A Phase I Trial of Anti-GD2 T-cells (1RG-CART)

Study Overview
=================
Brief 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.

Detailed Description
-----------------
The purpose of this trial is to explore the safety and feasibility of deploying autologous anti-GD2 CAR T-cells for the immunotherapy of neuroblastoma. The CAR T-cell trials employing second generation receptors and lymphodepleting conditioning regimes have produced objective clinical responses in patients with relapsed leukaemias. The trial aims to evaluate similar CAR T-cells but directed against the antigen GD2. Neuroblastoma is well suited to this form of targeted therapy because of the homogeneous and almost universal expression of GD2 on the surface of neuroblastoma cells, and because of the poor prognosis of eligible patients. 1RG-CART will be administered intravenously. As the CAR T-cells are designed to survive and proliferate on encountering antigen, no direct relationship is anticipated between cell dose and either efficacy or toxicity. Rather, clinical benefit is more likely to be observed in those patients in whom in vivo expansion successfully occurs. A possible key determinant of expansion will be prior lymphodepletion of the patients. For this reason this trial is designed to evaluate a phased introduction of lymphodepletion in successive patient cohorts, rather than T-cell dose escalation. Only if there is insufficient expansion of T-cells following full lymphodepletion will the T-cell dose be escalated. Rituximab (MabThera®) will be used as a rescue medication only when necessary, and will be considered a non-investigational medicinal product (NIMP) in this trial.

Official Title
-----------------
A Cancer Research UK Phase I Trial of Anti-GD2 Chimeric Antigen Receptor (CAR) Transduced T-cells (1RG-CART) in Patients With Relapsed or Refractory Neuroblastoma

Conditions
-----------------
Relapsed or Refractory Neuroblastoma

Intervention / Treatment
-----------------
* Other: Leukapheresis
* Drug: Cyclophosphamide
* Drug: Fludarabine
* Genetic: 1RG-CART


Participation Criteria
=================
Eligibility Criteria
-----------------
Eligibility Criteria for Leukapheresis/Venepuncture Inclusion Criteria: Written informed consent* for leukapheresis/venepuncture and transduction of T-cells. 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. Relapsed or refractory neuroblastoma (the patient must have evidence of active disease even if they do not currently require active treatment). Patients must have at least one lesion that can be evaluated for response by imaging and/or diffuse bone marrow infiltration. Adequate renal function, defined as a glomerular filtration rate (GFR) ≥ 30 mL/min/1.73m^2 (corrected). 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: Histologically proven neuroblastoma, which is relapsed or refractory to conventional treatment. Patients must have at least one lesion that can be evaluated for response by imaging and/or diffuse bone marrow infiltration. 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. Life expectancy of at least two months. Karnofsky score ≥60% if ≥16 years old or Lansky performance score of ≥60% if <16 years old Adequate renal function, defined as a GFR of ≥30 mL/min/1.73m^2 (corrected). 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: 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. Patients for whom rituximab is contraindicated due to severe previous hypersensitivity or any other reason. Patients must have recovered from the acute reversible effects of any previous therapy before infusion of the 1RG-CART. 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. Co-existing chronic progressive neurological disease. Airway compromise by direct tumoural invasion or compression. Patients with active autoimmune disease requiring systemic treatment. Patients who are taking or likely to require high dose systemic corticosteroids or other immunosuppressive therapy (patients on steroid replacement therapy are eligible). Patients at high medical risk because of non-malignant systemic disease including active uncontrolled infection. Major surgery from which the patient has not yet recovered. 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. 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. Known to be serologically positive for hepatitis B, hepatitis C or HIV. Any other condition which in the Investigator's opinion would not make the patient a good candidate for the clinical trial. 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.

Ages Eligible for Study
-----------------
Minimum Age: 1 Year

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Dose Level 1<br>Patients in Dose Level 1 will receive 1x10^7 1RG-CART/m^2 intravenously (IV) on Day 0. | Other: Leukapheresis<br> <br> Genetic: 1RG-CART<br> <br> |
| Other: Dose Level 2<br>Patients in Dose Level 2 will receive 300 mg/m^2/day of cyclophosphamide for four days (Days -4 to -1) followed by 1x10^7 1RG-CART/m^2 IV on Day 0. | Other: Leukapheresis<br> <br> Drug: Cyclophosphamide<br> <br> Genetic: 1RG-CART<br> <br> |
| Other: Dose Level 3<br>Patients in Dose Level 3 will receive 300 mg/m^2/day of cyclophosphamide for four days (Days -7 to -4) and 25 mg/m^2/day of fludarabine for five days (Days -8 to -4), followed by 1x10^7 1RG-CART/m^2 IV on Day 0. | Other: Leukapheresis<br> <br> Drug: Cyclophosphamide<br> <br> Drug: Fludarabine<br> <br> Genetic: 1RG-CART<br> <br> |
| Other: Dose Level 4<br>Patients in Dose Level 4 will receive 300 mg/m^2/day of cyclophosphamide for four days (Days -7 to -4) and 25 mg/m^2/day of fludarabine for five days (Days -8 to -4), followed by 1x10^8 1RG-CART/m^2 IV on Day 0. | Other: Leukapheresis<br> <br> Drug: Cyclophosphamide<br> <br> Drug: Fludarabine<br> <br> Genetic: 1RG-CART<br> <br> |
| Other: Dose Level 5<br>If the required level of 1RG-CART survival is not reached, a further cohort of patients (Dose Level 5) will receive 300 mg/m^2/day of cyclophosphamide for four days (Days -7 to -4) and 25 mg/m^2/day of fludarabine for five days (Days -8 to -4), followed by 5-10x10^8 1RG-CART/m^2 IV which could be be split over two days (Day 0 and Day 1). | Other: Leukapheresis<br> <br> Drug: Cyclophosphamide<br> <br> Drug: Fludarabine<br> <br> Genetic: 1RG-CART<br> <br> |
| Other: Patients who underwent leukapheresis but did not proceed to receive any IMP<br>Patients who were enrolled and underwent leukapheresis but who did not receive any IMP. | Other: Leukapheresis<br> <br> |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To Evaluate the Feasibility of 1RG-CART Therapy in Patients With Relapsed or Refractory Neuroblastoma | Feasibility of 1RG-CART therapy assessed as the number of patients who commence T-cell processing and are subsequently evaluable for 1RG-CART engraftment at Day 14. | Day 14 | 
| Safety and Tolerability of 1RG-CART Therapy | Number of serious adverse events, non-serious adverse events and adverse events that are related to fludarabine, cyclophosphamide or 1RG-CART. | From the time of informed consent to leukapheresis until withdrawal from the trial or start of other anti-cancer therapy (a median time period of 132 days [range 68 to 301 days]) | 
| To Determine Recommended Phase II Regimen by Assessing the Number of DLTs at Each Dose Level | Number of dose limiting toxicities (DLTs) at each dose level. | From the time of informed consent to leukapheresis until withdrawal from the trial or start of other anti-cancer therapy (a median time period of 132 days [range 68 to 301 days]) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 1RG-CART Counts in the Peripheral Blood | Number of patients with 1RG-CART levels in peripheral blood above the limit of quantification for the assay (10 cells/µL) by flow cytometry. | From Day 0 until end of trial (median 38.5 days, range 20 to 233 days) | 
| Assessment of Tumour Response From Baseline (RECIST) | Assessment of best tumour response from baseline according to Response Evaluation Criteria in Solid Tumours (RECIST) v1.1. | Day 28, 2 months and 4 months | 
| Assessment of Tumour Response From Baseline (irRC) | Assessment of best tumour response from baseline according to Immune Related Response Criteria (irRC). | Day 28, 2 months and 4 months | 
| Assessment of Tumour Response From Baseline (INRC) | Assessment of best tumour response from baseline according to International Neuroblastoma Response Criteria (INRC). | Day 28, 2 months and 4 months | 
| To Evaluate Anti-tumour Activity (Progression Free Survival) | Progression free survival (progression by RECIST criteria). | Up to 2 years | 
| To Evaluate Anti-tumour Activity (Overall Survival) | Overall survival. | Up to 2 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
GD2, Neuroblastoma, Immunotherapy, 1RG-CART, Cyclophosphamide, Fludarabine, CAR T-cells, Anti-GD2, CAR, Chimeric Antigen Receptor, Cytokine Release Syndrome