Relapsed or refractory Diffuse Large B Cell Lymphoma (DLBCL) and large B cell lymphoma subsets MedDRA version: 21.0 Level: PT Classification code 10012822 Term: Diffuse large B-cell lymphoma refractory System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 20.0 Level: HLT Classification code 10012819 Term: Diffuse large B-cell lymphomas System Organ Class: 100000004851 MedDRA version: 21.0 Level: PT Classification code 10012818 Term:
Conditions
Sponsors
Autolus Limited
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Male or female, aged =18 years that provide written informed consent. 2. Eastern Cooperative Oncology Group performance status 0 to 1. 3. Histologically confirmed DLBCL and large B cell lymphoma (at last relapse) and permitted subsets. 4. Chemotherapy-refractory disease or Relapse after at least two lines of therapy or after ASCT. 5. PET-positive disease per Lugano classification. 6. Females of childbearing potential must have a negative serum or urine pregnancy test at screening, prior to pre-conditioning and confirmed before receiving the first dose of AUTO3. 7. Adequate renal, hepatic, pulmonary, and cardiac function defined as: a. Creatinine clearance =40 cc/min b. Serum alanine aminotransferase (ALT)/ aspartate aminotransferase (AST) =2.5 x ULN. c. Total bilirubin =1.5 x ULN. d. Left Ventricular Ejection Fraction (LVEF) =50% unless the institutional lower limit of normal is lower. e. Baseline oxygen saturation >92% on room air and =Grade 1 dyspnoea. 8. Patient has adequate bone marrow function and meets the following criteria: a. Absolute neutrophil count =1.0 x 10e9/L. b. Absolute lymphocyte count =0.3 x 10e9/L (at enrolment and prior to leukapheresis). c. Haemoglobin =80 g/L; d. Platelets =75 x 10e9/L. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 101 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 70
Exclusion criteria
Exclusion criteria: 1. Prior allogeneic haematopoietic stem cell transplantation. 2. Females who are pregnant or lactating. 3. History or presence of clinically relevant central nervous system (CNS) pathology within 3 months prior to enrolment. 4. Patients with active CNS involvement by malignancy. 5. Clinically significant, uncontrolled heart disease or a recent cardiac event. 6. Active bacterial, viral disease or fungal infection requiring systemic treatment. 7. History of autoimmune disease resulting in end organ injury or requiring systemic immunosuppression/systemic disease modifying agents in the last 2 years. 8. Evidence of active pneumonitis on chest computed tomography (CT) scan at screening or history of drug-induced pneumonitis, idiopathic pulmonary fibrosis, organising pneumonia, idiopathic pneumonitis. 9. Prior treatment with therapy targeting programmed cell death protein 1 (PD-1), programmed cell death ligand 1 (PD-L1) or cytotoxic T lymphocyte-associated protein 4 (CTLA 4) or prior treatment with tumour necrosis factor receptor superfamily (TNFRSF) agonists and CD357 (glucocorticoid-induced tumour necrosis factor receptor family related protein) within 6 weeks prior to AUTO3 infusion. 10. Prior CD19 or CD22 targeted therapy. 11. The following medications are excluded: a. Steroids: Therapeutic doses of corticosteroids within 7 days of leukapheresis or 72 hours prior to AUTO3 administration. b. Immunosuppression: Immunosuppressive medication must be stopped =2 weeks prior to leukapheresis or AUTO3 infusion. c. Cytotoxic chemotherapies within 2 weeks of infusion and 1 week prior to leukapheresis. d. Antibody therapy use including anti-CD20 therapy within 4 weeks prior to infusion, or 5 half-lives of the respected antibody, whichever is shorter. e. Granulocyte-colony stimulating factor (G-CSF) less than 10 days prior to leukapheresis. f. Live vaccine =4 weeks prior to enrolment. g. Prophylactic intrathecal therapy: Methotrexate within 4 weeks and other intrathecal chemotherapy within 2 weeks prior to starting pre-conditioning chemotherapy. 12. Prior radiation therapy within 4 weeks or chest within 24 weeks of AUTO3 infusion . 13. Patients receiving any other investigational agents or concurrent biological, chemotherapy or radiation therapy. 14. Known allergy to albumin, dimethyl sulphoxide, cyclophosphamide or fludarabine, anti-PD-1 antibody or tocilizumab. 15. Contraindications to receive anti-PD1 antibody will be excluded from cohorts requiring administration this administration. Phase I expansion only: 16. Subjects who do not have adequate caregiver support for outpatient care. 17. Subjects who are staying greater than 60 minutes (or whatever is permissible per institutional outpatient transplant SOP)?from the clinical trial site at the time of treatment.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Phase I: Assess the safety and tolerability of AUTO3 with pembrolizumab and identify the recommended Phase II dose & maximum tolerated dose, where applicable. Phase 2: To evaluate the safety, tolerability and anti-tumour effect of AUTO3 and pembrolizumab.;Secondary Objective: - Evaluate the overall safety and tolerability of AUTO3 with pembrolizumab - Evaluate the clinical efficacy of AUTO3 with pembrolizumab - Evaluate feasibility of generating AUTO3 - Assess the expansion & persistence after AUTO3 treatment - Duration of B cell aplasia;Primary end point(s): Phase I: - Incidence of Grade 3-5 toxicity within 75 days of AUTO3 infusion - Frequency of dose limiting toxicity of AUTO3 Phase II: - Best overall response post AUTO3 infusion. ;Timepoint(s) of evaluation of this end point: - Safety endpoint evaluations will be conducted throughout the study - Grade 3-5 toxicity captured 75 days post dose - Overall response at 1, 3, 6, 9, 12, 18 and 24 months post AUTO3 infusion. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): -To assess the overall safety and tolerability of AUTO3 with pembrolizumab: Frequency and severity of all AEs and SAEs. Incidence and duration of severe hypogammaglobulinaemia. -To evaluate the feasibility of generating the ATIMP, AUTO3: Proportion of patients for whom an AUTO3 product can be generated (feasibility). -To evaluate the overall clinical efficacy of AUTO3 with pembrolizumab: Determine the CR rate following treatment with AUTO3. To evaluate clinical outcomes including duration of response (DOR), DFS, PFS and OS. -To determine the expansion and persistence of AUTO3 following adoptive transfer. - Duration of B cell aplasia. Polymerase Chain Reaction (PCR) and/or flow cytometry at a range of time points in the peripheral blood depletion of circulating B cells assessed by flow cytometry at a range of time points in the peripheral blood;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 - Objective response at 1, 3, 6 and 24 months post AUTO3 infusion - Duration of response from first observation of complete or partial response to progression, relapse or death - Disease free survival from first observation of complete response to progression or relapse or death - Progression free and overall survival measured from last AUTO3 treatment to relapse/disease progression and death, respectively - PK/PD/biomarker measurements taken at screening, pre-conditioning, day -5, 1, 4, 7, 10, 12, 14, 16, 18, 20, 28, 56 and at 3, 4, 5, 6, 9, 12, 15, 18 & 24 months post treatment. | — |
Countries
France, Italy, Spain, United Kingdom, United States
Contacts
Public ContactProject Manager
Autolus Limited
Outcome results
None listed