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- Catherine Thieblemont (Paris, France)
- Thomas Cluzeau (Nice, France)
617O - Lemzoparlimab, a differentiated anti-CD47 monoclonal antibody, in combination with azacitidine (AZA) in patients with newly diagnosed higher risk myelodysplastic syndrome (HR-MDS): Initial clinical results
- Chunkang Chang (Shanghai, China)
Abstract
Background
Lemzoparlimab (TJ011133) is a differentiated CD47 antibody targeting a distinct epitope to enable a unique red blood cell sparing property while retaining strong anti-tumor activity. We report initial data in an ongoing phase 2 trial in HR-MDS (NCT04202003).
Methods
Patients with untreated IPSS-R intermediate or high-risk MDS, received lemzoparlimab at 30 mg/kg IV weekly and AZA at 75 mg/m2 SC on Days 1–7 in a 28-day cycle. Efficacy was assessed by IWG 2006 criteria per investigator.
Results
As of March 31, 2022, 53 patients were enrolled and baseline characteristics includes median age of 65 years (range, 40-80), 74% male, 91% ECOG≤1, 87% MDS with excess blasts according to WHO classification, 59%/9%/32% with good, intermediate, and poor/very poor cytogenetic risk. The patients had aberrant baseline hematologic conditions with decreased median levels of hemoglobin (G3) 71 g/L, platelet (G3) 43×109/L and neutrophil (G2) 1.1×109/L, respectively. Common Grade 3/4 treatment-related AEs (TRAEs) occurring in ≥20% pts included decreased platelet count (60%), decreased neutrophil count (53%), decreased WBC count (53%) and anemia (40%). One patient had Grade 5 pneumonia TRAE. These hematologic changes were commonly observed in MDS patients treated with AZA monotherapy in China (Du 2018). Among the 29 efficacy evaluable patients who received initial treatment ≥ 4 mo, overall response rate (ORR) was 86.2%, with 31% complete response (CR) rate, 10% hematologic improvement (HI) alone, 44.8% marrow CR (5/13 also with HI), and a median treatment duration of 4.6 mo (range, 1.8-10.5). Among the 15 efficacy evaluable patients who received initial treatment ≥ 6 mo, CR rate was 40%. Most CR patients showed reduction in VAF of MDS-related gene mutation and MRD negativity (≤10-4) by flow cytometry. Biomarker analyses suggest potential correlation of certain gene mutation or bone marrow immunophenotyping with clinical response.
Conclusions
Without a priming dose of lemzoparlimab, combination treatment with AZA is well tolerated and showed clinically meaningful efficacy results in newly diagnosed HR-MDS. A randomized phase 3 MDS trial is planned.
Legal entity responsible for the study
I-Mab biopharma.
Funding
I-Mab biopharma.
Disclosure
All authors have declared no conflicts of interest.
Invited Discussant 617O
- Thomas Cluzeau (Nice, France)
Q&A
618O - A phase I study of TRS005: An anti-CD20-MMAE antibody-drug conjugate, in relapsed or refractory b cell non-Hodgkin lymphoma
- Yuan-Kai Shi (Beijing, China)
Abstract
Background
TRS005 is a newly developed anti-CD20-MMAE antibody-drug conjugate, targeting CD20+ tumor cells to deliver MMAE, a highly toxic antimitotic agent, into the cells via receptor-mediated endocytosis. Here we report the preliminary results of a phase I dose-escalation and expansion study which aimed to explore the safety, pharmacokinetics, and preliminary efficacy of TRS005 in CD20+ relapsed or refractory B-cell NHL (CTR20182204).
Methods
This was a single arm, multicenter, phase I study conducted at 11 centers in China. Eligible pts had histologically confirmed CD20-positive B-cell NHL and had failed ≥2 prior lines of standard treatment. The dose-escalation phase involved seven dose cohorts (0.1mg/kg, 0.5mg/kg, 1.0mg/kg, 1.5mg/kg, 1.8mg/kg, 2.1mg/kg, 2.3mg/kg) following a 3+3 design. Pts received TRS005 intravenously on day 1 of each 21-day cycle for 6 cycles. The dose cohort in which partial response or complete response was observed entered dose-expansion phase.
Results
From Aug 24, 2020 to Apr 29, 2022, 40 pts received treatment, including 14 pts in dose-escalation phase and 26 in dose expansion phase. The dose limiting toxicity was observed in first patient in the 2.1mg/kg cohort due to grade 3 drug-induced liver injury, and dose maximum tolerated dose was not reached by now. Overall, 78% of pts experienced treatment-related adverse events (TRAEs). TRAEs of ≥3 grade occurred in 34.1% of pts, with the most common being neutropenia (10.1%). At the data cutoff date on Apr 29, 2022, 35 pts were evaluable for efficacy and the confirmed objective response rate (ORR) was 37.1%, with a disease control rate (DCR) of 60%. ORR/DCR in different dose cohorts : 42.9% and 57.1% in 0.5mg/kg (n=7), 16.7% and 16.7% in 1.0mg/kg（n=6）, 43.8% and 68.8% in 1.5mg/kg, 50% and 100% in 1.8mg/kg (4 pts), 1 SD in 0.1mg/kg (1pt). ORR/DCR in different histology subtypes : 46.7% and 66.7% in DLBCL (n=15 ), 21.4% and 42.9% in FL (n=14), 100% and 100% in MCL(n=2), 50% and 100% in MZL (n=2).
Conclusions
TRS005 was well tolerated and showed promising efficacy in pts with relapsed or refractory B-cell NHL who failed standard second-line treatment.
Clinical trial identification
CTR20182204.
Legal entity responsible for the study
Zhejiang Teruisi Pharmaceutical Inc.
Funding
Zhejiang Teruisi Pharmaceutical Inc.
Disclosure
All authors have declared no conflicts of interest.
619O - shRNA-mediated PD1 gene knock-down anti-CD19 CAR-T cell therapy for relapsed/refractory b cell malignancies
- Hong Cen (Nanning, China)
Abstract
Background
PD-1 is expressed on CD4+ and CD8+ T lymphocytes,PD-L1 is mainly expressed on tumor cells. The PD-1/PD-L1 binding can inhibit T cell activation. Many studies have proved that blockade of PD-1/ PD-L1 axis is effective to enhance the function of CAR-T cells. However, this strategy has mainly been studied in vitro and the antitumor properties of CAR-T cells that continuously knock down PD-1 in vivo have not been thoroughly investigated.
Methods
Patients with relapsed or refractory CD19+ B-cell malignancies were included in this trial. Patients underwent leukapheresis , followed by FC conditioning chemotherapy and a single infusion of shRNA-mediated PD1 Gene knock-down anti-CD19 CAR-T Cells at a dose of 1∼2×106/kg. The objective was to assess the safety and efficacy.
Results
16 patients with relapsed or refractory B-cell malignancies were enrolled, including 8 with DLBCL, 4 with B-ALL, 2 with FL, one with CLL and one with HGBL. 6 patients achieved complete response(CR) (3 cases of B-ALL, 2 cases of DLBCL and one case of FL), and 4 patients achieved partial response (PR) (3 cases of DLBCL and one case of FL ). 2 patients with DLBCL and one patient with FL who achieved CR have not relapsed so far, the duration of CR is 36, 34 and 29 months, respectively. Three patients with B-ALL who obtained CR relapsed on day 59，78 and 110 after CAR-T infusion, respectively. CRS occurred in 11 patients (68.8%), 7 were grade 1 and 4 were grade 2. None had neurotoxicity. There was no death from CAR-T treatment-related toxicity. After infusion of CAR-T cells, most patients had an increase in IL6 level, but the degree of increase is significantly individualized, which seems to have no inevitable relationship with the severity of CRS. Two patients without CRS have an IL6 higher than 1000 pg/ml. The change of CRP and Ferritin was not as significant as that of IL6 after CAR-T infusion. It is suggested that cytokines are difficult to predict the occurrence and severity of CRS.
Conclusions
PD1 Gene knock-down anti-CD19 CAR-T therapy showed acceptable safety and anti-tumor activity in patients with relapsed or refractory CD19+ B cell malignancies.
Clinical trial identification
ChiCTR1800020306, first posted: Dec 23, 2018.
Legal entity responsible for the study
Department of Oncology, Guangxi Medical University Affiliated Tumor Hospital.
Funding
natural ScienceFoundation of Guangxi Province, Grant/Award Number: 2018GXNSFBA281026.
Disclosure
All authors have declared no conflicts of interest.
620O - CART-ddBCMA for multiple myeloma: Interim results from phase I study
- Matthew Frigault (Boston, United States of America)
Abstract
Background
Chimeric Antigen Receptor (CAR) T cell therapies targeting B-cell maturation antigen (BCMA) have demonstrated benefit in patients (pts) with relapsed/refractory Multiple Myeloma (RRMM). CART-ddBCMA is an autologous anti-BCMA CAR T cell therapy that utilizes a novel, synthetic binding domain, called a D-Domain, instead of a typical scFv binder. The objective of this first-in-human trial is to assess the safety & efficacy of CART-ddBCMA.
Methods
This is a phase I, multi-center, open label, dose escalation trial for pts with RRMM who have received ≥3 regimens or are triple refractory. Lymphodepletion is given days -5 to -3 followed by CART-ddBCMA infusion on day 0. Dose escalation was performed at 100 (DL1) & 300 (DL2) x 106 (± 20%) CAR+T cells, followed by expansion of DL1. The primary outcome measure is incidence of adverse events (AEs), including dose-limiting toxicities. Additional outcome measures are ORR, CR rate, DoR, MRD (clonoSEQ), PFS & OS.
Results
As of Jan 25, 2022, 25 pts received CART-ddBCMA, with median age 66 (range: 44-76), after a median of 5 prior lines of therapy (3-16), including 10 (40%) with extramedullary disease (EMD). Median follow-up was 296 d (58-716 d). Overall, 25 pts (19 DL1; 6 DL2) were evaluable for safety & 24 (18 DL1; 6 DL2) for efficacy analysis. All pts experienced CRS, but only 1 pt (in DL2) had grade (G) 3 CRS. All other CRS cases were G≤2, with no cases of G≥3 CRS in DL1. Four pts experienced ICANS (2, G≤2; 2, G3), with 1 G3 case in each of DL1 (5%) & DL2 (17%). All cases resolved without sequalae with standard management. The ORR was 100%, sCR/CR rate 67% & ≥VGPR rate 88%. Conversion to CR/sCR was observed with longer follow-up, as late as month 9 in this trial, & 5 pts with PR /VGPR in the DL1 have <9 months follow-up, with 4 (of 4 evaluable) negative at ≥10-5 for MRD. Overall, 17/20 (85%) evaluable pts have achieved best MRD response of ≥10-5. Of the first 6 pts dosed in DL1, 4 (67%) continue in ongoing sCR beyond 18 months, including 3 with EMD. Median duration of response, PFS & OS were not evaluable at the time of data-cut because 19 of 24 evaluable pts (79%) remain in ongoing response.
Conclusions
CART-ddBCMA has demonstrated clinical activity, including 100% ORR & durable responses.
Clinical trial identification
NCT04155749.
Legal entity responsible for the study
Arcellx.
Funding
Arcellx.
Disclosure
M. Frigault: Financial Interests, Personal, Other, Consultant: Celgene, Arcellx; Financial Interests, Personal, Research Grant: Novartis, Kite. J. Rosenblatt: Financial Interests, Personal, Other, Consultant: Attivare, Wolters Kluwer Health; Financial Interests, Personal, Research Grant: BMS. N. Raje: Financial Interests, Personal, Other, Consultant: Celgene. C. Cornwell: Financial Interests, Personal, Full or part-time Employment: Arcellx. K. Banerjee: Financial Interests, Personal, Full or part-time Employment: Arcellx. A. Rotte: Financial Interests, Personal, Full or part-time Employment: Arcellx. C. Heery: Financial Interests, Personal, Full or part-time Employment: Arcellx. D. Avigan: Financial Interests, Personal, Advisory Board: Celgene, Juno, Partner Tx, Karyopharm, BMS, Aviv MedTech, Takeda, Legend, Chugai; Financial Interests, Personal, Research Grant: Pharmacyclics, Kite; Financial Interests, Personal, Other, Consultant: Parexel. A. Jakubowiak: Financial Interests, Personal, Advisory Board: BMS, Celgene, Abbvie, Gracell, GSK, Janssen, Karyopharm, Amgen, Sanofi. M. Bishop: Financial Interests, Personal, Research Grant: Kite; Financial Interests, Personal, Invited Speaker: Incyte, BMS; Financial Interests, Personal, Member of the Board of Directors: Autolus, Novartis, CRISPR. All other authors have declared no conflicts of interest.
Invited Discussant 618O, 619O and 620O
- Catherine Thieblemont (Paris, France)
Q&A
- All Speakers (Lugano, Switzerland)