Acute lymphoblastic leukaemia (ALL) MedDRA version: 20.0 Level: LLT Classification code 10000845 Term: Acute lymphoblastic leukemia System Organ Class: 100000004864 MedDRA version: 20.0 Level: LLT Classification code 10063625 Term: Acute lymphoblastic leukemia recurrent System Organ Class: 100000004864
Conditions
Sponsors
Autolus Limited
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Paediatric and young adult patients 1. Male or female paediatric and young adults (age 1-24 years) with high risk relapsed or refractory B-cell Acute Lymphoblastic Leukaemia 2. Documented CD19 and or CD22 expression 3. Detectable disease in the bone marrow (Phase I) at enrolment 4. Absolute Lymphocyte Count =0.5 x 10e9/l at enrolment 5. Adequate renal, hepatic, pulmonary & cardiac function including: - Left ventricular shortening fraction =28% confirmed by ECHO, or left ventricular ejection fraction (LVEF) =45% confirmed by ECHO. - Baseline oxygen saturation >92% on room air. 6. Karnofsky (age 10-24 years) or Lansky (age 5% blasts in the BM by flow cytometry or molecular assay following frontline induction therapy OR - 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 - Isolated CNS relapse but with =CNS grade 2 disease at time of enrolment Adult patients 1. Age 25 or older 2. Eastern cooperative oncology group performance status of 0 or 1 3. Relapsed or refractory B-precursor ALL defined as one of the following: 4. Patients with Philadelphia chromosome positive ALL are eligible if they are intolerant to or have failed 2 lines of TKI therapy, or if TKI therapy is contraindicated 5. Documentation of CD19 and/ or CD22 expression on leukaemic blasts in the BM, peripheral blood, or CSF by flow cytometry within 3 months of screening 6. For females of childbearing potential, a negative serum or urine pregnancy test 7. For females who are not postmenopausal or who are not surgically sterile & males, two methods of contraception should be used 8. Absolute lymphocyte count =0.5 x 109/L at enrolment 9. Adequate renal, hepatic, pulmonary, and cardiac function defined as: - LVEF =45% confirmed by ECHO or MUGA. - Baseline oxygen saturation >92% on room air Are the trial subjects under 18? yes Number of subjects for this age range: 100 F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 40 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 4
Exclusion criteria
Exclusion criteria: Paediatric and young adult patients 1. Isolated extramedullary disease relapse (in Phase II, patients with isolated CNS relapse post-SCT or pre-SCT if high risk, aged 16-24 years on therapy relapse or = 2nd relapse with =CNS grade 2 disease at time of enrolment) 2. Active CNS involvement of ALL, defined by CNS Grade 3 per National Comprehensive Cancer Network guidelines. Patients developing CNS Grade 3 disease at any time after enrolment will also be excluded 3. Active infectious bacterial or viral disease requiring treatment. 4. Females who are pregnant or lactating. 5. Females of child-bearing potential and post-pubertal males who unwilling to use highly effective methods of contraception during the treatment period and 1 year after AUTO3 infusion. 6. Pre-existing significant neurological disorder 7. Stem Cell Transplant patients only: active significant (overall Grade =II, Seattle criteria) acute graft versus host disease (GVHD) or moderate/severe chronic GVHD (National Institutes of Health [NIH] consensus criteria) requiring systemic steroids or other immunosuppressant within 4 weeks of enrolment 8. The following treatments are excluded: - Steroids: Therapeutic doses must be stopped >72 hours prior to AUTO3 infusion and leukapheresis. - Allogeneic cellular therapy: Any donor lymphocyte infusions must be completed >6 weeks prior to AUTO3 infusion - GVHD therapies: Any drug used for GVHD must be stopped >4 weeks prior to AUTO3 infusion - Chemotherapy: Stopped 1 week prior to leukapheresis and 2 days prior to starting pre-conditioning chemotherapy - Intrathecal therapy: Methotrexate within 4 weeks and other intrathecal chemotherapy (eg Ara-C) within 2 weeks prior to starting pre conditioning chemotherapy. - Live vaccine = 4 weeks prior to enrolment. 9. Known allergy to albumin, dimethyl sulfoxide, cyclophosphamide or fludarabine. Adult patients 1. Isolated extramedullary disease 2. Diagnosis of Burkitt's leukaemia/lymphoma or chronic myelogenous leukaemia lymphoid blast crisis 3. Females who are pregnant or lactating 4. History or presence of clinically relevant CNS pathology within 3 months prior to enrolment, severe brain injuries, dementia, Parkinson’s disease, cerebellar disease, organic brain syndrome, uncontrolled mental illness, or psychosis 5. Presence of CNS-3 disease or CNS-2 disease with neurological changes. Patients developing CNS Grade 3 disease or symptomatic CNS-2 disease at any time after enrolment will also be excluded 6. Clinically significant, uncontrolled heart disease or a recent cardiac event 7. Patients with a history or evidence of pulmonary embolism requiring ongoing therapeutic anticoagulation at the time of pre-conditioning 8. Patients with active gastrointestinal bleeding 9. Patients with any major surgical intervention in the last 3 months 10. Active infectious bacterial or viral disease or fungal requiring treatment with i.v. antimicrobials 11. History of autoimmune disease resulting in end organ injury or requiring systemic immunosuppression/systemic disease modifying agents within the last 24 months. Any autoimmune disease with CNS involvement 12. History of other malignant neoplasms unless disease free for at least 24 months 13. History of concomitant genetic syndrome such as Fanconi anaemia, Shwachman-Diamond syndrome, Kostmann syndrome or any other known BM failure syndrome 14. Stem cell transplant patients only: Active significant acute GVHD or moderate/severe chronic GVHD) requiring systemic s
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Phase I: Assess the safety and tolerability of AUTO3 AUTO3 in both paediatric and adult patients and identify the recommended Phase II dose, dosing schedule & maximum tolerated dose, where applicable. Phase II: Evaluate the anti-leukaemic effect of AUTO3 in paediatric and young adult patients (aged 1-24 years).;Secondary Objective: - Evaluate safety and tolerability of AUTO3 - Evaluate the clinical efficacy of AUTO3 - Evaluate feasibility of generating AUTO3 - Assess the expansion & persistence of AUTO3 - Duration of B cell aplasia;Primary end point(s): Phase I: - Incidence of Grade 3-5 toxicity within the dose limiting toxicity (DLT) period of AUTO3 infusion - Frequency of dose limiting toxicity of AUTO3 Phase II: - Proportion of patients achieving morphological remission (Complete Response [CR] or complete response with incomplete recovery of counts [CRi]) and MRD-negative response in BM within approx. 30 days post AUTO3 infusion;Timepoint(s) of evaluation of this end point: - Safety endpoint evaluations will be conducted throughout the study - Grade 3-5 toxicity within the DLT period - MRD-negative response captured approx. 30 days post-dose - Morphological remission captured at time of CR/CRi | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): - Frequency and severity of AEs and SAEs. - Incidence and duration of severe hypogammaglobulinemia - Proportion of patients that AUTO3 can be generated - Proportion of patients achieving morphological remission (CR or CRi) and MRD-negative response in bone marrow approx. 30 days post-AUTO3 infusion - Proportion of patients in molecular remission without further therapy. - Relapse Free Survival (RFS), Event Free Survival (EFS), Progression-Free Survival (PFS) and Overall Survival (OS) following first AUTO3 treatment - Incidence of CD19 and or CD22 negative escape - Quantitative PCR and/or flow cytometry at a range of time points in the peripheral blood and bone marrow - Depletion of circulating B cell assessments - Health-related quality of life (HRQOL);Timepoint(s) of evaluation of this end point: - Safety endpoints and AUTO3 monitoring evaluations will be conducted throughout the study - Feasibility to generate AUTO3 assessed after manufacture - Morphological remission and MRD-negative response assessed approx. 30 days post AUTO3 dose - RFS, EFS at 6, 12 and 24 months - Progression free survival (PFS) and overall survival (OS) measured from last AUTO3 treatment to relapse/disease progression and death, respectively - Molecular remission at 6 months, 1 & 2 years post AUTO3 treatment - Biomarker/PD measurements taken at screening, pre-conditioning, day 0, 2, 5, 7, 9, 12, 14, 21, 30 and 2, 3, 4, 6, 8, 10, 12, 15, 18, 21 & 24 months post treatment - HRQOL at 1, 3, 6, 8, 12 and 24 months | — |
Countries
United Kingdom, United States
Contacts
Public ContactProject Manager
Autolus Limited
Outcome results
None listed