Multiple Myeloma Clinical Trial
Study of CART-ddBMCA in Relapsed or Refractory Multiple Myeloma (iMMagine-1)
This is a Phase II open-label study of CART-ddBCMA* in patients with relapsed or refractory multiple myeloma (MM). The study will have the following sequential phases: screening, enrollment, pre-treatment with lymphodepleting chemotherapy, treatment with CART-ddBCMA, and follow-up. If necessary, bridging therapy is allowed to control growth of MM disease while CART-ddBCMA is being manufactured.
Following a single infusion of CART-ddBCMA both safety and efficacy data will be assessed. Efficacy will be assessed monthly for the first 6 months, then quarterly up to 2 years, or upon patient relapse. The primary analysis will be conducted approximately 13 months after the final patient is dosed. This will allow approximately 12 months follow up from the time of the last observed response on study.
Long-term safety data will be collected under a separate long-term follow up study for up to 15 years per health authority guidelines.
*CART-ddBCMA drug product consists of autologous T cells that have been genetically modified ex vivo to express a D-domain Chimeric Antigen Receptor (CAR), followed by a cluster of differentiation 8 (CD8) hinge and transmembrane region that is fused to the intracellular signaling domains for 4-1BB and CD3ξ, that specifically recognizes B-cell maturation antigen (BCMA). The active substance of CART-ddBCMA is CAR+ CD3+ T cells that have undergone ex vivo T-cell activation, gene transfer by replication-deficient lentiviral vector, and expansion.
Age 18 years or older and has capacity to give informed consent
Relapsed or refractory multiple myeloma treated with at least 3 prior regimens of systemic therapy including proteasome inhibitor, immunomodulatory drugs (IMiD) and anti-CD38 antibody and are refractory to the last line of therapy. For each line, 2 consecutive cycles are required unless the best response after 1 cycle was progressive disease.
Note: IMWG criteria defines refractory disease as disease progression on or within 60 days of a therapy Note: Induction treatment with or without hematopoietic stem cell transplant and with or without maintenance is considered a single regimen
Documented measurable disease including at least one or more of the following criteria:
Serum M-protein ≥1.0 g/dL
Urine M-protein ≥200 mg/24 hours
Involved serum free light chain ≥10 mg/dL with abnormal κ/λ ratio (i.e., >4:1 or <1:2)
Eastern Cooperative Oncology Group (ECOG) performance status 0-1
Life expectancy >12 weeks
Adequate organ function defined as:
Oxygen (O2) saturation ≥92% on room air
Left Ventricular Ejection Fraction (LVEF) ≥45% by echocardiogram (ECHO) or multigated acquisition (MUGA) scan
Absolute neutrophil count (ANC) ≥1.0k/µl, platelet count (PLT) ≥50k/µl, [NOTE: Platelet transfusion not allowed within 14 days; filgrastim (or biosimilar) not allowed within 7 days, pegfilgrastim (or biosimilar) within 14 days]
Creatinine clearance ≥45 mL/min min (as determined by the Cockgroft-Gault equation) and not on dialysis
Aspartate transaminase (AST)/alanine transaminase (ALT) <3 x upper limits of normal (ULN)
Total bilirubin <1.5 x ULN (allow 3x ULN for Gilbert's syndrome)
Prothrombin time test (PTT), prothrombin time (PT)/international normalized ratio (INR) <1.5 x ULN, unless on a stable dose of anti-coagulant for a thromboembolic event (Subjects with any history of thromboembolic stroke; or history or Grade 2 (G2) or greater hemorrhage within one year are excluded)
Resolution of adverse events (AEs) from any prior systemic anticancer therapy, radiotherapy, or surgery to Grade 1 or baseline (except G2 alopecia and G2 sensory neuropathy)
Male and female participants of childbearing potential must agree to use highly effective methods of birth control through 12 months after the dose of study treatment
Willing to comply with and able to tolerate study procedures, including consent to participate in separate Long-term Safety Follow-up lasting up to 15 years per FDA guidance
Subject's leukapheresis product from non-mobilized cells is received and accepted for cell processing by manufacturing site. NOTE: Leukapheresis will be performed only after all other eligibility criteria are confirmed
Plasma cell leukemia or history of plasma cell leukemia
Treatment with the following therapies as specified below
Any prior systemic treatment for multiple myeloma within the 14 days prior to scheduled leukapheresis
Receiving high-dose (e.g., >10 mg prednisone or equivalent) systemic steroid therapy or any other form of immunosuppressive therapy within 14 days prior to leukapheresis
Prior treatment with any gene therapy or gene-modified cellular immune-therapy
Prior B-cell maturation antigen (BCMA) directed therapy
Autologous stem cell transplantation within 3 months prior to leukapheresis, or any prior allogeneic stem cell transplantation
Subjects with solitary plasmacytomas without evidence of other measurable disease are excluded
History of allergy or hypersensitivity to study drug components. Subjects with a history of severe hypersensitivity reaction to dimethyl sulphoxide (DMSO) are excluded
Contraindication to fludarabine or cyclophosphamide
Severe or uncontrolled intercurrent illness or laboratory abnormalities including
Active bacterial, viral, or fungal infection requiring systemic treatment (isolated fever may not constitute active infection in and of itself, (e.g., related to disease)
Symptomatic congestive heart failure (i.e., New York Heart Association stage III or IV)
Unstable angina, arrhythmia, or myocardial infarction (MI) within 6 months prior to Screening
Significant pulmonary dysfunction
Uncontrolled thromboembolic events or recent severe hemorrhage (i.e., within one year)
Any history of pulmonary embolism (PE) in the past 12 months or deep vein thrombosis (DVT) within three months of enrollment. Therapeutic dosing of anticoagulants (e.g., warfarin, low molecular weight heparin, Factor Xa inhibitors) is allowed for history of PE/DVT if greater than twelve and three months, respectively, from time of enrollment, and should be at a stable maintenance dose.
Auto-immune disease requiring immunosuppressive therapy within the last 24 months
Seropositive for and with evidence of active hepatitis B or C infection at time of Screening, or HIV seropositive
Subjects with a history of hepatitis B but have received antiviral therapy and have non-detectable viral DNA are eligible
Subjects seropositive because of hepatitis B virus vaccine with no signs or active infection are eligible
Subjects who had hepatitis C but have received antiviral therapy and show no detectable hepatitis C virus (HCV) viral RNA are eligible
Active central nervous system (CNS) involvement by malignancy
Any sign of active or prior CNS pathology including but not limited to history of epilepsy, seizure, paresis, aphasia, stroke, subarachnoid hemorrhage or CNS bleed, severe brain injury, dementia, cerebellar disease, Parkinson's disease, organic brain syndrome or psychosis
Active malignancy not related to myeloma that has required therapy in the last 3 years or is not in complete remission. Exceptions to this criterion include successfully treated non-metastatic basal cell or squamous cell skin carcinoma, or prostate cancer that does not require therapy.
Females who are pregnant or breastfeeding or females of childbearing potential not using an effective method of birth control
Subjects with any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in study (or full access to medical records) as written including follow up, the interpretation of data or place the subject at unacceptable risk
Any vaccine ≤ 6 weeks before leukapheresis and/or anticipation of the need for such a vaccine during the subject's participation in the study
Concurrent enrollment on another study using an investigational therapy for the treatment of RRMM
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There are 19 Locations for this study
Scottsdale Arizona, 85260, United States
Little Rock Arkansas, 72205, United States
Denver Colorado, 80218, United States
Tampa Florida, 33612, United States
Atlanta Georgia, 30342, United States
Chicago Illinois, 60637, United States
Baltimore Maryland, 21201, United States
Baltimore Maryland, 21205, United States
Boston Massachusetts, 02114, United States
Boston Massachusetts, 02215, United States
Boston Massachusetts, 02215, United States
Detroit Michigan, 48201, United States
Hackensack New Jersey, 07601, United States
Charlotte North Carolina, 28204, United States
Portland Oregon, 97239, United States
Dallas Texas, 75390, United States
Houston Texas, 77030, United States
Salt Lake City Utah, 84112, United States
Madison Wisconsin, 53792, United States
Milwaukee Wisconsin, 53226, United States
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