Clinical trial NCT03289455: CD19 /22 CAR T Cells (AUTO3) for the Treatment of B Cell Acute Lymphoblastic Leukemia (ALL)
Official title: A Single-Arm, Open-Label, Multi-Centre, Phase I/II Study Evaluating the Safety and Clinical Activity Of AUTO3, a CAR T Cell Treatment Targeting CD19 And CD22 in Paediatric And Young Adult Patients With Relapsed or Refractory B Cell Acute Lymphoblastic Leukaemia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: B Acute Lymphoblastic Leukemia
Recurrent Childhood Acute Lymphoblastic Leukemia
Refractory Childhood Acute Lymphoblastic Leukemia
B-cell Acute Lymphoblastic Leukemia
Keywords: Acute Lymphoblastic Leukaemia
CD19 Positive
CD22 Positive
Relapsed Acute Lymphoblastic Leukaemia
Refractory Acute Lymphoblastic Leukaemia
AUTO3
Lead sponsor: Autolus Limited
Sponsor class: INDUSTRY
First posted: 2017-09-21
Enrollment: 23
Sex: ALL
Minimum age (years): 1
Maximum age (years): 24
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to test the safety and efficacy of AUTO3, a CAR T cell treatment targeting CD19 and CD22 in paediatric or young adult patients with relapsed or refractory B cell acute lymphoblastic leukaemia.

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 or refractory B cell ALL will be enrolled in both phases of the study. Eligible patients will undergo leukapheresis in order to harvest T cells, which is the starting material for the manufacture of the autologous CAR T product AUTO3 which is a CD19 and CD22 dual targeting CAR T cell product. Following pre-conditioning by a chemotherapeutic regimen, the patient will receive AUTO3 intravenously as a single or split dose and will then enter a 24-month follow-up period.

Eligibility criteria: Key Inclusion Criteria:

1. Male or female patients aged 1-24 years with high risk (HR) relapsed/refractory B-lineage ALL, AND:

   1. Any bone marrow (BM) relapse or central nervous system (CNS) relapse with detectable BM disease after allogeneic stem cell transplant (SCT) and must be ≥6 months from SCT at the time of AUTO3 infusion; OR,
   2. HR first relapse; OR,
   3. Standard risk relapse patients with HR cytogenetics; OR,
   4. Second or greater relapse; OR,
   5. BM minimal residual disease (MRD) ≥10-³ prior to planned SCT; OR,
   6. Any on-treatment relapse in patients aged 16-24 years.

      (Phase II Only - Criteria in addition to those described above:)
   7. Primary refractory disease; OR,
   8. Patients with Philadelphia chromosome positive ALL are eligible if they are intolerant to or have failed 2 lines of tyrosine kinase inhibitor (TKI) therapy, or if TKI therapy is contraindicated; OR,
   9. Isolated CNS relapse but with ≤CNS Grade 2 disease at time of enrolment.
2. Documentation of CD19 and or CD22 expression on leukaemic blasts in the BM, peripheral blood, or cerebrospinal fluid within 3 months of screening.
3. Detectable disease in the BM at a level ≥10-⁴ (Phase I only).
4. Absolute lymphocyte count ≥0.5 x 10⁹/L.
5. Adequate renal, hepatic, pulmonary, and cardiac function.
6. Karnofsky (age ≥10 years) or Lansky (age \<10 years) score ≥50%.
7. Willing and able to give written, informed consent to the current study (patient and/or parent or legal guardian).

Exclusion Criteria:

1. Isolated extra-medullary disease relapse.
2. Active CNS involvement of ALL (CNS Grade 3 per National Comprehensive Cancer Network guidelines).
3. Active infectious bacterial or viral disease requiring IV anti-microbials for treatment.
4. Females who are pregnant or lactating.
5. Females of child-bearing potential and post pubertal male participants who are unwilling to use highly effective methods of contraception for a period of 1 year after the AUTO3 infusion.
6. Inability to tolerate leukapheresis.
7. Prior CD19 or CD22 targeted therapy with Grade 4 toxicity or ≥refractory Grade 3 cytokine release syndrome (CRS) or ≥Grade 3 drug related CNS toxicity.
8. Pre-existing significant neurological disorder.
9. Stem Cell Transplant patients only: active significant acute graft versus host disease (GVHD) or moderate/severe chronic GVHD requiring systemic steroids or other immunosuppressant within 4 weeks of enrolment.
10. The following medications are excluded:

    1. Steroids: Therapeutic doses of steroids must be stopped \>72 hours prior to AUTO3 infusion and leukapheresis. However, physiological replacement doses of steroids are allowed: \<12 mg/m2/day hydrocortisone or equivalent.
    2. Allogeneic cellular therapy: Any donor lymphocyte infusions must be completed \>6 weeks prior to AUTO3 infusion.
    3. Graft versus host disease therapies: Any drug used for GVHD must be stopped \>4 weeks prior to AUTO3 infusion.
    4. Chemotherapy: Should be stopped 1 week prior to leukapheresis and 2 days prior to starting pre-conditioning chemotherapy.
11. Known allergy to albumin, dimethyl sulfoxide, cyclophosphamide or fludarabine.

For AUTO3 Infusion: Patients meeting any of the following exclusion criteria will not be treated with AUTO3 or treatment will be delayed until they no longer meet these criteria:

1. Severe intercurrent infection.
2. Requirement for supplementary oxygen.
3. Allogeneic transplant recipients with active significant acute GVHD overall Grade ≥II or moderate/severe chronic GVHD requiring systemic steroids.

Primary outcomes:
measure: Number of Patients With Grade 3-5 Toxicities Occurring Within the Dose Limiting Toxicity (DLT) Period of AUTO3 Infusion
timeFrame: Within 30 days (+/- 3 days) after the last dose of AUTO3.
measure: Number of Patients With Dose Limiting Toxicity (DLT) of AUTO3
timeFrame: Within 30 days (+/- 3 days) after the last dose of AUTO3.
measure: Number of Patients Achieving Morphological Remission (Complete Response(CR) or Complete Response With Incomplete Count Recovery (CRi) and Minimal Residual Disease (MRD)-Negative Response in the Bone Marrow (PCR)).
timeFrame: Within 30 days (+/- 3 days) post AUTO3 infusion
Secondary outcomes:
measure: Feasibility of Generating AUTO3: Number of Patients' Cells Successfully Manufactured as a Proportion of the Number of Patients Undergoing Leukapheresis
timeFrame: Up to 8 weeks post leukapheresis
measure: Event-Free Survival (EFS) by Morphological Analysis
timeFrame: Up to 2 years
measure: Number of Patients With CD19- and/or CD22-negative Relapse
timeFrame: Up to 2 years
measure: Relapse-Free Survival (RFS) by Morphological Analysis
timeFrame: Up to 2 years
measure: Overall Survival (OS)
timeFrame: Up to 2 years after the last patient was infused
measure: Expansion of AUTO3 Following Adoptive Transfer
timeFrame: Up to 2 years
measure: Persistence of AUTO3 Following Adoptive Transfer
timeFrame: Up to 2 years
measure: Duration of B Cell Aplasia
timeFrame: Up to 2 years
Other outcomes:
Locations:
city: London
country: United Kingdom
facility: Great Ormond Street Hospital for Children NHS Foundation Trust
city: London
country: United Kingdom
facility: University College London Hospitals NHS Foundation Trust
city: Manchester
country: United Kingdom
facility: Royal Manchester Children's Hospital
Study officials:
References: