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 With Anti Programmed Cell Death Protein 1 (PD1) Antibody in Patients With Relapsed or Refractory Diffuse Large B Cell Lymphoma
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 52
- 试验地点
- 11
- 主要终点
- Phase I Escalation - Safety (Number of Participants With Grade 3-5 Toxicities) and Identification of Recommended Phase II Dose and Schedule (RP2D).
研究概览
简要总结
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
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Male or female, aged ≥18 years.
- •Willing and able to give written, informed consent.
- •Eastern Cooperative Oncology Group (ECOG) Performance Status 0 to
- •Histologically confirmed DLBCL and large B cell lymphoma subsets, including:
- •Phase I and Phase II Cohort 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).
- •Transformed DLBCL from follicular lymphoma (FL).
- •High-grade B cell lymphoma with MYC expression (excluding Burkitt's lymphoma) Phase I and Phase II Cohort
- •Transformed DLBCL from other indolent lymphomas (excluding Richter's transformation).
- •Primary mediastinal large B cell lymphoma.
- •Chemotherapy-refractory disease, defined as one or more of the following:
- •Stable disease (≤12 months) or progressive disease as best response to most recent chemotherapy containing regimen. Refractory disease after frontline chemo-immunotherapy is allowed.
- •Disease progression or recurrence in ≤12 months of prior autologous haematopoietic stem cell transplantation (ASCT).
- •Relapse after ≥two lines of therapy or after ASCT. At a minimum:
- •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.
- •Patients must have either failed ASCT, or be ineligible for or not consenting to ASCT.
- •Patients with transformed DLBCL must have received at least one line of therapy after transformation to DLBCL.
- •Positron emission tomography-positive disease per Lugano classification.
- •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.
- •For males, it must be agreed that that two acceptable methods of contraception are used.
- •Adequate renal, hepatic, pulmonary, and cardiac function defined as:
- •Creatinine clearance ≥40 cc/min.
- •Serum alanine aminotransferase / aspartate aminotransferase ≤2.5 x upper limit of normal (ULN).
- •Total bilirubin ≤1.5 x ULN, except in subjects with Gilbert's syndrome.
- •Left ventricular ejection fraction (LVEF) ≥50% (by echocardiogram [ECHO] or Multiple gated acquisition scan [MUGA]) unless the institutional lower limit of normal is lower.
- •Baseline oxygen saturation >92% on room air and ≤Grade 1 dyspnoea.
- •Patient has adequate bone marrow (BM) function without requiring ongoing blood product or granulocyte-colony stimulating factor support and meets the following criteria:
- •Absolute neutrophil count ≥1.0 × 10^9/L.
- •Absolute lymphocyte count ≥0.3 × 10^9/L (at enrolment and prior to leukapheresis).
- •Haemoglobin ≥80 g/L.
- •Platelets ≥75 × 10^9/L
- •No contra-indications for leukapheresis.
排除标准
- •Prior allogeneic haematopoietic stem cell transplant.
- •Females who are pregnant or lactating.
- •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.
- •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).
- •Clinically significant, uncontrolled heart disease or a recent (within 12 months) cardiac event.
- •Uncontrolled cardiac arrhythmia (patients with rate-controlled atrial fibrillation are not excluded).
- •Evidence of pericardial effusion
- •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.
- •Patients with active gastrointestinal bleeding.
- •Patients with any major surgical intervention in the last 3 months.
- •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.
- •History of autoimmune disease resulting in end organ injury or requiring systemic immunosuppression/systemic disease modifying agents within the last 24 months.
- •Patients with a known history or prior diagnosis of optic neuritis or other immunologic or inflammatory disease affecting the CNS.
- •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.
- •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).
- •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.
- •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.
- •Prior CD19 or CD22 targeted therapy.
- •The following medications are excluded:
- •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.
- •Immunosuppression: Immunosuppressive medication must be stopped ≥2 weeks prior to leukapheresis or AUTO3 infusion.
- •Cytotoxic chemotherapies within 2 weeks of AUTO3 infusion and 1 week prior to leukapheresis (2 weeks for lymphodepleting chemotherapy).
- •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.
- •Granulocyte-colony stimulating factor less than 10 days prior to leukapheresis.
- •Live vaccine ≤4 weeks prior to enrolment.
- •Prophylactic intrathecal therapy: Methotrexate within 4 weeks and other intrathecal chemotherapy (e.g. Ara-C) within 2 weeks prior to starting pre-conditioning chemotherapy.
- •Prior limited radiation therapy within 4 weeks of AUTO3 infusion or within 24 weeks for definitive radiation to chest.
- •Research participants receiving any other investigational agents, or concurrent biological, chemotherapy, or radiation therapy.
- •Known allergy to albumin, dimethyl sulphoxide (DMSO), cyclophosphamide or fludarabine, pembrolizumab or tocilizumab.
- •Any contraindications to receive anti-PD1 antibody pembrolizumab will be excluded from cohorts requiring administration of pembrolizumab.
- •Patients, who in the opinion of the Investigator, may not be able to understand or comply with the safety monitoring requirements of the study.
- •Any other condition that in the Investigator's opinion would make the patient unsuitable for the clinical trial.
- •Phase I outpatient cohort:
- •Subjects who do not have caregiver support (in line with institutional outpatient transplant guidelines) for outpatient/ambulatory care setting.
- •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 exclusion criteria must not be treated with AUTO3 or have treatment delayed until they no longer meet these criteria:
- •Severe intercurrent infection.
- •Requirement for supplementary oxygen or active pulmonary infiltrates.
- •Clinical deterioration of organ function (renal and hepatic) exceeding the criteria set at study entry.
研究组 & 干预措施
AUTO3
Patient with relapsed or refractory DLBCL
干预措施: AUTO3 (Biological)
结局指标
主要结局
Phase I Escalation - Safety (Number of Participants With Grade 3-5 Toxicities) and Identification of Recommended Phase II Dose and Schedule (RP2D).
时间窗: 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 I Expansion - Safety (Incidence of Grade 3-5 Toxicities) in the Outpatient / Ambulatory Care Setting
时间窗: 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)
Phase II - Overall Response Rate as Per Lugano Criteria
时间窗: 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.
次要结局
- 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.)
- Determine the Complete Response Rate Following Treatment With AUTO3, as Per Lugano Criteria.(Up to 2 years)
- Duration of Response (DOR).(Up to 2 years)
- Progression-free Survival (PFS).(Up to 2 years)
- Overall Survival (OS).(Up to 2 years)