Phase I/II Study Evaluating AUTO4 in Patients With T Cell Receptor Beta Constant (TRBC)1 Positive T Cell Lymphoma

Phase 2TerminatedNCT03590574

Autolus Limited20 enrolled

Overview

The purpose of this study is to test the safety and efficacy of AUTO4 a chimeric antigen receptor (CAR) T cell treatment targeting TRBC1 in patients with relapsed or refractory TRBC1 positive selected T-Non-Hodgkin Lymphoma (NHL).

The study will consist of 2 phases, a Phase I/dose escalation phase and a Phase II/expansion phase. Patients with relapsed or refractory TRBC1 positive selected T-NHL will be enrolled in both phases of the study. Eligible patients will undergo leukapheresis to harvest T cells, the starting material for the manufacture of the autologous CAR-T product AUTO4. Following preconditioning by a chemotherapeutic regimen, the patient will receive AUTO4 intravenously as a single dose following which they will then enter a 24-month follow-up period

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

T Cell Non-Hodgkin Lymphoma Peripheral T-Cell Lymphoma, Not Otherwise Specified Angioimmunoblastic T-cell Lymphoma Anaplastic Large Cell Lymphoma

Interventions

AUTO4BIOLOGICAL

AUTO4 (Ritux-QBEND/10-Ritux-CD8 sort-suicide gene generated as a marker/suicide gene for T cells \[RQR8\]/anti-T cell receptor beta constant \[aTRBC\]1 CAR T cells). Following pre-conditioning with chemotherapy (cyclophosphamide and fludarabine), patients will be treated with doses from 25 to 900 x 10\^6 RQR8/anti-TRBC1 CAR T cells in Phase I. Following dose determination patients will be treated with the selected doses of RQR8/aTRBC1 CAR T cells (AUTO4) in Phase II.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Male or female, aged ≥ 18 years. 2. Willing and able to give written, informed consent to be screened for TRBC1 positive T-NHL and to enter the main study. 3. Confirmed diagnosis of selected T-NHL, including: 1. Peripheral T cell lymphoma not otherwise specified, or 2. Angioimmunoblastic T cell lymphoma, or 3. Anaplastic large cell lymphoma 4. Confirmed TRBC1 positive tumour. 5. Relapsed or refractory disease and have had ≥1 prior lines of therapy. 6. Positron emission tomography (PET)-positive measurable disease per Lugano classification. 7. Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1. 8. Adequate bone marrow function without the requirement for ongoing blood products. 9. Adequate renal, hepatic, pulmonary, and cardiac function. 10. For females of childbearing potential (defined as \< 2 years after last menstruation or not surgically sterile), 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 (\< 24 months of amenorrhea) or who are not surgically sterile (absence of ovaries and/or uterus), a highly effective method of contraception together with a barrier method must be used from the start of the pre-conditioning stage and for at least 12 months after the last dose of AUTO4 (study treatment). They must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction during the study and for 12 months after receiving the last dose of study drug 11. For males, it must be agreed that 2 acceptable methods of contraception are used. 12. No contra-indications for leukapheresis, or the pre-conditioning regimen. Exclusion Criteria: Patients meeting any of the following exclusion criteria must not be enrolled into the study: 1. Patients with T cell leukaemia. 2. Females who are pregnant or lactating. 3. Prior treatment with investigational gene therapy or approved gene therapy or genetically engineered cell therapy product or allogeneic stem cell transplant. 4. Known history or presence of clinically relevant central nervous system (CNS) pathology. Patients with a known history or prior diagnosis of optic neuritis or other immunologic or inflammatory disease affecting the CNS. 5. Current or history of CNS involvement by malignancy. 6. Clinically significant, uncontrolled heart disease. 7. Patients with evidence of uncontrolled hypertension or with a history of hypertension crisis or hypertensive encephalopathy. 8. 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. 9. Patients with active gastrointestinal bleeding. 10. Active infectious bacterial, viral disease or fungal disease (hepatitis B virus, hepatitis C virus, human immunodeficiency virus, human T cell lymphotropic virus or syphilis) requiring treatment. 11. Active autoimmune disease requiring immunosuppression. 12. History of other neoplasms unless disease free for at least 2 years (adequately treated carcinoma in situ, curatively treated non-melanoma skin cancer, breast or prostate cancer on hormonal therapy are allowed). 13. Prior treatment with programmed cell death protein 1, programmed death ligand 1, or cytotoxic T lymphocyte-associated protein 4 targeted therapy, or tumour necrosis factor (TNF) receptor superfamily agonists including cluster of differentiation (CD)134 (OX40), CD27, CD137 (41BB), and CD357 (glucocorticoid induced TNF receptor family related protein) within 6 weeks prior to AUTO4 infusion. 14. Research participants receiving any other investigational agents, or concurrent biological, chemotherapy, or radiation therapy. 15. Use of rituximab (or rituximab biosimilar) within the last 6 months prior to AUTO4 infusion. 16. Patients, who in the opinion of the Investigator, may not be able to understand or comply with the safety monitoring requirements of the study.

Locations (5)

Vall d'Hebron Institute of Oncology

Barcelona, Spain

Queen Elizabeth University Hospital

Glasgow, United Kingdom

University College London Hospitals NHS Foundation Trust

London, United Kingdom

Manchester Royal Infirmary Hospital

Manchester, United Kingdom

Outcomes

Primary Outcomes

The Numbers of Patients With Grade 3 to 5 Toxicity Occurring Within 60 Days of AUTO4 Infusion.

To assess the safety and tolerability of AUTO4 administration. The incidence of Grade 3-5 toxicities occurring within 60 days of AUTO4 infusion.

Time frame: 60 days of AUTO4 infusion

Frequency of Dose-limiting Toxicity (DLT) of AUTO4 Within 28 Days of AUTO4 Infusion.

To identify the recommended Phase II dose and maximum tolerated dose (MTD), if an MTD exists, of AUTO4 by monitoring the frequency of DLT of AUTO4 within 28 days of AUTO4 infusion.

Time frame: 28 days of AUTO4 infusion

Secondary Outcomes

Frequency and Severity of All Adverse Events (AEs) and Serious Adverse Events (SAEs).

All AEs/SAEs were recorded from admission for pre-conditioning chemotherapy (Day -6 relative to AUTO4). Due to the long period between consent and AUTO4 treatment, any AEs/SAEs related to bridging chemotherapy not associated with study procedures did not require reporting as study AEs/SAEs. Any significant events were added to the patient's medical history. All AEs/SAEs related to study procedures (leukapheresis, bone marrow assessments) were reported.

Time frame: 24 months post treatment

To Assess the Overall Safety and Tolerability of AUTO4.

Incidence and severity of opportunistic infections following AUTO4 infusion.

Time frame: 24 months post treatment

Feasibility of Generating AUTO4: Number of Patients Whose Cells Achieve Successful AUTO4 Manufacture as a Proportion of the Number of Patients Undergoing Leukapheresis.

Feasibility of product generation was examined by assessing the number of AUTO4 successfully manufactured as a fraction of the number of patients undergoing leukapheresis (all patients enrolled).

Time frame: Up to 8 weeks post leukapheresis

Data from ClinicalTrials.gov

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