A New Study Evaluating the Activity of Modular CAR T for mYeloma

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)

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