E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Relapsed or refractory T cell Non-Hodgkin Lymphoma (T-NHL) |
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E.1.1.1 | Medical condition in easily understood language |
T cell Non-Hodgkin Lymphoma (T-NHL) is a type of blood cell cancer that develop from lymphocytes (a type of white blood cell). |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | HLGT |
E.1.2 | Classification code | 10025321 |
E.1.2 | Term | Lymphomas non-Hodgkin's T-cell |
E.1.2 | System Organ Class | 10005329 - Blood and lymphatic system disorders |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Phase I: To assess the safety and tolerability of AUTO4 administration. To identify the recommended phase II dose (RP2D) and maximum tolerated dose (MTD), if an MTD exists.
Phase II: To assess the safety and clinical activity of AUTO4 when administered at the RP2D |
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E.2.2 | Secondary objectives of the trial |
To assess the overall safety and tolerability of AUTO4. To evaluate the feasibility of generating the AUTO4. To evaluate the overall clinical efficacy of AUTO4. To determine the expansion and persistence of AUTO4 following infusion. Duration of TRBC1 positive T cell aplasia.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male or female, aged ≥18 years. 2. Willing and able to give written, informed consent to the study. 3. Confirmed diagnosis of selected T-NHL including: a. Peripheral T cell lymphoma, not otherwise specified (NOS), or b. Angioimmunoblastic T cell lymphoma or c. Anaplastic large cell lymphoma. 4. Confirmed TRBC1 positive tumour. 5. Relapse 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 or and meets the following criteria: a. Absolute Neutrophil Count ≥1.0 x 10e9/L b. Absolute lymphocyte count ≥0.5 x 10e9/L (at entry and prior to leukapheresis) c. Haemaglobin ≥80g/L d. Platelets ≥75 x 10e9/L 9. Adequate renal, hepatic, pulmonary, and cardiac function defined as: a. Creatinine clearance (as estimated by Cockcroft Gault) ≥60 cc/min. b. Serum alanine aminotransferase / aspartate aminotransferase ≤2.5 x upper limit of normal ULN. c. Total bilirubin ≤25 µmol/L (1.5 mg/dL), except in subjects with Gilbert’s syndrome. d. Left ventricular ejection fraction (LVEF) ≥50% by echocardiogram (ECHO) or multiple gated acquisition (MUGA) cardiac scan, unless the institutional lower limit of normal is lower e. Baseline oxygen saturation >92% on room air and ≤Grade 1 dyspnoea 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 preconditioning and confirmed before receiving the first dose of study treatment. |
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E.4 | Principal exclusion criteria |
1. Patients with T cell leukaemia. 2. Females who are pregnant or lactating. 3. Prior treatment with investigational 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, such as epilepsy, paresis, aphasia, stroke within the prior 3 months, severe brain injuries, dementia, Parkinson’s disease, cerebellar disease, organic brain syndrome, uncontrolled mental illness, or psychosis. 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 (New York Heart Association Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, sick-sinus syndrome, or electrocardiographic evidence of acute ischaemia or Grade 3 conduction system abnormalities unless the patient has a pacemaker) or a recent (within 12 months) cardiac event. a. Uncontrolled cardiac arrhythmia (rate-controlled atrial fibrillation are not excluded). b. Evidence of pericardial effusion. 7. Patients with evidence of uncontrolled hypertension or with a history of hypertension crisis or hypertensive encephalopathy. 8. Patients with a recent history or evidence of deep vein thrombosis or pulmonary embolism requiring ongoing therapeutic anticoagulation at the time of pre-conditioning. 9. Patients with active gastrointestinal (GI) bleeding. 10. Patients with any major surgical intervention in the last 3 months. 11. Active infectious bacterial, viral disease or fungal disease (hepatitis B virus,hepatitis C virus, human immunodeficiency virus [HIV], human T cell lymphotropic virus [HTLV] or syphilis) requiring treatment. 12. Active autoimmune disease requiring immunosuppression. 13. 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 allowed). 14. Prior treatment with programmed cell death protein 1 (PD1), programmed death-ligand 1 (PD-L1), or cytotoxic T lymphocyte-associated protein 4 (CTLA-4) targeted therapy, or tumour necrosis factor (TNF) receptor superfamily agonists including CD134 (OX40), CD27, CD137 (41BB), and CD357 (glucocorticoid-induced TNF receptor family-related protein) within 6 weeks prior to AUTO4 infusion. 15. The following medications are excluded: a. Steroids: Therapeutic doses of corticosteroids within 72 hours of leukapheresis or pre-conditioning chemotherapy administration. However, physiological replacement, topical, and inhaled steroids are permitted. b. Cytotoxic chemotherapies within 2 weeks prior to leukapheresis or AUTO4 infusion. c. Antibody therapy use within 2 weeks prior to AUTO4 infusion, or five half-lives of the respective antibody, whichever is shorter. d. Live vaccine within 4 weeks prior to enrolment. 16. Research participants receiving any other investigational agents, or concurrent biological, chemotherapy, or radiation therapy. 17. Use of rituximab within the last 6 months prior to AUTO4 infusion. 18. Patients, who in the opinion of the Investigator, may not be able to understand or comply with the safety monitoring requirements of the study. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Incidence of Grade 3 to 5 toxicity occurring within 60 days of AUTO4 infusion. Frequency of dose limiting toxicity (DLT) of AUTO4 within 28 days of AUTO4 infusion. Overall response (CR+PR) rate post AUTO4 infusion. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
- Safety endpoint evaluations will be conducted throughout the study - Grade 3-5 toxicity captured 60 days post dose - DLT Frequency within 28 days of AUTO4 infusion. - Overall response at 1, 3, 6, 9, 12, 15, 18 and 24 months post AUTO4 infusion. |
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E.5.2 | Secondary end point(s) |
Frequency and severity of all AEs and SAEs Incidence and severity of opportunistic infections following AUTO4 infusion. Proportion of patients (who are TRBC1 positive and undergo leukapheresis), for whom an AUTO4 product can be generated (feasibility). Determine the CR rate following treatment with AUTO4. Evaluate clinical outcomes including DOR, DFS, PFS, OS, time to response (PR+CR) and time to CR. RQR8/aTRBC1-CAR positive T cells as determined by PCR and/or flow cytometry at a range of time points in the peripheral blood. Enumeration of circulating TRBC1 positive T cells assessed by flow cytometry at a range of time points in the peripheral blood.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
- Safety endpoints and AUTO4 monitoring evaluations will be conducted throughout the study - Feasibility to generate AUTO4 assessed after manufacture - Objective response at 1, 3, 6, 9, 12,15, 18 and 24 months post AUTO4 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 first AUTO4 treatment to relapse/disease progression and death, respectively - biomarker measurements taken at pre-conditioning, day 0, 1, every other day until day 10 and weekly until day 28. then Month 3, 6, 9, 12, 15, 18 & 24 months post treatment. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | Yes |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 4 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The end of the trial will be 24 months after the last patient has received AUTO4 infusion (or earlier, if appropriate). |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |