from the toxic effect of previous chemotherapies: grade 4 and or 3 non-hematologic toxicities must have resolved to grade ≤2; if some effects of the therapies have become chronic (i.e. treatment associated thrombocytopenia), the patient must be clinically stable, according to the opinion of the treating physicians, and meet all other eligibility criteria. Age: 12 months -18 years. Voluntary informed consent is given. For subjects < 18 years old their legal guardian must give informed consent. Pediatric subjects will be included in age appropriate discussion and verbal assent will be obtained for those greater than or equal to 12 years of age, when appropriate. Clinical performance status: Patients > 16 years of age: Karnofsky greater than or equal to 60%; Patients less than or equal to 16 years of age: Lansky scale greater than or equal to 60%. Patients of child-bearing or child-fathering potential must be willing to practice birth control from the time of enrollment on this study and for four months after receiving the preparative regimen. Females of child-bearing potential must have a negative pregnancy test because of the potentially dangerous effects on the fetus. Phase II The patient must meet the following eligibility inclusion criteria to be enrolled to receive treatment in the Phase II study. Diagnosis of NBL that have been treated with frontline therapy and is judged to be incurable, based upon the following criteria: Relapse after first-line treatment, proved by a positive MIBG-scan Persistence/progression of disease after the initiation of the upfront treatment OR Diagnosis of extremely High Risk NBL at high risk of relapse, defined by stage III/IV and Myc-N amplification, at the end of the first-line treatment according to the Standard of Care, even if NED. OR Diagnosis of GD2+ tumors other than Neuroblastoma, considered incurable with conventional treatments by the treating physician. Patients with relapsed/refractory disease must have measurable or evaluable disease at the time of treatment enrollment, as shown by bone marrow biopsy/aspirate, US or CT/MRI scan or by MIBG-scan. Recover from the toxic effect of previous chemotherapies: grade 4 and or 3 non-hematologic toxicities must have resolved to grade ≤2; if some effects of the therapies have become chronic (i.e. treatment associated thrombocytopenia), the patient must be clinically stable, according to the opinion of the treating physicians, and meet all other eligibility criteria. Age: 12 months - 18 years. Voluntary informed consent is given. For subjects < 18 years old their legal guardian must give informed consent. Pediatric subjects will be included in age appropriate discussion and verbal assent will be obtained for those greater than or equal to 12 years of age, when appropriate. Clinical performance status: Patients > 16 years of age: Karnofsky greater than or equal to 60%; Patients less than or equal to 16 years of age: Lansky scale greater than or equal to 60%. Patients of child-bearing or child-fathering potential must be willing to practice birth control from the time of enrollment on this study and for four months after receiving the preparative regimen. Females of child-bearing potential must have a negative pregnancy test because of the potentially dangerous effects on the fetus Exclusion Criteria: Pregnant or lactating women Severe, uncontrolled active intercurrent infections Active hepatitis B or hepatitis C infection HIV infection Rapidly progressive disease with life-expectancy < 6 weeks History of grade 3 or 4 hypersensitivity to murine protein-containing products Hepatic function: Inadequate liver function defined as total bilirubin > 4x upper limit of normal (ULN) or transaminase (ALT and AST) > 6 x ULN based on age and laboratory specific normal ranges Renal function: serum creatinine > 3x ULN for age. Blood oxygen saturation < 90%. Cardiac function: Left ventricular ejection fraction lower than 45% by ECHO. Marrow function: ANC lower than 500/mm3 and/or platelets lower than 20.000 (not reached by transfusion). Congestive heart failure, cardiac arrhythmia, psychiatric illness, or social situations that would limit compliance with study requirements or in the opinion of the PI would pose an unacceptable risk to the subject. Untreated CNS metastasis; patients with previous CNS tumor involvement that has been treated and is stable for at least 6 weeks following completion of therapy are eligible. Concurrent or recent prior therapies, before infusion: Systemic steroids (at a dose equivalent to or greater 2 mg/kg prednisone) in the 2 weeks before infusion. Recent or current use of inhaled/topical/non-absorbable steroids is not exclusionary. Systemic chemotherapy in the 2 weeks preceding infusion. Immunosuppressive agents less than or equal to 30 days. Radiation therapy must have been completed at least 3 weeks prior to enrollment. I131-MIBG therapy must have been completes at least 6 weeks prior to enrollment Anti-GD2 murine monoclonal antibody (ch14.18 antibody) in the 2 weeks preceding infusion Other anti-neoplastic investigational agents currently or within 30 days prior to start of protocol therapy; Exceptions: Subjects receiving steroid therapy at physiologic replacement doses only are allowed provided there has been no increase in dose for at least 2 weeks prior to starting apheresis Patient-derived GD2-CART01 production failure.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Franco Locatelli, MD, PhD
Phone
066859
Ext
2678
Email
franco.locatelli@opbg.net
Facility Information:
Facility Name
Ospedale Pediatrico Bambino Gesù
City
Roma
Country
Italy
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Franco Locatelli, MD, PhD
Phone
066859
Ext
2678
Email
franco.locatelly@opbg.net
First Name & Middle Initial & Last Name & Degree
Franco Locatelli, MD, PhD

12. IPD Sharing Statement

Plan to Share IPD
Undecided
Citations:
PubMed Identifier
34772439
Citation
Tumino N, Weber G, Besi F, Del Bufalo F, Bertaina V, Paci P, Quatrini L, Antonucci L, Sinibaldi M, Quintarelli C, Maggi E, De Angelis B, Locatelli F, Moretta L, Vacca P, Caruana I. Polymorphonuclear myeloid-derived suppressor cells impair the anti-tumor efficacy of GD2.CAR T-cells in patients with neuroblastoma. J Hematol Oncol. 2021 Nov 12;14(1):191. doi: 10.1186/s13045-021-01193-0.
Results Reference
derived

Learn more about this trial

Anti-GD2 CAR T Cells in Pediatric Patients Affected by High Risk and/or Relapsed/Refractory Neuroblastoma or Other GD2-positive Solid Tumors

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