Open-label pilot study of genetically engineered NY-ESO-1–specific t cells (GSK3377794) alone or in combination with pembrolizumab in relapsed/refractory multiple myeloma.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS8555-TPS8555
Author(s):  
Aaron Rapoport ◽  
James Edward Hoffman ◽  
Jonathan L. Kaufman ◽  
Kristin Blouch ◽  
Emily Butler ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
Pilot Study ◽  
Clinical Activity ◽  
Cell Transplant ◽  
Antigenic Peptides ◽  
Single Infusion ◽  
Open Label ◽  
T Cell Therapy ◽  
Refractory Multiple Myeloma

TPS8555 Background: Adoptive cellular therapy may be practice-changing in relapsed/refractory multiple myeloma (MM). NY-ESO-1 TCR T (GSK3377794) are autologous polyclonal T cells transduced by a self-inactivating lentiviral vector to express an affinity-enhanced TCR capable of recognizing NY-ESO-1 or LAGE-1a antigenic peptides in complex with HLA-A*02. GSK3377794 has shown clinical activity in synovial sarcoma, melanoma, myxoid/round cell liposarcoma, and MM after autologous stem cell transplant. NY-ESO-1 and LAGE-1a are cancer/testis antigens frequently overexpressed in MM and linked to poor clinical outcome. PD-1 expression on CD8 T cells, which has been observed in MM patients previously treated with GSK3377794 as well as with CD19 CAR T-cell therapy, can limit adaptive immune response. We hypothesize that GSK3377794 alone, or in combination with the anti-PD-1 inhibitor pembrolizumab, may result in an antitumor effect in MM. Methods: This is an open-label, pilot study (NCT03168438) of GSK3377794 in patients with relapsed/refractory MM positive for HLA-A*02:01, HLA-A*02:05, ± HLA-A*02:06 and NY-ESO-1/LAGE-1a. Patients (n = 20) who have received ≥3 prior therapies containing ≥1 immunomodulatory imide, proteasome inhibitor, alkylator, CD38 monoclonal antibody, or glucocorticoid will be assigned to either single-infusion GSK3377794 (Arm 1, n = 10) or single-infusion GSK3377794 + pembrolizumab 200 mg IV every 3 weeks (Arm 2, n = 10). Arm 1 enrollment will be completed first. In Arm 2, pembrolizumab will begin in Week 3 (Week 6 if precluded by toxicity). Patients in both arms will provide cells via leukapheresis to manufacture autologous NY-ESO-1–specific T cells, undergo lymphodepletion (fludarabine + cyclophosphamide), and then receive GSK3377794 infusion (1−8x109 transduced T cells). Primary and secondary objectives are to assess safety/tolerability and antitumor activity, respectively, of GSK3377794 (± pembrolizumab). Arm 2 enrollment will pause for a 3-week safety review after 3 patients have received a first dose of pembrolizumab. Efficacy, safety, and biomarkers will be assessed every visit. The treatment phase will last 108 weeks, or until disease progression; follow-up will last ≤15 years. As of January 2020, 3 patients have been treated. Funding: GlaxoSmithKline (208470) Clinical trial information: NCT03168438 .

scholarly journals Allogeneic Vγ9Vδ2 T-Cell Therapy Promotes Pulmonary Lesion Repair: An Open-Label, Single-Arm Pilot Study in Patients With Multidrug-Resistant Tuberculosis

2021 ◽  
Vol 12 ◽  
Author(s):  
Juan Liang ◽  
Liang Fu ◽  
Man Li ◽  
Yuyuan Chen ◽  
Yi Wang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Pilot Study ◽  
Cell Therapy ◽  
Multidrug Resistant ◽  
Open Label ◽  
T Cell Therapy ◽  
Safety And Efficacy ◽  
Mdr Tb ◽  
Vγ9vδ2 T Cells

The WHO’s “Global tuberculosis report 2020” lists tuberculosis (TB) as one of the leading causes of death globally. Existing anti-TB therapy strategies are far from adequate to meet the End TB Strategy goals set for 2035. Therefore, novel anti-TB therapy protocols are urgently needed. Here, we proposed an allogeneic Vγ9Vδ2 T-cell-based immunotherapy strategy and clinically evaluated its safety and efficacy in patients with multidrug-resistant TB (MDR-TB). Eight patients with MDR-TB were recruited in this open-label, single-arm pilot clinical study. Seven of these patients received allogeneic Vγ9Vδ2 T-cell therapy adjunct with anti-TB drugs in all therapy courses. Cells (1 × 108) were infused per treatment every 2 weeks, with 12 courses of cell therapy conducted for each patient, who were then followed up for 6 months to evaluate the safety and efficacy of cell therapy. The eighth patient initially received four courses of cell infusions, followed by eight courses of cell therapy plus anti-MDR-TB drugs. Clinical examinations, including clinical response, routine blood tests and biochemical indicators, chest CT imaging, immune cell surface markers, body weight, and sputum Mycobacterium tuberculosis testing, were conducted. Our study revealed that allogeneic Vγ9Vδ2 T cells are clinically safe for TB therapy. These cells exhibited clinical efficacy in multiple aspects, including promoting the repair of pulmonary lesions, partially improving host immunity, and alleviating M. tuberculosis load in vivo, regardless of their application in the presence or absence of anti-TB drugs. This pilot study opens a new avenue for anti-TB treatment and exhibits allogeneic Vγ9Vδ2 T cells as promising candidates for developing a novel cell drug for TB immunotherapy.Clinical Trial Registration(https://clinicaltrials.gov/ct2/results?cond=&term=NCT03575299&cntry=&state=&city=&dist=) ( NCT03575299).

A Phase I Study of a Novel Fully Human BCMA-Targeting CAR (CT103A) in Patients with Relapsed/Refractory Multiple Myeloma

Blood ◽  
2021 ◽  
Author(s):  
Di Wang ◽  
Jue Wang ◽  
Guang Hu ◽  
Wen Wang ◽  
Yi Xiao ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
T Cell ◽  
Phase I ◽  
Complete Response ◽  
Clinical Trial Registry ◽  
T Cell Therapy ◽  
Refractory Multiple Myeloma ◽  
Car T Cell ◽  
Car T

B cell maturation antigen- (BCMA) specific chimeric antigen receptor (CAR) T-cell therapies have shown efficacy in relapsed, refractory multiple myeloma (RRMM). Since the non-human originated antigen-targeting domain may limit clinical efficacy, we developed a fully human BCMA-specific CAR, CT103A, and report its safety and efficacy in a phase I trial. Eighteen consecutive RRMM patients, including four patients with prior murine BCMA CAR exposures, were enrolled. CT103A was administered at 1, 3, and 6 × 106 CAR-positive T cells/kg in the dose-escalation phase, and 1 × 106 CAR-positive T cells/kg in the expansion cohort. The overall response rate (ORR) was 100%, with 72.2% of the patients achieving complete response or stringent complete response (sCR). For the four murine BCMA CAR-exposed patients, three achieved sCR, and one achieved a very good partial response. At one year, the progression-free survival rate was 58.3% for all cohorts and 79.1% for the patients without extramedullary myeloma. Hematologic toxicities were the most common adverse events. 70.6% of the patients experienced grade 1 or 2 cytokine release syndromes. No immune effector cell-associated neurotoxicity syndrome was observed. To the cutoff date, CAR transgenes were detectable in 77.8% of the patients. The median CAR transgene persistence was 307.5 days. Only one patient was positive for the anti-drug antibody. Altogether, CT103A is safe and highly active in RRMM patients and can be developed as a promising therapy for RRMM. Patients who relapsed from prior murine BCMA CAR T-cell therapy may still benefit from CT103A. (Chinese Clinical Trial Registry ChiCTR1800018137)

Phase 1, multicenter, open-label study of single-agent bispecific antibody T-cell engager GBR 1342 in relapsed/refractory multiple myeloma.

2018 ◽  
Vol 36 (5_suppl) ◽  
pp. TPS81-TPS81 ◽  
Author(s):  
Joshua Ryan Richter ◽  
Martin Wermke ◽  
John S. Kauh ◽  
Jonathan Back ◽  
Yacine Salhi ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
Bispecific Antibody ◽  
Single Agent ◽  
Objective Response ◽  
Human Study ◽  
Clinical Activity ◽  
Single Subject ◽  
Myeloma Cells ◽  
Refractory Multiple Myeloma

TPS81 Background: Available therapies have improved outcomes in multiple myeloma but patients eventually relapse, requiring treatment with agents that are active in refractory disease. CD38, a transmembrane glycoprotein, is upregulated on myeloma cells and is a validated disease target, evidenced by the anti-myeloma activity of daratumumab, an anti-CD38 human IgG1κ monoclonal antibody. GBR 1342 is a CD3xCD38 bispecific antibody engineered (using Glenmark’s BEAT® platform) to direct T-cells to CD38-expressing myeloma cells. In preclinical studies, GBR 1342 redirected the cytotoxic potential of T-cells to human myeloma cell lines in vitro and in mouse xenograft models. This ongoing, 2-part, first-in-human study aims to: (1) evaluate the safety profile and maximum tolerable dose (MTD) of GBR 1342 monotherapy in subjects with relapsed/refractory multiple myeloma ( > 3 prior therapies); and (2) further elucidate the safety, tolerability, and preliminary clinical activity of GBR 1342 at the MTD. The study is also evaluating the mechanisms by which GBR 1342 redirects T-cells to tumor and enhances cytolytic activity of cytotoxic T-cells. Methods: In Part 1, intravenous GBR 1342 is administered on Day 1 and Day 15 in 28-day treatment cycles at escalating dose levels (Table). The first 4 cohorts consist of a single subject. Subsequent cohorts will enroll using a 3+3 design. In Part 2, 65 evaluable subjects will be treated at the MTD identified in Part 1 until disease progression or unacceptable toxicity occurs. Primary endpoints include frequency and severity of AEs, number of dose-limiting toxicities during Cycle 1 (Part 1 only), and objective response to GBR 1342 (Part 2 only). Secondary endpoints include pharmacokinetics and anti-tumor activity of GBR 1342 (objective response, progression-free and overall survival). [Table: see text]

scholarly journals TIG-007: Study of EOS884448/GSK4428859A Alone, and in Combination with Iberdomide with or without Dexamethasone, in Participants with Relapsed or Refractory Multiple Myeloma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2745-2745
Author(s):  
Philippe Moreau ◽  
Leona Holmberg ◽  
Nathalie Meuleman ◽  
Philippa Graham ◽  
Olivier De Henau ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
T Cell ◽  
Immune Checkpoint ◽  
Research Funding ◽  
Effective Control ◽  
Clinical Activity ◽  
Synergistic Activity ◽  
Publicly Traded ◽  
Refractory Multiple Myeloma

Abstract Background: T-cell immunoreceptor with Ig and ITIM domains (TIGIT) is an inhibitory immune checkpoint receptor expressed on subsets of T cells and NK cells. In multiple myeloma (MM), TIGIT expression increases as the disease progresses and correlates with defective T cell effector functions. Higher TIGIT expression was observed in MM bone marrow CD8+ T cells in mice and patients compared to other immune checkpoint inhibitors, including PD-1, TIM-3, LAG-3, or CTLA-4 (Guillerey, C. et al, Blood 2018; Minnie, S. A. et al . Blood 2018). EOS884448/GSK4428859A (EOS-448) is a potent and highly selective fully human antagonist IgG1 antibody targeting TIGIT. Preclinically, anti-TIGIT Ab elicits superior anti-tumor immune responses compared to anti-PD1 mAbs (Guillerey, C. et al, Blood 2018). In murine Vk*Myc MM models, Fc-enabled a-TIGIT Ab elicits effective control of MM disease progression after autologous stem-cell transplant (ASCT), while Fc-disabled version is inactive. Anti-tumor activity is seen with monotherapy after ASCT at high T cell doses and provides significant synergistic activity when combined with an Immunomodulatory imide drug (IMiD) if T cell doses are suboptimal (Minnie, S. A. et al, Abstract submitted ASH 2021). Iberdomide (also known as CC-220) is a novel potent cereblon (CRBN) E3 ligase modulatory compound (CELMoD) that regulates multiple transcription factors within immune cells (Gandhi, A. K. et al . Brit J Haematol 2014). Iberdomide has shown notable clinical activity and acceptable tolerability in heavily pre-treated patients with relapsed or refractory multiple myeloma (RRMM), including those refractory to prior IMiDs (Lonial, S. et al. J Clin Oncol 2019). Given the dominant role of TIGIT in the immune suppression associated with MM, we hypothesize that TIGIT represents an ideal checkpoint to target clinically. EOS-448 alone or the synergistic combination of EOS-448 with iberdomide may provide a therapeutic opportunity to amplify myeloma-specific T-cell anti-tumor responses in difficult to treat RRMM patients previously exposed to IMiD, proteasome inhibitors (PIs) and anti-CD38. Methods: This phase I/II, open-label, multicenter, dose-escalation/expansion study will assess the safety, tolerability and preliminary activity of EOS-448 as monotherapy and in combination with iberdomide with or without dexamethasone in up to 158 adults with RRMM, who have progressed after prior treatments with IMiDs, PI and anti-CD38. EOS-448 will be infused intravenously on Day 1 of 28-day cycles. In Part 1, the safety and tolerability of EOS-448 as monotherapy and in combination with iberdomide with or without dexamethasone will be assessed in cohorts of up to 18 participants to identify the maximum tolerated dose and recommended phase II dose (RP2D) in each of the 3 treatment arms. In Part 2, the safety and anti-cancer activity of the RP2D will be assessed in up to 102 RRMM participants. Primary endpoints are treatment emergent adverse events, laboratory abnormalities, dose-limiting toxicities and clinical activity according to the International Myeloma Working Group (IMWG) Uniform Response Criteria. Secondary endpoints include overall response rates, duration of response, PK, and antidrug antibodies. Exploratory biomarkers including study treatment-mediated pharmacodynamic (PD) effects, PK-PD correlations, and correlative analyses of predictive and PD measurements with response, toxicity, and resistance will be investigated. Minimal residual disease (MRD) status with therapy will also be assessed as clinically indicated. The study is planned to open in November 2021 in North America and Europe. Disclosures Moreau: Abbvie: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Sanofi: Honoraria; Celgene BMS: Honoraria; Oncopeptides: Honoraria. Holmberg: Janssen: Research Funding; Merck: Research Funding; Seattle Genetics: Research Funding; Sanofi: Research Funding; Millennium-Takeda: Research Funding; Bristol Myers Squibb: Research Funding; Up-To-Date: Patents & Royalties. Meuleman: iTeos Therapeutics: Consultancy. Graham: iTeos Therapeutics: Current Employment. De Henau: iTeos Therapeutics: Current Employment, Current equity holder in publicly-traded company; Bristol-Meyer-Squibb: Current equity holder in publicly-traded company. Driessens: iTeos Therapeutics: Current Employment, Current equity holder in publicly-traded company. McGrath: iTeos Therapeutics: Current Employment, Current equity holder in publicly-traded company; Norgine: Other: Spouse Current Employment. Lager: iTeos Therapeutics: Current Employment, Current equity holder in publicly-traded company. Hill: NeoLeukin Therapeutics: Consultancy; Applied Molecular Transport: Research Funding; Syndax Pharmaceuticals: Research Funding; NapaJen Pharma: Consultancy; iTeos Therapeutics: Consultancy, Research Funding; Compass Therapeutics: Research Funding; Generon Corporation: Consultancy; Roche: Research Funding.

scholarly journals Open-Label Pilot Study of Genetically Engineered NY-ESO-1 Specific T Cells (GSK3377794) Alone or in Combination with Pembrolizumab in Relapsed and Refractory Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3134-3134
Author(s):  
Taiga Nishihori ◽  
Jonathan L. Kaufman ◽  
James E. Hoffman ◽  
Kristin Blouch ◽  
Sunil Pandit ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
Board Of Directors ◽  
Research Funding ◽  
Treatment Phase ◽  
Single Infusion ◽  
Open Label ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership

Background: Emerging clinical data demonstrate that adoptive cellular therapy has potential to be practice-changing in the management of relapsed/refractory multiple myeloma (MM). NY-ESO-1 TCR T (GSK3377794) are autologous polyclonal T cells transduced by a self-inactivating lentiviral vector to express an affinity-enhanced TCR capable of recognizing NY-ESO-1 or LAGE-1a antigenic peptides in complex with HLA-A2. In prior studies, encouraging clinical activity has been observed with GSK3377794 treatment in patients with synovial sarcoma, melanoma, myxoid/round cell liposarcoma, and in MM patients receiving GSK3377794 after autologous stem cell transplant (ASCT). NY-ESO-1 and LAGE-1a are immunogenic cancer/testis antigens frequently overexpressed in MM and are linked to poor clinical outcome. While a number of phase 1 and 2 trials are evaluating GSK3377794 in solid tumors, this abstract presents a trial in progress aiming to evaluate safety and efficacy of GSK3377794 alone or in combination with the anti-PD1 inhibitor, pembrolizumab, in patients with MM. PD-1 expression on CD8 T cells has been observed in MM patients previously treated with GSK3377794 and can limit adaptive immune response. This has also been described as a mechanism of resistance and relapse in CD19 CAR T-cell trials (Fraietta et al, Nat Med 2018). Thus, we hypothesize that combining GSK3377794 and pembrolizumab may result in a synergistic antitumor effect. Study design and methods: This is an open-label, pilot study (NCT03168438) of GSK3377794 in patients who are HLA-A*02:01, HLA-A*02:05, and/or HLA-A*02:06 positive and have NY-ESO-1/LAGE-1a positive relapsed/refractory MM. Twenty patients who have received at least three prior therapies containing at least one of the following drug classes as separate or combined lines of therapy (including ASCT): an immunomodulatory imide, proteasome inhibitor, alkylator, CD38 monoclonal antibody, and glucocorticoid, will be assigned to one of two arms: GSK3377794 alone as a single infusion (Arm 1, n=10) or GSK3377794 as a single infusion in combination with pembrolizumab 200 mg IV every 3 weeks (Arm 2, n=10). Enrollment of Arm 1 will be completed before enrolling subjects to Arm 2. Administration of pembrolizumab will start from Week 3 (or Week 6 if toxicities preclude Week 3 treatment). Patients will undergo leukapheresis to obtain cells for the manufacture of autologous NY-ESO-1-specific T cells. Each patient will then undergo lymphodepleting chemotherapy with fludarabine and cyclophosphamide followed by GSK3377794 infusion of 1−8x109 transduced T cells. Primary and secondary objectives are to assess safety and tolerability, and antitumor activity, respectively, of GSK3377794 treatment (with and without pembrolizumab). Patients will be monitored for adverse events and combination-related treatment-limiting toxicities; efficacy will be assessed using International Myeloma Working Group Response Criteria (Rajkumar et al, Blood 2011). In Arm 2, enrollment will be temporarily paused for a 3-week safety review period after the first 3 patients have received their first dose of pembrolizumab. Efficacy, safety, and biomarker assessments will be conducted at each visit. Patients will complete the treatment phase upon progression of disease or 108 weeks after GSK3377794 infusion. After completion of the treatment phase, patients will transfer to the long-term follow-up study (NCT03391778) to continue safety and survival monitoring for up to 15 years. As of January 27, 2019, 50 patients have undergone screening for HLA status and NY-ESO-1/LAGE-1a antigen expression. Among 50 patients screened for HLA, 25 (50%) tested positive for HLA-A*02:01, 05, and/or 06. Of these patients, bone marrow samples from 12/21 (57%) tested positive for NY-ESO-1, LAGE-1a, or both, illustrating high expression of this antigen in MM. To date, 3 patients have been treated with GSK3377794, demonstrating feasibility of identifying and treating HLA/antigen-positive patients with relapsed/refractory MM. Further work is underway towards introducing flexibility in screening procedures in order to permit wider screening of patients and to minimize time between screening and leukapheresis and for cell manufacturing, which will enhance patient eligibility. Acknowledgment: Medical writing support by O Conn PhD of Fishawack Indicia Ltd, funded by GSK. This study (NCT03168438) is funded by GSK. Disclosures Nishihori: Karyopharm: Research Funding; Novartis: Research Funding. Kaufman:Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; AbbVie: Consultancy; Takeda: Consultancy; Celgene: Consultancy; Amgen: Consultancy; Winship Cancer Institute of Emory University: Employment; TG Therapeutics: Consultancy; Bristol-Myers Squibb: Consultancy; Incyte: Consultancy; Karyopharm: Membership on an entity's Board of Directors or advisory committees. Blouch:GSK: Employment, Equity Ownership. Pandit:GSK: Employment, Equity Ownership. Butler:GSK: Employment, Equity Ownership. Jain:GSK: Employment. Wu:GSK: Employment, Equity Ownership. DeYoung:GSK: Employment, Equity Ownership. Hasan:GSK: Employment, Equity Ownership; Atara Biotherapeutics: Patents & Royalties; Merck: Equity Ownership.

Clinical responses and pharmacokinetics of fully human BCMA targeting CAR T-cell therapy in relapsed/refractory multiple myeloma.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 8013-8013 ◽  
Author(s):  
chunrui li ◽  
Jianfeng Zhou ◽  
Jue Wang ◽  
Guang Hu ◽  
Aihua Du ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
T Cell ◽  
Rapid Response ◽  
High Dose ◽  
T Cell Therapy ◽  
Refractory Multiple Myeloma ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T

8013 Background: Previous studies indicate patients with relapsed/refractory multiple myeloma (RRMM) who receive high-dose BCMA-targeting CAR-T cells may achieve better remission but have worse adverse events. Moreover, once the disease progresses again, the re-infusion of CAR-T cells is not effective. To solve this dilemma, we have developed a novel BCMA-targeting CAR-T (CT103A) with a lentiviral vector containing a CAR structure with a fully human scFv, CD8a hinger and transmembrane, 4-1BB co-stimulatory and CD3z activation domains. Methods: ChiCTR1800018137 is a single-center and single-arm trial of CT103A in patients with RRMM. The primary objectives are to characterize the safety and tolerability in patients with R/R MM. The secondary objectives include evaluation of anti-myeloma activity, cytokines, CAR-T cell persistence, and pharmacokinetics. Between September 21, 2018, and January 21, 2019, nine patients (including 3 patients having relapsed after being given a murine BCMA CAR-T) received CT103A in 3+3 dose-escalation trial (three doses at 1, 3, 6 ×106/kg) after a conditioning chemotherapy regimen of cyclophosphamide and fludarabine. All Patients had received a median of 4 prior lines (range 3 - 5) of MM therapy. Results: At the time of the February 4, 2019 data analysis, the overall response rate was 100% (Table), and all patients had a rapid response within 14 days, with 67% (2/3) reaching CR/sCR at the lowest dose. The pharmacokinetics of CT103A were assessed by a digital polymerase chain reaction. Robust expansions were seen even at the lowest dosage level. In addition, Cmax and AUC0-28 reached levels comparable to reported CD19 CAR-T. In the first two dose groups, the grade of cytokine release syndrome (CRS) was 0 - 2. In the 6 ×106 /kg dose group, DLT had been observed in one patient. Conclusions: Data from this early-stage clinical study showed the unparalleled safety and efficacy of CT103A. Major AEs were transient, manageable, and reversible. three patients who relapsed the murine BCMA CAR-T were treated with CT103A, two patients achieved CR, and one patient achieved VGPR. 100% ORR and a rapid response within 2 weeks, suggests CT103A could be developed as a competitive therapeutic to treat patients with RRMM. Treatment Response (Case 1,5 and 7 are patients who relapsed the murine BCMA CAR-T). Clinical trial information: ChiCTR1800018137. [Table: see text]

Phase I/II, open-label, 2-arm study to evaluate safety, tolerability, and clinical activity of GSK2857916 in combination with 2 standard-of-care (SoC) regimens in relapsed/refractory multiple myeloma: (DREAMM 6).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS8053-TPS8053 ◽  
Author(s):  
Luciano J. Costa ◽  
Hang Quach ◽  
Keith Stockerl-Goldstein ◽  
Bradley Augustson ◽  
Geraldine Ferron-Brady ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Monoclonal Antibody ◽  
Dose Escalation ◽  
Standard Of Care ◽  
Autologous Stem Cell Transplant ◽  
Clinical Activity ◽  
Cell Transplant ◽  
Open Label ◽  
Heavily Pretreated ◽  
Line Of Therapy

TPS8053 Background: B-cell maturation antigen (BCMA) is a validated therapeutic target in Multiple Myeloma (MM). GSK2857916 is a humanized (IgG1) anti-BCMA monoclonal antibody conjugated to monomethyl auristatin-F via protease resistant maleimidocaproyl linker and produced in afucosylated form to enhance antibody-dependent cellular cytotoxicity. In FTIH study BMA117159, GSK2857916 was well tolerated and showed unprecedented clinical activity [ORR=60%; mPFS 7.9 months (95% CI, 3.1–not estimable)] as monotherapy in heavily pretreated MM patients. GSK2857916 in combination with SoC regimens, could potentially further improve outcomes for patients with relapsed/refractory (RR) MM. Methods: DREAMM 6 is a 2-part study: Part 1 (dose escalation) is evaluating safety and tolerability of 2 doses (2.5 mg/kg and 3.4 mg/kg) of GSK2857916, in combination with SoC regimens in two independent arms: Arm A with Lenalidomide/Dexamethasone, and Arm B with Bortezomib/Dexamethasone. Modified Toxicity Probability Interval design will guide dose escalation and RP2D of GSK2857916 in each arm for Part 2 (cohort expansion). Part 2 will confirm safety, evaluate clinical activity of GSK2857916 RP2D with either combination and collect pharmacokinetic information on GSK2857916, Lenalidomide and bortezomib. Up to 90 subjects previously treated with at least 1 prior line of therapy who have undergone autologous stem cell transplant or are transplant-ineligible will be enrolled; up to 24 in Part 1 and up to 66 in Part 2. Subjects in Arm A will continue combination treatment until progression, intolerance, consent withdrawal or death. Subjects in Arm B will receive up to 8 cycles of GSK2857916 in combination with Bor/Dex and then continue GSK2857916 monotherapy until progression, intolerance, consent withdrawal, or death. Enrolment on study started in October 2018 and is ongoing. Study funded by GlaxoSmithKline; drug linker technology licensed from Seattle Genetics; monoclonal antibody produced using POTELLIGENT Technology licensed from BioWa. ClinicalTrials.gov Identifier: NCT03544281.

scholarly journals High efficacy and safety of CD38 and BCMA bispecific CAR-T in relapsed or refractory multiple myeloma

2022 ◽  
Vol 41 (1) ◽  
Author(s):  
Yuanyan Tang ◽  
Haisen Yin ◽  
Xinying Zhao ◽  
Dan Jin ◽  
Yan Liang ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
Trial Registration ◽  
Efficacy And Safety ◽  
Clinical Trial Registration ◽  
T Cell Therapy ◽  
Refractory Multiple Myeloma ◽  
Car T Cells ◽  
Car T

Abstract Background B-cell maturation antigen (BCMA) chimeric antigen receptor T (CAR-T) cell therapy has obtained promising results in relapsed or refractory multiple myeloma (R/R MM), while some patients do not response, or relapse in short term after treatment. Combining with anti-CD38 might solve the problem of targeting BCMA alone. We aimed to assess the efficacy and safety of BCMA and CD38 (BCMA-CD38) bispecific CAR-T cells in R/R MM patients. Methods We did a single-center, single-arm clinical study at the Second Affiliated Hospital of Yangtze University in China. Patients meeting with the inclusion criteria were administered with fludarabine and cyclophosphamide before CAR-T cells infusion. Response and adverse events were assessed after infusion. This study was registered with the Chinese Clinical Trial Registration Center (ChiCTR1900026286). Results First, we found BCMA-CD38 CAR-T cells exhibited enhanced killing effect on BCMA+CD38+ cells in vitro, compared to BCMA CAR-T and CD38 CAR-T cells. We further demonstrated its anti-tumor activity in vivo. Then, we enrolled 16 R/R MM patients for safety and efficacy analyses. Of the 16 evaluable patients, 14 (87.5%) respond to the treatment, including 13 stringent complete response (sCR) and one partial response (PR), while two patients did not respond. At a median follow-up of 11.5 months, of the 13 patients who achieved sCR, 76.9% (10/13) did not relapse or progress during follow-up. Relapse occurred in 3 patients (Patient 2, 3 and 4) after achieving sCR. In sum, four patients died, of which one died of hemophagocytic lymphohistiocytosis syndrome secondary to severe cytokine release syndrome (CRS) and three died of disease progression or relapse. The 1-year progression-free survival rates was 68.8%. The 1-year overall survival rate was 75.0%. Extramedullary lesions were eliminated in 62.5% (5/8) patients. The most common symptoms after CAR-T infusion were cytopenia (16, 100%), fever (10, 62.5%), fatigue (8, 50.0%) and myalgias (8, 50.0%). Twelve patients (75.0%) were observed with various grades of CRS, of which five patients (31.3%) got serious CRS (Grade ≥ 3). The CAR+ cell expansion levels were associated with the severity of CRS. Transient clonal isotype switch was observed after CAR-T infusion. Conclusion Our results confirm that BCMA-CD38 CAR-T cells therapy is feasible in treating R/R MM patients, with high response rate, low recurrence rate and manageable CRS, which will be a promising treatment option for R/R MM. Trial registration ChiCTR1900026286, registered on September 29, 2019, retrospectively registered, URL: https://www.chictr.org.cn/showproj.aspx?proj=43805

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