Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL)
Conditions
Keywords
Diffuse Large B Cell Lymphoma, Relapsed Diffuse Large B Cell Lymphoma, Refractory Diffuse Large B Cell Lymphoma, AUTO3, PD-1, Anti PD-1 antibody
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 with consolidation or pre-conditioning with anti-PD1 antibody in patients with DLBCL
Detailed description
The study will consist of 2 phases, a Phase I or dose escalation and expansion phase, and a Phase II. Patients with relapsed or refractory DLBCL 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, a CD19 and CD22 dual targeting CAR T cell product. Following pre-conditioning by a chemotherapeutic regimen, the patient will receive AUTO 3 intravenously as a single dose and in addition a limited duration of treatment with an anti-PD1 antibody (either as part of the pre-conditioning regimen or consolidation). Patients will then enter a 36-month follow-up period.
Interventions
BIOLOGICALAUTO3
Following preconditioning with chemotherapy (cyclophosphamide and fludarabine) patients will be treated with doses from 50 x 10⁶ to 900 x 10⁶ CD19/ CD22 Chimeric Antigen Receptor (CAR) positive T cells with limited duration of anti-PD1 antibody (pembrolizumab).
Sponsors
Autolus Limited
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
A dose escalation and expansion phase (Phase I) followed by Phase II
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Male or female, aged ≥18 years. 2. Willing and able to give written, informed consent. 3. Eastern Cooperative Oncology Group (ECOG) Performance Status 0 to 1. 4. Histologically confirmed DLBCL and large B cell lymphoma subsets, including: Phase I and Phase II Cohort 1: 1. DLBCL, not otherwise specified (NOS), per World Health Organisation classification and DLBCL with MYC oncogene (MYC) and B cell lymphoma 2 (BCL2) gene and/or B cell lymphoma 6 (BCL6) gene rearrangements (double/triple hit). 2. Transformed DLBCL from follicular lymphoma (FL). 3. High-grade B cell lymphoma with MYC expression (excluding Burkitt's lymphoma) Phase I and Phase II Cohort 2. 4. Transformed DLBCL from other indolent lymphomas (excluding Richter's transformation). 5. Primary mediastinal large B cell lymphoma. 5. Chemotherapy-refractory disease, defined as one or more of the following: 1. Stable disease (≤12 months) or progressive disease as best response to most recent chemotherapy containing regimen. Refractory disease after frontline chemo-immunotherapy is allowed. 2. Disease progression or recurrence in ≤12 months of prior autologous haematopoietic stem cell transplantation (ASCT). OR 6. Relapse after ≥two lines of therapy or after ASCT. At a minimum: 1. Patients must have received rituximab or another anti-cluster of differentiation antigen 20 (CD20) monoclonal antibody (unless Investigator determines that tumour is CD20-negative) and an anthracycline-containing chemotherapy regimen. 2. Patients must have either failed ASCT, or be ineligible for or not consenting to ASCT. 3. Patients with transformed DLBCL must have received at least one line of therapy after transformation to DLBCL. 7. Positron emission tomography-positive disease per Lugano classification. 8. For females of childbearing potential, a negative serum or urine pregnancy test must be documented at screening, prior to pre-conditioning and confirmed before receiving the first dose of study treatment. For females who are not postmenopausal or surgically sterile, highly effective methods of contraception must be used during the treatment period and for at least 12 months after the last dose of study treatment. 9. For males, it must be agreed that that two acceptable methods of contraception are used. 10. Adequate renal, hepatic, pulmonary, and cardiac function defined as: 1. Creatinine clearance ≥40 cc/min. 2. Serum alanine aminotransferase / aspartate aminotransferase ≤2.5 x upper limit of normal (ULN). 3. Total bilirubin ≤1.5 x ULN, except in subjects with Gilbert's syndrome. 4. Left ventricular ejection fraction (LVEF) ≥50% (by echocardiogram \[ECHO\] or Multiple gated acquisition scan \[MUGA\]) unless the institutional lower limit of normal is lower. 5. Baseline oxygen saturation \>92% on room air and ≤Grade 1 dyspnoea. 11. Patient has adequate bone marrow (BM) function without requiring ongoing blood product or granulocyte-colony stimulating factor support and meets the following criteria: 1. Absolute neutrophil count ≥1.0 × 10\^9/L. 2. Absolute lymphocyte count ≥0.3 × 10\^9/L (at enrolment and prior to leukapheresis). 3. Haemoglobin ≥80 g/L. 4. Platelets ≥75 × 10\^9/L 12. No contra-indications for leukapheresis.
Exclusion criteria
1. Prior allogeneic haematopoietic stem cell transplant. 2. Females who are pregnant or lactating. 3. History or presence of clinically relevant CNS pathology such as epilepsy, paresis, aphasia, stroke within prior 3 months, severe brain injuries, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, uncontrolled mental illness, or psychosis. 4. Patients with active CNS involvement by malignancy. Patients with history of central nervous system (CNS) involvement with malignancy may be eligible if CNS disease has been effectively treated and provided treatment was at least 4 weeks prior to enrolment (at least 8 weeks prior to AUTO3 infusion). 5. Clinically significant, uncontrolled heart disease or a recent (within 12 months) cardiac event. 1. Uncontrolled cardiac arrhythmia (patients with rate-controlled atrial fibrillation are not excluded). 2. Evidence of pericardial effusion 6. Patients with a history (within 3 months) or evidence of deep vein thrombosis or pulmonary embolism requiring ongoing therapeutic anticoagulation at the time of pre-conditioning. 7. Patients with active gastrointestinal bleeding. 8. Patients with any major surgical intervention in the last 3 months. 9. Active bacterial, viral or fungal infection requiring systemic treatment. Active or latent hepatitis B infection or hepatitis C infection. Testing positive for human immunodeficiency virus, human T cell lymphotropic virus (HTLV1 and 2) or syphilis. 10. History of autoimmune disease resulting in end organ injury or requiring systemic immunosuppression/systemic disease modifying agents within the last 24 months. 11. Patients with a known history or prior diagnosis of optic neuritis or other immunologic or inflammatory disease affecting the CNS. 12. Evidence of active pneumonitis on chest computed tomography (CT) scan at screening or history of drug-induced pneumonitis, idiopathic pulmonary fibrosis, organising pneumonia, or idiopathic pneumonitis. 13. History of other malignant neoplasms unless disease free for at least 24 months (carcinoma in situ, non-melanoma skin cancer, breast or prostate cancer on hormonal therapy allowed). 14. Prior treatment with PD1, programmed cell death ligand 1 (PD-L1), or cytotoxic T lymphocyte-associated protein-4-targeted therapy, or tumour necrosis factor (TNF) receptor superfamily agonists within 6 weeks prior to AUTO3 infusion. 15. Prior treatment with investigational or approved gene therapy or cell therapy products until a dose level has treated at least three patients and has been declared safe. 16. Prior CD19 or CD22 targeted therapy. 17. The following medications are excluded: 1. Steroids: Therapeutic doses of corticosteroids within 7 days of leukapheresis or 72 hours prior to AUTO3 administration. However, physiological replacement, topical, and inhaled steroids are permitted. 2. Immunosuppression: Immunosuppressive medication must be stopped ≥2 weeks prior to leukapheresis or AUTO3 infusion. 3. Cytotoxic chemotherapies within 2 weeks of AUTO3 infusion and 1 week prior to leukapheresis (2 weeks for lymphodepleting chemotherapy). 4. Antibody therapy use including anti-CD20 therapy within 2 weeks prior to AUTO3 infusion, or 5 half-lives of the respective antibody, whichever is shorter. 5. Granulocyte-colony stimulating factor less than 10 days prior to leukapheresis. 6. Live vaccine ≤4 weeks prior to enrolment. 7. Prophylactic intrathecal therapy: Methotrexate within 4 weeks and other intrathecal chemotherapy (e.g. Ara-C) within 2 weeks prior to starting pre-conditioning chemotherapy. 18. Prior limited radiation therapy within 4 weeks of AUTO3 infusion or within 24 weeks for definitive radiation to chest. 19. Research participants receiving any other investigational agents, or concurrent biological, chemotherapy, or radiation therapy. 20. Known allergy to albumin, dimethyl sulphoxide (DMSO), cyclophosphamide or fludarabine, pembrolizumab or tocilizumab. 21. Any contraindications to receive anti-PD1 antibody pembrolizumab will be excluded from cohorts requiring administration of pembrolizumab. 22. Patients, who in the opinion of the Investigator, may not be able to understand or comply with the safety monitoring requirements of the study. 23. Any other condition that in the Investigator's opinion would make the patient unsuitable for the clinical trial. Phase I outpatient cohort: 24. Subjects who do not have caregiver support (in line with institutional outpatient transplant guidelines) for outpatient/ambulatory care setting. 25. Subjects who are staying greater than 60 minutes (or whatever is permissible per institutional outpatient transplant guidelines) from the clinical trial site at the time of treatment. For AUTO3 Infusion: Patients meeting any of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase I Escalation - Safety (Number of Participants With Grade 3-5 Toxicities) and Identification of Recommended Phase II Dose and Schedule (RP2D). | Within 75 days of AUTO3 infusion | Number of patients with Grade 3-5 toxicities during escalation part of Phase I (Cohorts: 50x10\^6 CD19/22 CAR+ T Cells; 50x10\^6 CD19/22 CAR+ T Cells+Pembrolizumab \[Pem\] Day 14; 150-450x10\^6 CD19/22 CAR+ T Cells+Pem Day 14; 150-450x10\^6 CD19/22 CAR+ T Cells+Pem Day -1 in Inpatient Setting) Dose-limiting toxicity defined as: * New non-hematological AE Grade \>=3 using NCI CTCAE (5.0), probably/definitely related to AUTO3, occurring in DLT evaluation period, which did not resolve to Grade 2 or better in 14 days, despite supportive measures. * Grade 4 CRS, neurotoxicity (NT), or cerebral edema, or Grade 3 NT that lasted \>72 hrs * Grade \>3 Disseminated Intravascular Coagulation * Grade \>2 Infusion Reaction with AUTO3 * Grade 4 or 5 event not managed with conventional supportive measures or necessitating dose reduction or modification to trial therapy * Any event that in opinion of Investigator and/or medical monitor put patient at undue risk could also have been considered DLT |
| Phase II - Overall Response Rate as Per Lugano Criteria | Up to 2 years | This was not analysed due to study termination prior to initiation of Phase II. End of study notification submitted to Medicines and Healthcare products Regulatory Agency (MHRA) (reference 46113/0003/001-0016) - The Last patient last visit was 19 October 2023 (at end of Phase 1) and the study is considered completed (End of study). As per protocol v10.0, end of study is defined as 36 months after the last patient has received AUTO3 infusion or earlier in the event of death or consent withdrawal. Fifty-two patients received AUTO3 in the Phase I part of the study. After reviewing the data and taking into consideration the available treatment landscape in r/r DLBCL, Autolus didn't progress AUTO3-DB1 into the Phase II part of the study. Autolus notified MHRA on 08 November 2021 about enrolment to Phase II of the study (Autolus has decided not to progress AUTO3-DB1 into the Phase II part of the study), and MHRA acknowledged it on 09 November 2021. |
| Phase I Expansion - Safety (Incidence of Grade 3-5 Toxicities) in the Outpatient / Ambulatory Care Setting | Within 75 days of AUTO3 infusion | The incidence of Grade 3-5 toxicities during the expansion part of Phase I (Dose cohort: 150 to 450 x 10\^6 CD19/CD22 CAR-positive T Cells + Pembrolizumab at Day -1 in an Outpatient Setting) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS). | Up to 2 years | The progression-free survival was defined as the time from first AUTO3 treatment until the first progression of disease or death from any cause, whichever occurred first. Patients who reached the time point of analysis without a known record of progression had the PFS censored at the date of last adequate disease assessment. Patients who received a new stem cell transplantation (SCT) were censored at the start date of this new SCT. Patients who received a new anti-cancer therapy or discontinued from the study for other reason than disease progression and who were lost to follow-up were censored at the date of last adequate disease assessment. Response defined by Lugano classification (see Outcome Measure 5). |
| Overall Survival (OS). | Up to 2 years | Overall survival (OS) was defined as the time from the date of first AUTO3 treatment up to the date of death, regardless of cause of death. Patients alive at the time of the analysis had the OS censored at the date of last assessment when the patient was known alive. |
| Duration of Response (DOR). | Up to 2 years | Duration of response was defined as the time from the first observed complete response or partial response \[from the first post-baseline response assessment\] until the date of first progressive disease or death due to underlying cancer (primary reason for death=progressive disease), whichever occurred first. Only responders (patients with complete response \[CR\] or partial response \[PR\]) were included in the analysis of duration of response. Response defined by Lugano classification (see Outcome Measure 5). Patients with death not due to underling cancer (primary reason for death=adverse event \[AE\] or Other or Unknown) or who received new anti-cancer therapy other than SCT or discontinued from the study for other reason than progressive disease (PD) or who were lost to follow-up or reached the time point of analysis without a known record of progression or death had the duration of response censored at the date of last adequate disease assessment for response. |
| Feasibility of Generating AUTO3: Number of Patients' Cells Successfully Manufactured as a Proportion of the Number of Patients Undergoing Leukapheresis. | Up to 8 weeks post leukapheresis. | Feasibility of product generation was examined by assessing the number of AUTO3 successfully manufactured as a fraction of the number of patients undergoing leukapheresis (all patients enrolled). |
| Determine the Complete Response Rate Following Treatment With AUTO3, as Per Lugano Criteria. | Up to 2 years | Participants achieving objective response per Lugano criteria based on independent central radiology review. The Lugano classification of response by 18F-2-fluoro-2-deoxy-D-glucose fluorodeoxyglucose (FDG) PET-CT: 1. no uptake or no residual uptake (when used interim) 2. slight uptake, but below blood pool (mediastinum) 3. uptake above mediastinal, but below or equal to uptake in the liver 4. uptake slightly to moderately higher than liver 5. markedly increased uptake or any new lesion (on response evaluation) Non-progressive disease * complete metabolic response - score of 1, 2 or 3 in nodal or extranodal sites with or without a residual mass * partial metabolic response - score of 4 or 5 with reduced uptake compared with baseline and residual mass(es) of any size * stable disease or no metabolic response - score of 4 or 5 with no obvious change in FDG uptake Progressive disease score 4 or 5 in any lesion with an increase in intensity of FDG uptake from baseline (and/or |
Other
| Measure | Time frame | Description |
|---|---|---|
| To Determine the Expansion and Persistence of AUTO3 Following Adoptive Transfer in Different Lymphoma Subtypes (Maximum Concentration) | Up to 2 years | Analysis of cells in peripheral blood by polymerase chain reaction and/or flow cytometry at a range of time points in the peripheral blood. |
| To Determine the Expansion and Persistence of AUTO3 Following Adoptive Transfer in Different Lymphoma Subtypes (Time to Maximum Concentration) | Up to 2 years | Analysis of cells in peripheral blood by polymerase chain reaction and/or flow cytometry at a range of time points in the peripheral blood. |
| To Determine the Expansion and Persistence of AUTO3 Following Adoptive Transfer in Different Lymphoma Subtypes (Area Under the Curve From Day 0 to Day 28) | Up to 2 years | Analysis of cells in peripheral blood by polymerase chain reaction and/or flow cytometry at a range of time points in the peripheral blood. |
Countries
United Kingdom, United States
Participant flow
Pre-assignment details
A total of 73 adult patients with r/r DLBCL were screened and 62 patients were enrolled. For these 62 patients AUTO3 was manufactured using leukapheresed autologous peripheral blood mononuclear cells, modified with a bicistronic transgene. Ten patients did not receive AUTO3 infusion, in 6 patients this was due to death, in 3 patients due to progressive disease (without death), and in 1 patient due to failed eligibility.
Participants by arm
| Arm | Count |
|---|---|
| 50 x 10^6 Cluster of Differentiation (CD) 19/CD22 CAR-positive T Cells Patients in this cohort received actual doses of 50 to 150 x 10\^6 CD19/CD22 CAR-positive T cells | 4 |
| 50 x 10^6 CD19/CD22 CAR-positive T Cells + Pembrolizumab at Day 14 All patients in this cohort received actual dose of 50 x 10\^6 CD19/CD22 CAR-positive T cells + pembrolizumab at Day 14 | 3 |
| 150 to 450 x 10^6 CD19/CD22 CAR-positive T Cells + Pembrolizumab at Day 14 Patients in this cohort received actual doses of 150 to 495 x 10\^6 CD19/CD22 CAR-positive T cells + pembrolizumab at Day 14 | 8 |
| 150 to 450 x 10^6 CD19/CD22 CAR-positive T Cells + Pembrolizumab at Day -1 in an Inpatient Setting Patients in this cohort received actual doses of 125 to 450 x 10\^6 CD19/CD22 CAR-positive T cells + pembrolizumab at Day -1 in an inpatient setting | 17 |
| 150 to 450 x 10^6 CD19/CD22 CAR-positive T Cells + Pembrolizumab at Day -1 in an Outpatient Setting Patients in this cohort received actual doses of 129 to 450 x 10\^6 CD19/CD22 CAR-positive T cells + pembrolizumab at Day -1 in an outpatient setting | 20 |
| Total | 52 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Death | 0 | 0 | 2 | 3 | 4 |
| Overall Study | Physician Decision | 0 | 0 | 0 | 1 | 0 |
| Overall Study | Progressive disease | 4 | 2 | 3 | 10 | 8 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 0 | 4 |
Baseline characteristics
| Characteristic | 50 x 10^6 CD19/CD22 CAR-positive T Cells + Pembrolizumab at Day 14 | 50 x 10^6 Cluster of Differentiation (CD) 19/CD22 CAR-positive T Cells | Total | 150 to 450 x 10^6 CD19/CD22 CAR-positive T Cells + Pembrolizumab at Day -1 in an Outpatient Setting | 150 to 450 x 10^6 CD19/CD22 CAR-positive T Cells + Pembrolizumab at Day -1 in an Inpatient Setting | 150 to 450 x 10^6 CD19/CD22 CAR-positive T Cells + Pembrolizumab at Day 14 |
|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 15 Participants | 4 Participants | 10 Participants | 1 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 4 Participants | 37 Participants | 16 Participants | 7 Participants | 7 Participants |
| Current lymphoma subtype Activated B cell type | 2 Participants | 2 Participants | 5 Participants | 0 Participants | 0 Participants | 1 Participants |
| Current lymphoma subtype Follicular lymphoma | 1 Participants | 0 Participants | 10 Participants | 5 Participants | 2 Participants | 2 Participants |
| Current lymphoma subtype Germinal center B cell type | 0 Participants | 0 Participants | 24 Participants | 9 Participants | 11 Participants | 4 Participants |
| Current lymphoma subtype High Grade B Cell Lymphoma | 0 Participants | 0 Participants | 3 Participants | 1 Participants | 2 Participants | 0 Participants |
| Current lymphoma subtype Missing | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Current lymphoma subtype Nodal marginal zone lymphoma | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Current lymphoma subtype Non-Germinal center B cell type | 0 Participants | 1 Participants | 7 Participants | 3 Participants | 2 Participants | 1 Participants |
| Current lymphoma subtype Primary Mediastinal Large B Cell Lymphoma | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Disease stage Stage II | 0 Participants | 0 Participants | 6 Participants | 3 Participants | 2 Participants | 1 Participants |
| Disease stage Stage III | 2 Participants | 0 Participants | 11 Participants | 4 Participants | 3 Participants | 2 Participants |
| Disease stage Stage IV | 1 Participants | 4 Participants | 35 Participants | 13 Participants | 12 Participants | 5 Participants |
| Eastern Cooperative Oncology Group (ECOG) score ECOG = 0 | 1 Participants | 1 Participants | 26 Participants | 8 Participants | 9 Participants | 7 Participants |
| Eastern Cooperative Oncology Group (ECOG) score ECOG = 1 | 2 Participants | 3 Participants | 26 Participants | 12 Participants | 8 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 6 Participants | 5 Participants | 1 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 4 Participants | 40 Participants | 9 Participants | 16 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 6 Participants | 6 Participants | 0 Participants | 0 Participants |
| Extranodal disease present No | 2 Participants | 2 Participants | 20 Participants | 7 Participants | 6 Participants | 3 Participants |
| Extranodal disease present Yes | 1 Participants | 2 Participants | 32 Participants | 13 Participants | 11 Participants | 5 Participants |
| International Prognostic Index High-intermediate risk | 0 Participants | 2 Participants | 13 Participants | 2 Participants | 6 Participants | 3 Participants |
| International Prognostic Index High risk | 0 Participants | 0 Participants | 10 Participants | 5 Participants | 5 Participants | 0 Participants |
| International Prognostic Index Low-intermediate risk | 2 Participants | 1 Participants | 16 Participants | 9 Participants | 3 Participants | 1 Participants |
| International Prognostic Index Low risk | 1 Participants | 1 Participants | 8 Participants | 3 Participants | 2 Participants | 1 Participants |
| International Prognostic Index Not done/Unknown | 0 Participants | 0 Participants | 5 Participants | 1 Participants | 1 Participants | 3 Participants |
| Lactate Dehydrogenase | 403.00 U/L | 331.50 U/L | 243.50 U/L | 235.00 U/L | 231.00 U/L | 262.00 U/L |
| Lines of therapy | 3.0 Lines of therapy | 2.5 Lines of therapy | 3.0 Lines of therapy | 3.0 Lines of therapy | 3.0 Lines of therapy | 3.0 Lines of therapy |
| Molecular Subtype Double Expressor (myc and bcl2 overexpression) | 1 Participants | 0 Participants | 8 Participants | 3 Participants | 3 Participants | 1 Participants |
| Molecular Subtype No High Risk Molecular Features | 2 Participants | 2 Participants | 15 Participants | 3 Participants | 6 Participants | 2 Participants |
| Molecular Subtype Not done/Unknown | 0 Participants | 2 Participants | 10 Participants | 7 Participants | 0 Participants | 1 Participants |
| Molecular Subtype ouble Hit (myc/bcl2 or myc/bcl6 rearrangement) | 0 Participants | 0 Participants | 14 Participants | 6 Participants | 4 Participants | 4 Participants |
| Molecular Subtype Triple Hit (myc/bcl2/bcl6 rearrangement) | 0 Participants | 0 Participants | 5 Participants | 1 Participants | 4 Participants | 0 Participants |
| Prior stem cell transplantation | 1 Participants | 0 Participants | 16 Participants | 10 Participants | 3 Participants | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 4 Participants | 3 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 3 Participants | 3 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 3 Participants | 4 Participants | 44 Participants | 14 Participants | 15 Participants | 8 Participants |
| Relapsed/Refractory disease Refractory | 1 Participants | 0 Participants | 12 Participants | 3 Participants | 6 Participants | 2 Participants |
| Relapsed/Refractory disease Relapsed | 0 Participants | 0 Participants | 16 Participants | 11 Participants | 4 Participants | 1 Participants |
| Relapsed/Refractory disease Relapsed and Refractory | 2 Participants | 4 Participants | 24 Participants | 6 Participants | 7 Participants | 5 Participants |
| Sex: Female, Male Female | 3 Participants | 2 Participants | 35 Participants | 16 Participants | 7 Participants | 7 Participants |
| Sex: Female, Male Male | 0 Participants | 2 Participants | 17 Participants | 4 Participants | 10 Participants | 1 Participants |
| Sum of Product of Perpendicular Diameters | 19.31 cm | 17.91 cm | 18.69 cm | 13.19 cm | 21.54 cm | 28.55 cm |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 4 | 2 / 3 | 5 / 8 | 11 / 17 | 6 / 20 | 6 / 10 |
| other Total, other adverse events | 4 / 4 | 3 / 3 | 8 / 8 | 15 / 17 | 19 / 20 | 1 / 10 |
| serious Total, serious adverse events | 2 / 4 | 0 / 3 | 3 / 8 | 10 / 17 | 14 / 20 | 0 / 10 |
Outcome results
Primary
Phase I Escalation - Safety (Number of Participants With Grade 3-5 Toxicities) and Identification of Recommended Phase II Dose and Schedule (RP2D).
Number of patients with Grade 3-5 toxicities during escalation part of Phase I (Cohorts: 50x10\^6 CD19/22 CAR+ T Cells; 50x10\^6 CD19/22 CAR+ T Cells+Pembrolizumab \[Pem\] Day 14; 150-450x10\^6 CD19/22 CAR+ T Cells+Pem Day 14; 150-450x10\^6 CD19/22 CAR+ T Cells+Pem Day -1 in Inpatient Setting) Dose-limiting toxicity defined as: * New non-hematological AE Grade \>=3 using NCI CTCAE (5.0), probably/definitely related to AUTO3, occurring in DLT evaluation period, which did not resolve to Grade 2 or better in 14 days, despite supportive measures. * Grade 4 CRS, neurotoxicity (NT), or cerebral edema, or Grade 3 NT that lasted \>72 hrs * Grade \>3 Disseminated Intravascular Coagulation * Grade \>2 Infusion Reaction with AUTO3 * Grade 4 or 5 event not managed with conventional supportive measures or necessitating dose reduction or modification to trial therapy * Any event that in opinion of Investigator and/or medical monitor put patient at undue risk could also have been considered DLT
Time frame: Within 75 days of AUTO3 infusion
Population: Patients who received at least 1 (complete or partial) dose of AUTO3 (infused set)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 50 x 10^6 CD19/CD22 CAR+ T Cells | Phase I Escalation - Safety (Number of Participants With Grade 3-5 Toxicities) and Identification of Recommended Phase II Dose and Schedule (RP2D). | Patients with Grade 3-5 toxicity | 4 participants |
| 50 x 10^6 CD19/CD22 CAR+ T Cells | Phase I Escalation - Safety (Number of Participants With Grade 3-5 Toxicities) and Identification of Recommended Phase II Dose and Schedule (RP2D). | Patients with dose-limiting toxicity | 0 participants |
| 50 x 10^6 CD19/CD22 CAR+ T Cells + Pembrolizumab at Day 14 | Phase I Escalation - Safety (Number of Participants With Grade 3-5 Toxicities) and Identification of Recommended Phase II Dose and Schedule (RP2D). | Patients with dose-limiting toxicity | 0 participants |
| 50 x 10^6 CD19/CD22 CAR+ T Cells + Pembrolizumab at Day 14 | Phase I Escalation - Safety (Number of Participants With Grade 3-5 Toxicities) and Identification of Recommended Phase II Dose and Schedule (RP2D). | Patients with Grade 3-5 toxicity | 3 participants |
| 150 to 450 x 10^6 CD19/CD22 CAR+ T Cells + Pembrolizumab at Day 14 | Phase I Escalation - Safety (Number of Participants With Grade 3-5 Toxicities) and Identification of Recommended Phase II Dose and Schedule (RP2D). | Patients with Grade 3-5 toxicity | 7 participants |
| 150 to 450 x 10^6 CD19/CD22 CAR+ T Cells + Pembrolizumab at Day 14 | Phase I Escalation - Safety (Number of Participants With Grade 3-5 Toxicities) and Identification of Recommended Phase II Dose and Schedule (RP2D). | Patients with dose-limiting toxicity | 0 participants |
| 150 to 450 x 10^6 CD19/CD22 CAR+ T Cells + Pembrolizumab at Day -1 in an Inpatient Setting | Phase I Escalation - Safety (Number of Participants With Grade 3-5 Toxicities) and Identification of Recommended Phase II Dose and Schedule (RP2D). | Patients with Grade 3-5 toxicity | 13 participants |
| 150 to 450 x 10^6 CD19/CD22 CAR+ T Cells + Pembrolizumab at Day -1 in an Inpatient Setting | Phase I Escalation - Safety (Number of Participants With Grade 3-5 Toxicities) and Identification of Recommended Phase II Dose and Schedule (RP2D). | Patients with dose-limiting toxicity | 0 participants |
Primary
Phase I Expansion - Safety (Incidence of Grade 3-5 Toxicities) in the Outpatient / Ambulatory Care Setting
The incidence of Grade 3-5 toxicities during the expansion part of Phase I (Dose cohort: 150 to 450 x 10\^6 CD19/CD22 CAR-positive T Cells + Pembrolizumab at Day -1 in an Outpatient Setting)
Time frame: Within 75 days of AUTO3 infusion
Population: Patients who received at least 1 (complete or partial) dose of AUTO3 (infused set)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 50 x 10^6 CD19/CD22 CAR+ T Cells | Phase I Expansion - Safety (Incidence of Grade 3-5 Toxicities) in the Outpatient / Ambulatory Care Setting | 0 Participants |
| 50 x 10^6 CD19/CD22 CAR+ T Cells + Pembrolizumab at Day 14 | Phase I Expansion - Safety (Incidence of Grade 3-5 Toxicities) in the Outpatient / Ambulatory Care Setting | 0 Participants |
| 150 to 450 x 10^6 CD19/CD22 CAR+ T Cells + Pembrolizumab at Day 14 | Phase I Expansion - Safety (Incidence of Grade 3-5 Toxicities) in the Outpatient / Ambulatory Care Setting | 0 Participants |
| 150 to 450 x 10^6 CD19/CD22 CAR+ T Cells + Pembrolizumab at Day -1 in an Inpatient Setting | Phase I Expansion - Safety (Incidence of Grade 3-5 Toxicities) in the Outpatient / Ambulatory Care Setting | 0 Participants |
| 150 to 450 x 10^6 CD19/CD22 CAR+ T Cells + Pembrolizumab at Day -1 in an Outpatient Setting | Phase I Expansion - Safety (Incidence of Grade 3-5 Toxicities) in the Outpatient / Ambulatory Care Setting | 13 Participants |
Primary
Phase II - Overall Response Rate as Per Lugano Criteria
This was not analysed due to study termination prior to initiation of Phase II. End of study notification submitted to Medicines and Healthcare products Regulatory Agency (MHRA) (reference 46113/0003/001-0016) - The Last patient last visit was 19 October 2023 (at end of Phase 1) and the study is considered completed (End of study). As per protocol v10.0, end of study is defined as 36 months after the last patient has received AUTO3 infusion or earlier in the event of death or consent withdrawal. Fifty-two patients received AUTO3 in the Phase I part of the study. After reviewing the data and taking into consideration the available treatment landscape in r/r DLBCL, Autolus didn't progress AUTO3-DB1 into the Phase II part of the study. Autolus notified MHRA on 08 November 2021 about enrolment to Phase II of the study (Autolus has decided not to progress AUTO3-DB1 into the Phase II part of the study), and MHRA acknowledged it on 09 November 2021.
Time frame: Up to 2 years
Population: This was not evaluated because no dose-limiting toxicities occurred in the Phase 1 part of the study to identify the recommended dose
Secondary
Determine the Complete Response Rate Following Treatment With AUTO3, as Per Lugano Criteria.
Participants achieving objective response per Lugano criteria based on independent central radiology review. The Lugano classification of response by 18F-2-fluoro-2-deoxy-D-glucose fluorodeoxyglucose (FDG) PET-CT: 1. no uptake or no residual uptake (when used interim) 2. slight uptake, but below blood pool (mediastinum) 3. uptake above mediastinal, but below or equal to uptake in the liver 4. uptake slightly to moderately higher than liver 5. markedly increased uptake or any new lesion (on response evaluation) Non-progressive disease * complete metabolic response - score of 1, 2 or 3 in nodal or extranodal sites with or without a residual mass * partial metabolic response - score of 4 or 5 with reduced uptake compared with baseline and residual mass(es) of any size * stable disease or no metabolic response - score of 4 or 5 with no obvious change in FDG uptake Progressive disease score 4 or 5 in any lesion with an increase in intensity of FDG uptake from baseline (and/or
Time frame: Up to 2 years
Population: All participants who received at least one dose of AUTO3. Five patients had no positive disease by FDG PET scan prior to pre-conditioning (1 in the 50 x 10\^6 group, 1 in the 150-450 x 10\^6 inpatient group, and 3 in the 15-450 x 10\^6 outpatient group). Hence, they were not evaluable for best overall response.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 50 x 10^6 CD19/CD22 CAR+ T Cells | Determine the Complete Response Rate Following Treatment With AUTO3, as Per Lugano Criteria. | 1 Participants |
| 50 x 10^6 CD19/CD22 CAR+ T Cells + Pembrolizumab at Day 14 | Determine the Complete Response Rate Following Treatment With AUTO3, as Per Lugano Criteria. | 1 Participants |
| 150 to 450 x 10^6 CD19/CD22 CAR+ T Cells + Pembrolizumab at Day 14 | Determine the Complete Response Rate Following Treatment With AUTO3, as Per Lugano Criteria. | 4 Participants |
| 150 to 450 x 10^6 CD19/CD22 CAR+ T Cells + Pembrolizumab at Day -1 in an Inpatient Setting | Determine the Complete Response Rate Following Treatment With AUTO3, as Per Lugano Criteria. | 8 Participants |
| 150 to 450 x 10^6 CD19/CD22 CAR+ T Cells + Pembrolizumab at Day -1 in an Outpatient Setting | Determine the Complete Response Rate Following Treatment With AUTO3, as Per Lugano Criteria. | 8 Participants |
Secondary
Duration of Response (DOR).
Duration of response was defined as the time from the first observed complete response or partial response \[from the first post-baseline response assessment\] until the date of first progressive disease or death due to underlying cancer (primary reason for death=progressive disease), whichever occurred first. Only responders (patients with complete response \[CR\] or partial response \[PR\]) were included in the analysis of duration of response. Response defined by Lugano classification (see Outcome Measure 5). Patients with death not due to underling cancer (primary reason for death=adverse event \[AE\] or Other or Unknown) or who received new anti-cancer therapy other than SCT or discontinued from the study for other reason than progressive disease (PD) or who were lost to follow-up or reached the time point of analysis without a known record of progression or death had the duration of response censored at the date of last adequate disease assessment for response.
Time frame: Up to 2 years
Population: Patients who received at least 1 (complete or partial) dose of AUTO3 (infused set). Patients with death not due to underling cancer or who received new anti-cancer therapy other than SCT or discontinued from the study for other reason than progressive disease (PD) or who were lost to follow-up or reached the time point of analysis without a known record of progression or death had the duration of response censored at the date of last adequate disease assessment for response.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 50 x 10^6 CD19/CD22 CAR+ T Cells | Duration of Response (DOR). | 6.31 months |
| 50 x 10^6 CD19/CD22 CAR+ T Cells + Pembrolizumab at Day 14 | Duration of Response (DOR). | NA months |
| 150 to 450 x 10^6 CD19/CD22 CAR+ T Cells + Pembrolizumab at Day 14 | Duration of Response (DOR). | NA months |
| 150 to 450 x 10^6 CD19/CD22 CAR+ T Cells + Pembrolizumab at Day -1 in an Inpatient Setting | Duration of Response (DOR). | 4.96 months |
| 150 to 450 x 10^6 CD19/CD22 CAR+ T Cells + Pembrolizumab at Day -1 in an Outpatient Setting | Duration of Response (DOR). | NA months |
Secondary
Feasibility of Generating AUTO3: Number of Patients' Cells Successfully Manufactured as a Proportion of the Number of Patients Undergoing Leukapheresis.
Feasibility of product generation was examined by assessing the number of AUTO3 successfully manufactured as a fraction of the number of patients undergoing leukapheresis (all patients enrolled).
Time frame: Up to 8 weeks post leukapheresis.
Population: Patients who underwent leukapheresis. This outcome is measured before patients received infusion with AUTO3. Therefore, no split by dose cohort can be provided.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 50 x 10^6 CD19/CD22 CAR+ T Cells | Feasibility of Generating AUTO3: Number of Patients' Cells Successfully Manufactured as a Proportion of the Number of Patients Undergoing Leukapheresis. | 52 Participants |
Secondary
Overall Survival (OS).
Overall survival (OS) was defined as the time from the date of first AUTO3 treatment up to the date of death, regardless of cause of death. Patients alive at the time of the analysis had the OS censored at the date of last assessment when the patient was known alive.
Time frame: Up to 2 years
Population: Patients who received at least 1 (complete or partial) dose of AUTO3 (infused set) and were not censored.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 50 x 10^6 CD19/CD22 CAR+ T Cells | Overall Survival (OS). | 10.04 months |
| 50 x 10^6 CD19/CD22 CAR+ T Cells + Pembrolizumab at Day 14 | Overall Survival (OS). | 6.67 months |
| 150 to 450 x 10^6 CD19/CD22 CAR+ T Cells + Pembrolizumab at Day 14 | Overall Survival (OS). | 5.67 months |
| 150 to 450 x 10^6 CD19/CD22 CAR+ T Cells + Pembrolizumab at Day -1 in an Inpatient Setting | Overall Survival (OS). | 9.17 months |
| 150 to 450 x 10^6 CD19/CD22 CAR+ T Cells + Pembrolizumab at Day -1 in an Outpatient Setting | Overall Survival (OS). | NA months |
Secondary
Progression-free Survival (PFS).
The progression-free survival was defined as the time from first AUTO3 treatment until the first progression of disease or death from any cause, whichever occurred first. Patients who reached the time point of analysis without a known record of progression had the PFS censored at the date of last adequate disease assessment. Patients who received a new stem cell transplantation (SCT) were censored at the start date of this new SCT. Patients who received a new anti-cancer therapy or discontinued from the study for other reason than disease progression and who were lost to follow-up were censored at the date of last adequate disease assessment. Response defined by Lugano classification (see Outcome Measure 5).
Time frame: Up to 2 years
Population: Patients who received at least 1 (complete or partial) dose of AUTO3 (infused set) and were not censored.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 50 x 10^6 CD19/CD22 CAR+ T Cells | Progression-free Survival (PFS). | 2.14 months |
| 50 x 10^6 CD19/CD22 CAR+ T Cells + Pembrolizumab at Day 14 | Progression-free Survival (PFS). | 2.43 months |
| 150 to 450 x 10^6 CD19/CD22 CAR+ T Cells + Pembrolizumab at Day 14 | Progression-free Survival (PFS). | 5.67 months |
| 150 to 450 x 10^6 CD19/CD22 CAR+ T Cells + Pembrolizumab at Day -1 in an Inpatient Setting | Progression-free Survival (PFS). | 3.22 months |
| 150 to 450 x 10^6 CD19/CD22 CAR+ T Cells + Pembrolizumab at Day -1 in an Outpatient Setting | Progression-free Survival (PFS). | 3.22 months |
Other Pre-specified
To Determine the Expansion and Persistence of AUTO3 Following Adoptive Transfer in Different Lymphoma Subtypes (Area Under the Curve From Day 0 to Day 28)
Analysis of cells in peripheral blood by polymerase chain reaction and/or flow cytometry at a range of time points in the peripheral blood.
Time frame: Up to 2 years
Population: Patients who received at least 1 (complete or partial) dose of AUTO3 (infused set).
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| 50 x 10^6 CD19/CD22 CAR+ T Cells | To Determine the Expansion and Persistence of AUTO3 Following Adoptive Transfer in Different Lymphoma Subtypes (Area Under the Curve From Day 0 to Day 28) | 41511.0 day*copies/microgram DNA |
| 50 x 10^6 CD19/CD22 CAR+ T Cells + Pembrolizumab at Day 14 | To Determine the Expansion and Persistence of AUTO3 Following Adoptive Transfer in Different Lymphoma Subtypes (Area Under the Curve From Day 0 to Day 28) | 109945.2 day*copies/microgram DNA |
| 150 to 450 x 10^6 CD19/CD22 CAR+ T Cells + Pembrolizumab at Day 14 | To Determine the Expansion and Persistence of AUTO3 Following Adoptive Transfer in Different Lymphoma Subtypes (Area Under the Curve From Day 0 to Day 28) | 38397.9 day*copies/microgram DNA |
| 150 to 450 x 10^6 CD19/CD22 CAR+ T Cells + Pembrolizumab at Day -1 in an Inpatient Setting | To Determine the Expansion and Persistence of AUTO3 Following Adoptive Transfer in Different Lymphoma Subtypes (Area Under the Curve From Day 0 to Day 28) | 37722.7 day*copies/microgram DNA |
| 150 to 450 x 10^6 CD19/CD22 CAR+ T Cells + Pembrolizumab at Day -1 in an Outpatient Setting | To Determine the Expansion and Persistence of AUTO3 Following Adoptive Transfer in Different Lymphoma Subtypes (Area Under the Curve From Day 0 to Day 28) | 32152.1 day*copies/microgram DNA |
Other Pre-specified
To Determine the Expansion and Persistence of AUTO3 Following Adoptive Transfer in Different Lymphoma Subtypes (Maximum Concentration)
Analysis of cells in peripheral blood by polymerase chain reaction and/or flow cytometry at a range of time points in the peripheral blood.
Time frame: Up to 2 years
Population: Patients who received at least 1 (complete or partial) dose of AUTO3 (infused set).
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| 50 x 10^6 CD19/CD22 CAR+ T Cells | To Determine the Expansion and Persistence of AUTO3 Following Adoptive Transfer in Different Lymphoma Subtypes (Maximum Concentration) | 7979.7 copies/microgram DNA |
| 50 x 10^6 CD19/CD22 CAR+ T Cells + Pembrolizumab at Day 14 | To Determine the Expansion and Persistence of AUTO3 Following Adoptive Transfer in Different Lymphoma Subtypes (Maximum Concentration) | 13157.4 copies/microgram DNA |
| 150 to 450 x 10^6 CD19/CD22 CAR+ T Cells + Pembrolizumab at Day 14 | To Determine the Expansion and Persistence of AUTO3 Following Adoptive Transfer in Different Lymphoma Subtypes (Maximum Concentration) | 5726.1 copies/microgram DNA |
| 150 to 450 x 10^6 CD19/CD22 CAR+ T Cells + Pembrolizumab at Day -1 in an Inpatient Setting | To Determine the Expansion and Persistence of AUTO3 Following Adoptive Transfer in Different Lymphoma Subtypes (Maximum Concentration) | 4121.4 copies/microgram DNA |
| 150 to 450 x 10^6 CD19/CD22 CAR+ T Cells + Pembrolizumab at Day -1 in an Outpatient Setting | To Determine the Expansion and Persistence of AUTO3 Following Adoptive Transfer in Different Lymphoma Subtypes (Maximum Concentration) | 3195.6 copies/microgram DNA |
Other Pre-specified
To Determine the Expansion and Persistence of AUTO3 Following Adoptive Transfer in Different Lymphoma Subtypes (Time to Maximum Concentration)
Analysis of cells in peripheral blood by polymerase chain reaction and/or flow cytometry at a range of time points in the peripheral blood.
Time frame: Up to 2 years
Population: Patients who received at least 1 (complete or partial) dose of AUTO3 (infused set).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 50 x 10^6 CD19/CD22 CAR+ T Cells | To Determine the Expansion and Persistence of AUTO3 Following Adoptive Transfer in Different Lymphoma Subtypes (Time to Maximum Concentration) | 16.4 Days |
| 50 x 10^6 CD19/CD22 CAR+ T Cells + Pembrolizumab at Day 14 | To Determine the Expansion and Persistence of AUTO3 Following Adoptive Transfer in Different Lymphoma Subtypes (Time to Maximum Concentration) | 13.9 Days |
| 150 to 450 x 10^6 CD19/CD22 CAR+ T Cells + Pembrolizumab at Day 14 | To Determine the Expansion and Persistence of AUTO3 Following Adoptive Transfer in Different Lymphoma Subtypes (Time to Maximum Concentration) | 9.7 Days |
| 150 to 450 x 10^6 CD19/CD22 CAR+ T Cells + Pembrolizumab at Day -1 in an Inpatient Setting | To Determine the Expansion and Persistence of AUTO3 Following Adoptive Transfer in Different Lymphoma Subtypes (Time to Maximum Concentration) | 10.0 Days |
| 150 to 450 x 10^6 CD19/CD22 CAR+ T Cells + Pembrolizumab at Day -1 in an Outpatient Setting | To Determine the Expansion and Persistence of AUTO3 Following Adoptive Transfer in Different Lymphoma Subtypes (Time to Maximum Concentration) | 13.1 Days |