Multiple Myeloma
Conditions
Brief summary
This is a Phase 1 rolling 6 trial design evaluating safety of a novel BCMA Chimeric Antigen Receptor (CAR) alone and of CAR T cells engineered to co-express BCMA CAR and a CD19 CAR in patients with relapsed / refractory Multiple Myeloma. The study will assess the feasibility of generating these Advanced Therapy Investigational Products (ATIMPs) and the safety of administering the CAR T cells (either BCMA alone or co-expressed with CD19) in patients with relapsed / refractory multiple myeloma.
Detailed description
This is a Phase 1 rolling 6 trial design evaluating safety of a novel BCMA CAR alone and of CAR T cells engineered to co-express BCMA CAR and a CD19 CAR in patients with triple refractory Multiple Myeloma. The first 3-6 patients will be treated at the lower dose of BCMA CAR T cells in cohort 1 (50 x 10\^6 cells). If the lower dose is deemed tolerable, recruitment into cohort 1 at a higher dose (150 x 10\^6 BCMA CAR T cells) and cohort 2 at a dose of 50 x 10\^6 BCMA/CD19 cells will begin in parallel. * If the 50 x 10\^6 cells BCMA/CD19 CAR dose in cohort 2 is deemed intolerable, then no further patients will be recruited to cohort 2. * If both 150 x 10\^6 cells BCMA CAR (cohort 1) and 50 x 10\^6 cells BCMA/CD19 CAR (cohort 2) are deemed tolerable then recruitment will begin to a higher BCMA/CD19 CAR dose of 150 x 10\^6 cells. * If 150 x 10\^6 cells BCMA CAR is intolerable and 50 x 10\^6 cells BCMA/CD19 CAR is tolerable then no further patients will be recruited to cohorts 1 or 2. With the 150x10\^6 cells dose being deemed tolerable in both cohorts 1 and 2, a dose level 3 of 450x10\^6 CAR T cells has been added to the design via a substantial amendment. Dose level 3 will first open in cohort 1 and, if deemed tolerable, will then proceed to be opened in cohort 2. A Summary of dosing on trial is outlined below: Cohort 1 (BCMA CAR-T cells) * Dose level 1: 50x10\^6 BCMA CAR-T cells * Dose level 2: 150x10\^6 BCMA CAR-T cells * Dose level 3: 450x10\^6 BCMA CAR-T cells administered as a split dose on D0 and D7 (if 1st infusion tolerated well) Cohort 2 (BCMA/CD19 CAR-T cells) * Dose level 1: 50x10\^6 BCMA/CD19 CAR-T cells * Dose level 2: 150x10\^6 BCMA/CD19 CAR-T cells * Dose level 3: 450x10\^6 BCMA/CD19 CAR-T cells administered as a split dose on D0 and D7 (if 1st infusion tolerated well)
Interventions
BIOLOGICALBCMA CAR T cells
Infusion with ATIMP: BCMA CAR T-cells
BIOLOGICALBCMA/CD19 CAR T cells
Infusion with ATIMP: BCMA/CD19 CAR T-cells
Sponsors
University College, London
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Rolling 6 trial design
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Age ≥ 18 2. Relapsed/Refractory Multiple Myeloma 3. Secretory disease: PP≥5g/L and/or sFLC≥100mg/L of involved light chain with abnormal K:L ratio. 4. ≥3 prior lines of therapies (including proteasome inhibitor, IMiD, anti CD38 antibody) 5. Refractory to last line of therapy (not achieved at least PR and progressed within 60 days of last dose or achieved at least PR but progressed within 6 months of last dose) 6. Has previously received or is not suitable for ASCT 7. Eastern Cooperative Oncology Group (ECOG) performance status 0/1 8. Creatinine Clearance (CrCl)≥40ml/min, Absolute Neutrophil Count (ANC)≥1x10\^9/L, Platelets (plt)≥50x10\^9/L, Haemoglobin (Hb)≥80 /L, lymphocyte count ≥0.3x10\^9/L 9. Patients must weigh \>30 kg 10. Agreement to have a pregnancy test, use adequate contraception (if applicable) 11. Written informed consent
Exclusion criteria
1. Previous diagnosis of systemic light chain amyloidosis 2. Prior treatment with investigational or approved gene therapy or cell therapy products 3. Stem cell transplant patients only: * allogeneic stem cell transplant within 12 months prior to registration into the study * moderate/ severe chronic GVHD (NIH consensus criteria) requiring immunosuppressive therapy and/or systemic steroids 4. Oxygen saturation ≤ 90% on air 5. Patients with clinically significant, uncontrolled heart disease or a recent (within 6 months) cardiac event 6. Left ventricular ejection fraction \< 50% (ECHO or MUGA) 7. Corrected QT interval (QTc)\>470 ms on ECG 8. Uncontrolled cardiac arrhythmia (patients with rate-controlled atrial fibrillation are not excluded) 9. History or evidence of deep vein thrombosis or pulmonary embolism requiring ongoing therapeutic anticoagulation at preconditioning 10. Chronic renal impairment requiring dialysis 11. Patients with significant liver disease: alanine aminotransferase or aspartate aminotransferase ≥3x upper limit normal (ULN), or total bilirubin ≥25umol/L (1.5mg/dL), except in patients with Gilbert's syndrome, or evidence of end-stage liver disease (e.g. ascites, hepatic encephalopathy) 12. Patients with any major surgical intervention in the last 3 months, cement augmentation for vertebral collapse is permitted 13. Patients with active gastrointestinal bleeding 14. Patients with active infectious bacterial or viral disease requiring treatment 15. Known active central nervous system involvement of MM. History or presence of clinically relevant central nervous system pathology such as epilepsy, paresis, aphasia, stroke within 3 months prior to enrolment, severe brain injuries, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, uncontrolled mental illness, or psychosis 16. Patients receiving corticosteroids at a dose of \>5 mg prednisolone per day (or equivalent) that cannot be discontinued 17. Active autoimmune disease requiring immunosuppression 18. Past or current history of other neoplasms 19. Received any radiotherapy within the last 7 days prior to lymphodepletion or leukapheresis. Localised radiation to a single site, e.g. for bone pain is permitted at any time 20. Patients with any anti-myeloma therapy within the last 7 days prior to LD or leukapheresis 21. Inability to tolerate leucapheresis 22. Life expectancy \<3 months 23. Women who are pregnant or breastfeeding 24. Known allergy to albumin or DMSO
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Toxicity evaluated by the incidence of grade 3-5 toxicity causally related to the Advanced Therapy Investigational Product (ATIMP) | 28 days | The incidence of grade 3-5 toxicity assessed using the Common Terminology Criteria for Adverse Events (CTCAE) v5.0 and the American Society for Transplantation and Cellular Therapy (ASTCT) Cytokine Release Syndrome (CRS) and Neurotoxicity tool |
| Feasibility of manufacturing CAR T-cells evaluated by the number of therapeutic products generated | 30 days | Feasibility of generation of CAR T cells as evaluated by the number of therapeutic products generated. |
Countries
United Kingdom
Contacts
Primary ContactMCARTY Trial Coordinator
Backup ContactLydia Lee
Outcome results
None listed