American Society of Hematology Annual Meeting December 10, 2017
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1 Safety and Efficacy of B-Cell Maturation Antigen (BCMA)-Specific Chimeric Antigen Receptor T cells (CART-BCMA) with Cyclophosphamide Conditioning for Refractory Multiple Myeloma (MM) Adam D. Cohen, Alfred L. Garfall, Edward A. Stadtmauer, Simon F. Lacey, Eric Lancaster, Dan T. Vogl, Brendan M Weiss, David E. Ambrose, Anne Marie Nelson, Fang Chen, Gabriela Plesa, Irina Kulikovskaya, Vanessa Gonzalez, Minnal Gupta, Regina Young, Karen Dengel, Laura O Keefe, Samantha Le, Celeste Richardson, Randi E. Isaacs, J. Joseph Melenhorst, Bruce L. Levine, Carl H. June, Michael C. Milone American Society of Hematology Annual Meeting December 10, 2017
2 Background BCMA expressed on normal and malignant plasma cells Promotes MM cell survival BCMA-targeted therapies, including CAR T cells, show pre-clinical and early clinical activity in myeloma Penn/Novartis CART-BCMA cells Autologous T cell product Human anti-bcma scfv CD3ζ /41BB stimulatory domains Lentiviral vector CD3/CD28 bead-stimulated manufacturing Tai et al, Blood 2014; Carpenter et al, Clin Can Res 2013; Tai et al, Blood 2016; Ali et al, Blood 2016; Cohen et al, ASH 2016, #1147; Lin et al, EHA 2017; Fan et al ASCO 2017, #LBA3001; Singh R et al. submitted 2017
3 Study design Cohort x 10 8 CAR+ T cells (n=3-6) Cohort 2 Cytox 1.5 g/m x 10 7 CAR+ T cells (n=3-6) Cohort 3 Cytox 1.5 g/m x 10 8 CAR+ T cells (n=3-6) 4 week delay between subjects expansion expansion expansion Primary objective Safety Secondary Feasibility Efficacy (response rates, PFS, OS, MRD) Exploratory: CART-BCMA expansion, persistence, phenotype Impact on normal B cell and PC compartments BCMA expression pre- and post-treatment Cytokine/chemokine levels Soluble BCMA, BAFF, APRIL levels Assess for anti-car immune responses Impact on tumor microenvironment 1) Flow BCMA-CAR Pre Day 7 CD8 2) qpcr
4 Study design
5 Key inclusion/exclusion criteria Relapsed or refractory MM after 3 prior lines 2 prior lines if dual-refractory to PI and IMiD 2 week therapy washout before apheresis and infusions 4 wks for monoclonal antibodies Measurable disease at screening ECOG PS 0-2 Adequate organ function at screening Serum Creatinine 2.5 mg/dl or Estimated CrCl 30 ml/min ANC 1000/µl, platelets 50/µl ( 30 if BM PC 50%) AST 3x ULN and total bilirubin 2.0 Left ventricle EF 45% No CNS myeloma BCMA expression level not used for eligibility
6 Accrual and patient flow (as of Nov. 2017) Opened Nov consented 5 screen fails 4 manufactured, never treated due to clinical decline/rapid disease progression 1 currently manufacturing 24 treated 9 in cohort 1: 1-5 x 10 8 CART-BCMA (no lymphodepleting chemo) 5 in cohort 2: Cytox x 10 7 CART-BCMA 10 in cohort 3: Cytox x 10 8 CART-BCMA All successfully manufactured at least minimum target dose 1 required 2 collections Median transduction efficiency=17.4% ( %) 20/24 got 100% of planned dose 4 got 40% due to fevers/crs on day 2
7 Treated Patient characteristics All patients (n=24) Age 58 (44-75) Gender 67% M; 33% F Yrs from diagnosis 4.6 ( ) Prior lines of therapy 7 (3-13) Lenalidomide 100% Bortezomib 100% Pomalidomide 92% Carfilzomib or Oprozomib 96% Cohort 1 (n=9) Cohort 2 (n=5) Cohort 3 (n=10) Daratumumab 75% Dual- / Quad- / Penta-refractory 96% / 54% / 42% 44% 80% 100% 89% / 56% / 33% 100% / 60% / 40% 100% / 50% / 50% Autologous / Allogeneic SCT 92% / 4% Cyclophosphamide 100% Anti-PD1 29% High-risk genetics -17p or TP53 mutation 96% 71% Extramedullary dz 29% % BM plasma cells 70% (0-95)
8 Safety (n=24) Cohort 1 1 DLT: Grade 4 PRES in pt 03 Encephalopathy, seizures, obtundation, intraventricular hemorrhage Resolved s/p steroids, cyclophosphamide 1 death on study: pt 08 (day +24) Candidemia, progressive myeloma/evolving plasma cell leukemia Cohort 2 no DLTs Cohort 3 1 DLT: Grade 4 pleural hemorrhage (spontaneous hemothorax), Grade 3 cardiomyopathy Also Gr 3 cytokine release syndrome, Gr 3 encephalopathy, prolonged Gr 4 thrombocytopenia
9 Safety (n=24) Toxicity Cytokine release syndrome All grade Penn Grade 3/4 Toci/Siltux used Neurotoxicity All grade Grade 3/4 Cohort 1 (n=9) 8 (89%) 3 (33%) 4 (44%) 3 (33%) 2 (22%) Cohort 2 (n=5) 3 (60%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) Cohort 3 (n=10) 9 (90%) 5 (50%) 2 (20%) 3 (33%) 1 (10%) Grade 3/4 Toxicity Cohort 1 (n=9) Cohort 2 (n=5) Cohort 3 (n=10) Febrile neutropenia 0 4 (80%) 2 (20%) Hypophosphatemia 4 (44%) 0 3 (30%) Infection 4 (44%) 1 (20%) 0 Thrombocytopenia 3 (33%) 2 (40%) 2 (20%) Anemia 2 (22%) 1 (20%) 1 (10%) Neutropenia 2 (22%) 4 (80%) 2 (20%) Hypocalcemia 2 (22%) 0 2 (20%) Hypokalemia 2 (22%) 0 0 Lymphopenia 1 (11%) 2 (40%) 5 (50%) Fatigue 1 (11%) 0 0 Alk phos increased 1 (11%) 0 0 AST increased 1 (11%) 0 1 (10%) Hypofibrinogenemia 1 (11%) 0 0 Leukopenia 1 (11%) 4 (80%) 6 (60%) Hypertension 1 (11%) 0 0 Pleural effusion 1 (11%) 0 0 Hyponatremia 1 (11%) 0 3 (30%) Abdominal pain (10%) Decreased ejection fraction (10%) Pleural hemorrhage (10%)
10 Clinical activity Cohort x 10 8 CART-BCMA Cohort 2 Cytox x 10 7 CART-BCMA 3 4 Cohort 3 Cytox x 10 8 CART-BCMA * P D P D * * V G P R M R * M R D -n e g S D P R V G P R M R P F S (m o n th s ) s C R 2 2 S D 1 6 P R 1 4 S D 1 3 M R 1 2 S D P F S (m o n th s ) 3 3 P R * * 2 7 P R 3 2 M R 2 9 S D 2 5 P R 2 3 M R 2 0 V G P R 1 9 C R 2 1 P D 1 7 P R P F S (m o n th s ) * * M e a s u r a b le b y P E T /C T ; F D G -n e g a t d 2 8, d 9 0 ORR ( PR) = 11/24 (46%) MR = 16/24 (67%) ORR ( 10e8 = 10/19 (53%) Median DOR = 4 months
11 CART-BCMA expansion M e d ia n + in te r q u a r tile r a n g e P e a k e x p a n s io n b y q P C R c o p ie s / g D N A C o h o rt 1 C o h o rt 2 C o h o rt 3 c o p ie s / g D N A * ** * p = * * p = D a y s C o h o r t 1 C o h o r t 2 C o h o r t 3
12 CART-BCMA persistence C o h o r t 1 C o h o r t c o p ie s / g D N A c o p ie s / g D N A D a y s p o s t C A R in fu s io n D a y s p o s t C A R in fu s io n C o h o r t c o p ie s / g D N A D a y s p o s t C A R in fu s io n
13 Baseline BCMA expression and soluble BCMA E x p a n s io n v s. b a s e lin e B C M A in te n s ity B e s t r e s p o n s e v s. b a s e lin e B C M A in te n s ity r= p = p = B C M A M F I B C M A M F I P R < P R P e a k e x p a n s io n (c o p ie s / g D N A ) E x p a n s io n v s. b a s e lin e s B C M A B e s t r e s p o n s e v s b a s e lin e s B C M A r= p = p = s B C M A (n g /m l) s B C M A (n g /m l) P R < P R P e a k e x p a n s io n (c o p ie s /m g D N A )
14 Serial BCMA expression on MM cells (n=17) Subj 16 Subj 17 Subj 12 Baseline B C M A e x p r e s s io n Day 28 B C M A M F I Day # 0 P r e - t x D 2 8 D 9 0 P r e - t x D 2 8 # D a y P R < P R
15 Conclusions CART-BCMA has activity in heavily pre-treated MM Lymphodepletion is not required for robust expansion and response Cyclophosphamide may increase frequency of patients with strong expansion CART-BCMA detectable by qpcr up to 21 months typically 4-6+ months Toxicities remain CRS and neurotoxicity No increased toxicity with cyclophosphamide Responses: PR in 11/24 (47%) 4 ongoing at 3+, 3+, 6+ and 24+ months 1-5 x10 8 dose more active Not clearly associated with baseline BCMA expression or sbcma concentration Decreased BCMA expression may be escape mechanism
16 Acknowledgments Co-investigators Ed Stadtmauer Al Garfall Dan Vogl Brendan Weiss Eric Lancaster (neurology) TCSL/PDCS Jos Melenhorst Simon Lacey David Ambrose Farzana Nazimuddin Vanessa Gonzalez Fang Chen CVPF Bruce Levine Megan Davis Don Siegel Andrew Fesnak Andrea Brennan Anne Lamontagne Alex Malykhin Theresa Colligon Center for Cellular Immunotherapeutics Karen Dengel Regina Ferthio Tenesia Carey Naseem Kerr Lee Dengel Gabriela Plesa Les Lledo Wei-Ting Hwang Jamella Knots-Miller Cynthia Desir Amy Marshall Laurel Caffee Jane Anderson Desire Fenderson Mary Truran Annemarie Nelson Laura O Keefe Samantha Le Carl June Office of Clinical Research (Sponsor) Emma Meagher David Vaughn (Medical Director) Penn MM CAR Working Group Regina Young Marco Ruella John Scholler Selene Nunez-Cruz Michael Milone (scientific advisor) Marcela Maus (MGH) Novartis Celeste Richardson Keith Mansfield Reshma Singh Eugene Choi Jennifer Brogdon Heather Huet Greg Motz Randi Isaacs Ewelina Morawa
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