A Phase I Trial of Anti-GD2 T-cells (1RG-CART)
Condition: Relapsed or Refractory Neuroblastoma
MeSH terms: Neuroblastoma
Intervention: Leukapheresis; Cyclophosphamide; Fludarabine; 1RG-CART
Intervention MeSH terms: Cyclophosphamide; Fludarabine
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Sequential Assignment
Masking: None (Open Label)
Enrollment: 17.0
Sex: All
Minimum age: 1 Year
Healthy volunteers: No
Keywords: Neuroblastoma; Immunotherapy; 1RG-CART; Cyclophosphamide; Fludarabine; CAR T-cells; Anti-GD2; GD2; CAR; Chimeric Antigen Receptor; Cytokine Release Syndrome

Summary:

      The purpose of this first in human study is to determine the safety and feasibility of
      1RG-CART therapy in patients with relapsed or refractory neuroblastoma. 1RG-CART therapy is a
      novel immunotherapy under investigation in which patients have their T-cells (a type of white
      blood cell) collected and modified in the laboratory, before they are given back to the
      patient. The T-cells are modified to express a chimeric antigen receptor (CAR) which targets
      disialoganglioside (GD2), a marker expressed on the surface of neuroblastoma cells.
    

Eligibility criteria:

        Eligibility Criteria for Leukapheresis/Venepuncture

        Inclusion Criteria:

          1. Written informed consent* for leukapheresis/venepuncture and transduction of T-cells.

          2. Suitability for leukapheresis/venepuncture defined as:

               -  Negative for human immunodeficiency virus (HIV), human T-cell lymphotropic virus
                  (HTLV) 1, HTLV 2, syphilis and hepatitis B.

               -  Minimum T-lymphocyte count of 0.25x10^9/L.

          3. Relapsed or refractory neuroblastoma (the patient must have evidence of active disease
             even if they do not currently require active treatment).

          4. Patients must have at least one lesion that can be evaluated for response by imaging
             and/or diffuse bone marrow infiltration.

          5. Adequate renal function, defined as a glomerular filtration rate (GFR) ≥ 30
             mL/min/1.73m^2 (corrected).

          6. Karnofsky score ≥60% if ≥16 years old or Lansky performance score of ≥60% if <16 years
             old

               -  *Informed consent from the patient's parent or legal guardian is required for all
                  patients under 16 years of age. Patients under 16 years of age may also provide
                  written assent to take part in the trial.

        Exclusion Criteria:

        Patients should not meet (or be anticipated to meet) any of the exclusion criteria for the
        main trial, see criteria below

        Eligibility Criteria for the Main Trial

        Inclusion Criteria:

          1. Histologically proven neuroblastoma, which is relapsed or refractory to conventional
             treatment.

          2. Patients must have at least one lesion that can be evaluated for response by imaging
             and/or diffuse bone marrow infiltration.

          3. Aged ≥12 months at the time written consent is given for the dose escalation phase or
             aged ≥6 months at the time written consent is given for the dose expansion phase of
             the trial.

          4. Life expectancy of at least two months.

          5. Karnofsky score ≥60% if ≥16 years old or Lansky performance score of ≥60% if <16 years
             old

          6. Adequate renal function, defined as a GFR of ≥30 mL/min/1.73m^2 (corrected).

          7. Written (signed and dated) informed consent to the main trial* and be capable of
             co-operating with treatment and follow-up.

               -  *Informed consent from the patient's parent or legal guardian is required for all
                  patients under 16 years of age. Patients under 16 years of age may also provide
                  written assent to take part in the trial.

        Exclusion Criteria:

          1. Patients who have received anti-GD2 antibody treatment within the previous 2 weeks
             (based on the half life of ch14.18 antibody being 1-3 days in children); patients who
             have received dinutuximab or other anti-GD2-directed antibody may need a longer
             washout period.

          2. Patients for whom rituximab is contraindicated due to severe previous hypersensitivity
             or any other reason.

          3. Patients must have recovered from the acute reversible effects of any previous therapy
             before infusion of the 1RG-CART.

          4. Current CNS involvement (including intradural meningeal involvement). Patients who
             previously had CNS involvement but have been surgically treated and disease free for
             ≥2 months are eligible.

          5. Co-existing chronic progressive neurological disease.

          6. Airway compromise by direct tumoural invasion or compression.

          7. Patients with active autoimmune disease requiring systemic treatment.

          8. Patients who are taking or likely to require high dose systemic corticosteroids or
             other immunosuppressive therapy (patients on steroid replacement therapy are
             eligible).

          9. Patients at high medical risk because of non-malignant systemic disease including
             active uncontrolled infection.

         10. Major surgery from which the patient has not yet recovered.

         11. Female patients who are able to become pregnant (or already pregnant or lactating).
             However, those patients who have a negative serum or urine pregnancy test before
             enrolment and agree to use two highly effective forms of contraception (oral; injected
             or implanted hormonal contraception and condom; have an intra-uterine device and
             condom; diaphragm with spermicidal gel and condom) effective at the first
             administration of the lymphodepleting regimen or at administration of the 1RG-CART
             (whichever comes first), throughout the trial and for six months afterwards are
             considered eligible. Note that for female patients who receive cyclophosphamide or
             rituximab, the contraceptive period should be extended to 12 months after
             cyclophosphamide/rituximab administration.

         12. Male patients with partners of child-bearing potential (unless they agree to take
             measures not to father children by using one form of highly effective contraception
             [condom plus spermicide] effective at the first administration of the lymphodepleting
             regimen or at administration of the 1RG-CART [whichever comes first], throughout the
             trial and for six months afterwards). Men with pregnant or lactating partners must be
             advised to use barrier method contraception (for example: condom plus spermicidal gel)
             to prevent exposure to the foetus or neonate.

         13. Known to be serologically positive for hepatitis B, hepatitis C or HIV.

         14. Any other condition which in the Investigator's opinion would not make the patient a
             good candidate for the clinical trial.

         15. Is a participant in another clinical trial of an investigational medicinal product
             (CTIMP). Participation in an observational trial or in the follow-up phase of a CTIMP
             would be acceptable.