Overview
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.
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)
Eligibility
Inclusion Criteria:
- Age ≥ 18
- Relapsed/Refractory Multiple Myeloma
- Secretory disease: PP≥5g/L and/or sFLC≥100mg/L of involved light chain with abnormal K:L ratio.
- ≥3 prior lines of therapies (including proteasome inhibitor, IMiD, anti CD38 antibody)
- 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)
- Has previously received or is not suitable for ASCT
- Eastern Cooperative Oncology Group (ECOG) performance status 0/1
- 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
- Patients must weigh \>30 kg
- Agreement to have a pregnancy test, use adequate contraception (if applicable)
- Written informed consent
Exclusion Criteria:
- Previous diagnosis of systemic light chain amyloidosis
- Prior treatment with investigational or approved gene therapy or cell therapy products
- 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
- Oxygen saturation ≤ 90% on air
- Patients with clinically significant, uncontrolled heart disease or a recent (within 6 months) cardiac event
- Left ventricular ejection fraction \< 50% (ECHO or MUGA)
- Corrected QT interval (QTc)\>470 ms on ECG
- Uncontrolled cardiac arrhythmia (patients with rate-controlled atrial fibrillation are not excluded)
- History or evidence of deep vein thrombosis or pulmonary embolism requiring ongoing therapeutic anticoagulation at preconditioning
- Chronic renal impairment requiring dialysis
- 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)
- Patients with any major surgical intervention in the last 3 months, cement augmentation for vertebral collapse is permitted
- Patients with active gastrointestinal bleeding
- Patients with active infectious bacterial or viral disease requiring treatment
- 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
- Patients receiving corticosteroids at a dose of \>5 mg prednisolone per day (or equivalent) that cannot be discontinued
- Active autoimmune disease requiring immunosuppression
- Past or current history of other neoplasms
- 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
- Patients with any anti-myeloma therapy within the last 7 days prior to LD or leukapheresis
- Inability to tolerate leucapheresis
- Life expectancy \<3 months
- Women who are pregnant or breastfeeding
- Known allergy to albumin or DMSO
Exclusion criteria for CAR-T cell infusion:
- Active infection requiring systemic anti-microbial therapy, or with temperature more or equal to 38 C within 48 hours before scheduled CAR-T cell infusion
- Requirement for supplementary oxygen at the time of scheduled CAR-T cell infusion
- Clinical deterioration of organ functions (hepatic or renal function) exceeding criteria set at study entry