Phase 1 rolling 6 trial design evaluating safety of a novel D8 alone and of D8/CAT CAR T cells in patients with AL amyloid. This trial consists of two initial cohorts: Cohort 1 assesses D8 CAR T cells and Cohort 2 assesses combined D8/CAT CAR T cells.

Cohort 1: D8 CAR T cells (BCMA CAR alone)

Cohort 2: D8/CAT CAR T cells (BCMA CAR and CD19 CAR)

Leucapheresis: following registration, patients will undergo an unstimulated leucapheresis which will be sent to ‘Centre for Cell, Gene & Tissue Therapeutics’ (CCGTT) at the Royal Free Hospital for manufacture of the autologous CAR T cells

Lymphodepletion: prior to CAR T cell infusion, patients will receive cyclophosphamide 300 mg/m² and fludarabine 30 mg/m² administered on days -5 to -3

CAR T cell administration: a single infusion of CAR T cells (corresponding to the cohort and dose assigned) will be administered intravenously

Key inclusion criteria:

1. Age ≥18 years old

2. Histopathological diagnosis of amyloidosis 

3. ECOG performance status 0-2

4. Measurable disease

5. Patients must have adequate organ function

6. At least 1 previous line of therapy and relapsed or less than CR to last line

7. Patients must weigh ≥45 kg

8. Women of childbearing potential must have a negative pregnancy test and agree to comply with the pregnancy reporting requirements of the protocol (if applicable)

9. Provide written informed consent and be willing and able to comply with all study procedures

Key exclusion criteria:

1. Have any other form of amyloidosis other than AL amyloidosis

2. Have POEMS syndrome

3. Have systolic blood pressure less than 100 mmHg or symptomatic orthostatic hypotension

4. Receiving haemodialysis

5. Have had myocardial infarction, uncontrolled angina within 6 months prior to screening or percutaneous cardiac intervention with recent stent or coronary artery bypass grafting within 4 months prior to screening

6. LVEF is less than 40% by echocardiogram at screening

7. Have severe valvular stenosis or severe congenital heart disease

8. Have history of sustained ventricular tachycardia or aborted ventricular fibrillation or a history of atrioventricular nodal or sinoatrial nodal dysfunction for which a pacemaker/implantable cardioverter defibrillator (ICD) is indicated but not placed 

9. Corrected QT interval (QTc) >500 ms on the screening electrocardiogram (ECG) in absence of bundle branch block or paced rhythm

10. Current unstable liver or biliary disease defined by the presence of ascites requiring paracentesis, encephalopathy, coagulopathy, or cirrhosis

11. Prior treatment with investigational or approved gene therapy or cell therapy products

12. Oxygen saturation ≤90% on air

13. Patients with any major surgical intervention in the last 3 months 

14. Patients with active gastrointestinal bleeding

15. Patients with active infectious bacterial or viral disease requiring treatment

16. Known active central nervous system involvement of AL amyloid or multiple myeloma 

17. Active autoimmune disease requiring immunosuppression

18. Patients receiving corticosteroids at a dose of >5 mg prednisolone per day (or equivalent) that cannot be discontinued

19. Past or current history of other neoplasms (including lymphoma), with some exceptions

20. Received any radiotherapy within the last 7 days prior to lymphodepletion or leucapheresis 

21. Patients that received any plasma cell directed therapy within the last 7 days prior to lymphodepletion or leucapheresis

22. Inability to tolerate leucapheresis

23. Life expectancy less than 3 months

24. Women who are pregnant or breastfeeding

25. Known allergy to albumin, DMSO, PBS/EDTA 

26. Patients who have received any live vaccine within 1 month prior to lymphodepletion

27. Any contraindications to lymphodepletion or to the use of cyclophosphamide or fludarabine 

Please note: the full list of inclusion and exclusion criteria can be found on the ISRCTN website (ISRCTN49320109)