A Phase I Trial of CpG-7909, Rituximab Immunotherapy, and Y90 Zevalin Radioimmunotherapy for Patients (Pts) with Previously Treated CD20+ Non-Hodgkin Lymphoma (NHL).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 124-124
Author(s):  
Thomas E. Witzig ◽  
Gregory A. Wiseman ◽  
George Weiner ◽  
Stephen M. Ansell ◽  
Ivana Micallef ◽  
...  
Keyword(s):  
T Cell ◽  
Phase I ◽  
B Cell ◽  
Dose Level ◽  
Nk Cell ◽  
Multiple Time ◽  
Indium 111 ◽  
Dose Levels ◽  
Yttrium 90

Abstract Background: CpG 7909 is a synthetic 24 mer oligodeoxynucleotide designed to provide optimal activation of immune mechanisms through the TLR9 receptors on B-cells and plasmacytoid dendritic cells. In vitro CpG can upregulate CD20 expression as well as stimulate the immune system. Radioimmunotherapy (RIT) with anti-CD20 radioimmunoconjugates such as Zevalin produces responses in approximately 80% of patients with relapsed indolent lymphoma; however, only 30% obtain a complete response and 20% have long-term disease free survival. Objectives: To combine CpG 7909 with rituximab and Zevalin to enhance the response to RIT. Patients and Methods: Patients were eligible if they had biopsy proven relapsed, refractory, or residual CD20+ NHL. Disease types included relapsed indolent and aggressive B-cell NHL. Patients were required to have measurable disease, a platelet count >150,000, and an absolute neutrophil count >1,500. This was a phase I study where all patients received a standard dose of Zevalin (0.4mCi/kg with a maximum of 32mCi for patients over 80kg) along with a phase I dose of CpG 7909. Four dose levels were studied—0.08mg/kg; 0.16mg/kg; 0.32mg/kg; and 0.48mg/kg. CpG was dosed on Day 6, 13, 20, and 27; rituximab was provided Day 1, 8, and 15; indium-111 Zevalin on Day 1 and 8 (followed by indium-111 Zevalin imaging); and yttrium-90 Zevalin on Day 15. Response was assessed at week 4 and week 12. Patients are also being assayed pre- and post-CpG and at multiple time points up to 1 year following treatment for changes in T-cell, NK-cell, and cytokine levels. Results: A total of 30 patients have now been enrolled—6 at each of the first 3 dose levels and 12 at dose level 4. Three pts had relapsed diffuse large cell (DLC) and 27 pts were relapsed indolent. One of the first 6 patients at dose level 4 (0.48mg/kg) had a dose limiting toxicity (DLT - hematologic with full recovery). The other 5 patients at dose level 4 did not have DLT; and thus, 0.48mg/kg was determined to be the dose for further studies. An additional 6 patients at dose level 0.48mg/kg were accrued. Response information is available on the first 26 pts and the median follow-up is 12.4 months (range, 0–30.8). The overall response rate, to date, is 92% (24/26) – 66% (2/3) for the DLC pts and 96% (22/23) for the indolent pts. The complete remission rate is 58% (15/26). After follow-up, 7 of the 26 patients have progressed and one has died of relapsed NHL; therefore, 73% (19/26) remain in response and overall survival is 97% (29/30). As part of the study, we performed indium-111 Zevalin imaging before CpG and after 1 dose of CpG (prior to the yttrium-90 Zevalin) to evaluate the effect of CpG on the biodistribution of the radioimmunoconjugate. In the first 24 patients treated to date, review of the paired gamma camera images does not show any significant effects of CpG on tumor or normal organ biodistribution. To date, there has been no significant differences in T-cell, NK-cell, and cytokine activation by CpG dose level. Summary: CpG 7909 can be safely combined with Zevalin RIT in patients with advanced stage relapsed B-cell NHL.

scholarly journals Efficacy and Safety of JWCAR029 in Adult Patients with Relapsed and Refractory B-Cell Non-Hodgkin Lymphoma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4187-4187 ◽  
Author(s):  
Zixun Yan ◽  
Wen Wang ◽  
Zhong Zheng ◽  
Ming Hao ◽  
Su Yang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Hodgkin Lymphoma ◽  
Dose Level ◽  
Car T Cells ◽  
Car T Cell ◽  
Non Hodgkin Lymphoma ◽  
Car T

Abstract Introduction JWCAR029 is a novel CD19-directed 4-1BB stimulated chimeric antigen receptor T (CAR-T) cell type, which is different from JWCAR017 with independent production of CD4 and CD8 T cells and transfusion in non-fixed ratio. We conducted a single arm, open-label, dose escalation Phase I trial of JWCAR029 in relapsed and refractory B-cell non-Hodgkin lymphoma (NCT03355859). Methods From January to July 2018, 10 patients have been enrolled in this trial, including eight diffused large B cell lymphoma (DLBCL) and two MALT lymphoma, with median age of 47 years (range 32 to 59 years). All the patients received immunochemotherapy as induction and more than two lines of salvage treatment. Two patients received bridging chemotherapy after T-cell collection due to rapid tumor progression, followed by re-evaluation before CAR-T cell infusion. Lymphodepletion preconditioning was accomplished by fludarabine 25mg/m2/d and cyclophosphamide 250mg/m2/d on Day-4 to D-2, followed by CAR-T cell infusion on Day0. JWCAR029 was administrated as a single infusion in escalation dose levels, from 2.5×107 CAR-T cells (dose level 1, DL1) to 5.0×107 CAR-T cells (dose level 2, DL2) and to 1.0×108 CAR-T cells (dose level 3, DL3) according to mTPI-2 algorithm. Circulating blood count, serum biochemistry, and coagulation status were follow-up after infusion. Cytokines were assessed on a Luminex platform. Tumor evaluation was performed on Day 29 by PET-CT. PK data were detected by flow cytometry and real-time quantitative polymerase chain reaction system. All the adverse events were recorded. The study was approved by the Shanghai Rui Jin Hospital Review Board with informed consent obtained in accordance with the Declaration of Helsinki. Results The demographic characteristics of the patients were demonstrated in Table 1. Among six evaluable patients (3 of DL1 and 3 of DL2), the ORR was 100% on Day 29, including four complete remission and 2 partial remission. Cytokine release syndrome (CRS) was 100% in Gr 1, with main symptoms as fever (<39.0 degrees), fatigue, and muscle soreness. No neurotoxicity was observed. Four of the six patients with fever >38.0 degrees used prophylactic IL-6 Inhibitor (8mg/kg, ACTEMRA, two patients administered twice). No patients received steroids. The CRS showed no difference between dose level groups (p>0.99). Adverse effects included leukopenia (Gr 3-4: 83.3%, Gr 1-2: 16.7%), hypofibrinogenemia (Gr 1: 16.7%, Gr 2-4: 0%), liver dysfunction (Gr 1: 33.3%, Gr 2-4: 0%), elevated CRP (Gr 1: 83.3%, Gr 2-4: 0%), ferritin (Gr 1-2: 83.3%, Gr 2-4: 0%), or IL-6 (Gr 1-2:100%, Gr 3-4: 0%, Table 2). Conclusion Although long-term follow-up was needed, the preliminary data of six patients in this trial have demonstrated high response rates and safety of JWCAR029 in treating relapsed and refractory B-cell non-Hodgkin lymphoma. Disclosures Hao: JW Therapeutics: Employment, Equity Ownership.

Final Results of a Phase I Study of the Fc Engineered CD19 Antibody XmAb®5574 (MOR00208) in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL).

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2894-2894 ◽  
Author(s):  
Jennifer A. Woyach ◽  
Farrukh Awan ◽  
Ian W. Flinn ◽  
Rolondo Enoch ◽  
Paul A. Foster ◽  
...  
Keyword(s):  
High Risk ◽  
Febrile Neutropenia ◽  
Adverse Events ◽  
Phase I ◽  
B Cell ◽  
Dose Level ◽  
Phase I Trial ◽  
Hematologic Toxicity ◽  
B Cell Malignancies ◽  
Dose Levels

Abstract Abstract 2894 Antibody (Ab) therapies such as the CD20 monoclonal abs rituximab and ofatumumab are commonly used in CLL alone and in combination with chemotherapy, however, CD20 density is low on CLL cells, suggesting this may not be the ideal target. CD19, which is ubiquitously expressed on CLL cells and those of other B cell malignancies is a reasonable candidate for ab targeting. XmAb5574 is a novel humanized IgG1 CD19 monoclonal ab with an engineered Fc region to enhance Fc gamma receptor binding affinity. In vitro, this ab demonstrates direct cytotoxicity and antibody dependent cellular phagocytosis similar to rituximab, however, shows enhanced natural killer antibody dependent cellular cytotoxicity compared to other therapeutic abs used in CLL (Awan, FT Blood 2009). We have performed a first in human trial of this ab as a single agent in relapsed or refractory (R/R) CLL, and present the results in this report. This study is a multi-institutional phase I trial of XmAb5574 in patients (pts) with R/R CLL. Eligible pts were those with CLL who had at least 1 prior therapy and required treatment by International Working Group on CLL (IWCLL) 2008 Guidelines (Hallek, M Blood 2008), had Eastern Cooperative Oncology Group Performance Status <3, had platelets ≥50,000/mm3, and had adequate organ function. Primary endpoints were to determine maximal tolerated dose (MTD), describe toxicity, and characterize pharmacokinetics (PK). A secondary endpoint was to explore efficacy. An accelerated titration design was used in which 1 pt was accrued to the first two dose levels provided there were no dose limiting toxicities (DLT) or ≥ grade 2 adverse events (AE), and then a standard 3×3 design was employed from dose level 3 forward. Dose levels included 0.3, 1, 3, 6, 9, and 12 mg/kg with an expansion to a total of 16 pts at the MTD. XmAb5574 was administered as an intravenous infusion on days 1, 4, 8, 15, and 22 of cycle (C) 1, and on days 1, 8, 15, and 22 of C2. Toxicity was assessed using the National Cancer Institute's Common Criteria for Adverse Events v4.0 for non-hematologic toxicity, and IWCLL 2008 guidelines for hematologic toxicity. Disease response assessment by physical exam was performed on C1D28, C2D28, and 4, 8, and 12 weeks after the end of C2. Radiographic assessment was performed C2D28. 27 pts were enrolled to this phase I trial. The median age of all pts was 66 years (range 40–84). The pts were generally high risk: 14 (52%) had high-risk disease by Rai stage, 8 (30%) had del(11q22.3) and 10 (37%) had del(17p13.1) by FISH, and 24 (89%) had IgVH unmutated disease. The median number of prior therapies was 4 (range 1–14). Toxicity with this agent was modest. Dose escalation continued without dose limiting toxicity (DLT) until the highest dose level, in which one patient experienced grade 4 neutropenia associated with febrile neutropenia which required dose discontinuation. 100% of patients experienced any AE, with the majority of AE being grade 1–2. The most common AEs were infusion reactions in 18 patients (67%), all of which were grade 1 or 2. Treatment-related Grade 3 or 4 AEs occurred in 5 pts (19%), and included neutropenia (n=3), thrombocytopenia (n=2), increased aspartate aminotransferase (AST) (n=1), febrile neutropenia (n=1), and tumor lysis syndrome (n=1). All were on the 12 mg/kg dose level except one pt receiving 1mg/kg who experienced neutropenia. Overall response rate by IWCLL 2008 criteria is 11%, all of which have been partial responses (PR). Using IWCLL 1996 response criteria which does not include CT scan assessment of disease resulted in a PR in 13 pts (42%). Only 2 pts had PD at the 8 week evaluation point. Responses occurred at the 6, 9, and 12 mg/kg dose levels. All objective responses were in pts categorized as CLL as opposed to SLL, and no patients with lymph nodes >5cm responded. PK was best modeled by a two-compartment model. Half-life was 14 days, with clearance 5mL/day/kg that was not dose-dependent. Across the dose range, area under the curve increased in a dose-proportional manner, while maximum concentration increased in a less than proportional manner. A steady-state was reached at or before infusion 9. XmAb5574 shows acceptable toxicity and signs of preliminary efficacy in patients with high-risk, heavily pretreated CLL. These results justify movement into phase II study in CLL as well as other B cell malignancies. Modest toxicity, in particular infectious toxicity, will potentially allow combinations with other active agents in CLL. Disclosures: Enoch: Xencor, Inc.: Employment. Foster:Xencor, Inc: Consultancy.

Optimized Cyclophosphamide (CY) Dosing in Combination with Fludarabine, TBI and ATG As Conditioning for Unrelated Donor Bone Marrow Transplantation (BMT) in Severe Aplastic Anemia (SAA): A Phase I/II Study from the Blood and Marrow Transplant Clinical Trials Network (BMT CTN)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 541-541
Author(s):  
Paolo Anderlini ◽  
Juan Wu ◽  
H. Joachim Deeg ◽  
Iris Gersten ◽  
Marian Ewell ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Absolute Neutrophil Count ◽  
Neutrophil Count ◽  
Graft Failure ◽  
Early Death ◽  
Marrow Transplant ◽  
Unrelated Donor ◽  
Dose Levels

Abstract Objective : To determine toxicity and efficacy of adding fludarabine (FLU) to a standard preparative regimen of low-dose total body irradiation (TBI), anti-thymocyte globulin (ATG) and CY (Deeg J et al, Blood 108:1485, 2006), with de-escalation of the CY dose. Patients and Methods : Between May 2006 and December 2013, the BMT CTN (sponsored by the NHLBI and NCI) conducted a Phase I/II trial of unrelated donor BMT in SAA (BMT CTN 0301; NCT 00326417). Patients were eligible if they were aged < 65 years, with adequate organ function, and an available unrelated marrow donor matched at 7 or 8 of 8 HLA-A, B, C, and DRB1 loci. The trial accrued 97 patients, although analyses are limited to 96; 1 patient withdrew consent prior to BMT. All patients received TBI 200 cGy (day -1), ATG (either thymoglobulin 3 mg/kg IV or ATGAM 30 mg/kg IV daily x 3, days –4 to –2), FLU (30 mg/m2 IV daily x 4, days –5 to –2). The Phase I portion of the trial tested four CY dose levels: 150 mg/kg (days –4 to –2); 100 mg/kg (days –3 to –2); 50 mg/kg (day –2); and 0 mg/kg. The Phase I design allowed enrollment of up to six patients at each CY dose level unless toxicity or graft failure boundaries were crossed. In the Phase II portion, patients were enrolled onto the optimal CY dose level, using adaptive Bayesian criteria to rank desirability of CY doses based on Day 100 outcomes of engraftment and early death. The primary endpoint of the study was determination of the optimal CY dose based on Day 100 assessments of graft failure (primary: absolute neutrophil count <0.5 x 109/L and secondary: sustained decline in absolute neutrophil count to <0.5 x 109/L), major (grade 3 or higher) regimen-related toxicity (RRT) and early death. Early stopping guidelines were based on a composite endpoint of graft failure and treatment-related mortality through day 100. Results : Twenty-one patients accrued to the Phase I portion of the trial and all CY dose levels were tested. CY dose level 0 mg/kg was closed after 3 of the first 3 patients developed secondary graft failure. The Phase II portion of the trial opened with CY dose level 150 mg/kg. However, this dose level was closed for excess toxicity (7 of 14 patients died; organ failure n=4, ARDS n=2 and infection n=1; Tolar et al, Biol Blood Marrow Transplant, 2012). Patients were subsequently assigned to CY dose level 100 mg/kg (CY DL 100; n=41) or CY dose level 50 mg/kg (CY DL 50; n=38), depending on Bayesian assessment of criteria noted above except that the last 20 patients were preferentially assigned to CY DL 50 to balance accrual to the two dose levels. Approximately half of patients were male and 79% Caucasian. The median age was 20.6 years. The median age for CY DL 50 and DL 100 was 24.5 (0.5-65) and 17.6 (1.9-63) years, respectively. The number of transplants with a mismatched (i.e.7/8) donor was 7 (18%) in the CY DL 50 group and 14 (34%) in the CY DL 100 group. All patients reached their Day 100 endpoint. The cumulative incidence of grade 2-4 acute GVHD was comparable between the two CY dose levels: 24% (DL 50) vs 27% (DL 100). All deaths before Day 100 were due to primary or secondary graft failure (CY DL 50; n=1 and CY DL 100; n=2),. Table 1 shows individual Day 100 outcomes for CY DL 50 and CY DL 100. Median follow up is 15 (3-27) and 24 (12-50) months for CY DL 50 and 100, respectively. All surviving patients on CY dose level 100 mg/kg have achieved a minimum follow up of 12 months, as opposed to only 75% of surviving patients on CY dose level 50 mg/kg. Conclusion : Results of the adaptive Bayesian dose selection suggest that the most desirable CY dose is 50 mg/kg followed by CY dose, 100 mg/kg. However, interpretation of data needs to take into account the potential imbalance of donor-recipient HLA disparity in the CY 50 mg/kg dose level. CY dose 150 mg/kg and 0 mg/kg should be avoided. Table 1 Day 100 Outcome CY DL 50 (n=38) CY DL 100 (n=41) Graft Failure, primary and secondary 3 (8%) 6 (15%) Survival 37 (97%) 39 (95%) Major RRT (Grade III or higher) 4 (11%) 9 (22%) Disclosures No relevant conflicts of interest to declare.

Bendamustine and Rituximab for the Treatment of Multiply Relapsed Hairy Cell Leukemia,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3909-3909
Author(s):  
Robert J. Kreitman ◽  
Maryalice Stetler-Stevenson ◽  
Wyndham H. Wilson ◽  
Sapolsky Jeffrey ◽  
Laura Roth ◽  
...  
Keyword(s):  
B Cell ◽  
Dose Level ◽  
Hairy Cell Leukemia ◽  
Research Funding ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
Purine Analog ◽  
Prospective Phase ◽  
Dose Levels

Abstract Abstract 3909 Background: Hairy cell leukemia (HCL) is highly sensitive to purine analogs cladribine (CdA) and pentostatin (DCF), but patients who relapse have decreasing remission rates with each course and can eventually become purine analog-refractory. Bendamustine and rituximab (BR) have been reported as effective with acceptable toxicity in several B-cell malignancies, particularly B-cell lymphomas and chronic lymphocytic leukemia. The structure of bendamustine contains an alkylating group and also part of cladribine, suggesting it might be useful in HCL. In one case report, bendamustine achieved a transient partial response in a patient with relapsed/refractory HCL, but its activity in other patients with this disease is not reported. The combination of DCF and rituximab (DCFR) is reported to achieve high complete remission (CR) rates in HCL in retrospective series, but prospective phase II trials of this combination have not been reported. Methods: To determine the activity of BR relative to DCFR in HCL, a randomized trial was undertaken in multiply relapsed HCL comparing the 2 regimens in which each arm could constitute a prospective phase II trial, with 2-way crossover for lack of response to or relapse from the originally assigned regimen. The primary endpoint is an overall response rate of 65% for each arm and the 2 arms will be compared with respect to response and other secondary endpoints including toxicity, response duration, and eradication of minimal residual disease (MRD). Patients received 6 cycles at 4-week intervals of rituximab 375 mg/m2 days 1 and 15 with either pentostatin at 4 mg/m2 days 1 and 15, or bendamustine days 1 and 2. To test the tolerability of bendamustine prior to randomizing 56 patients between the 2 arms, 12 non-randomized patients received BR using 70 (n=6) or 90 (n=6) mg/m2/dose of bendamustine. Doses of all agents could be delayed but not reduced. Results: A total of 20 patients are so far enrolled and the 12 patients receiving the 2 dose levels of BR are evaluable for response and toxicity. Patients had 1–6 (median 3) prior courses of purine analog and 8 (67%) had prior rituximab. All toxicity was reversible and only 1 patient at 90 mg/m2 required >2-week delay due to prolonged neutropenia and thrombocytopenia. However, this delay was only between cycles 1 and 2 and not between subsequent cycles after responding to BR. Of the 36 cycles of BR administered to each group of 6 patients on the 2 dose levels of bendamustine, 90 vs 70 mg/m2/dose, common grade 3–4 toxicities included lymphopenia (28 vs 22%), leukopenia (19 vs 17%), and thrombocytopenia (14 vs 17%). Febrile neutropenia requiring hospitalization occurred just once in 3 patients at 90 vs 0 patients at 70 mg/m2/dose. Major response was achieved in 10 (83%) of 12 patients. CR was achieved in 3 (50%) of 6 patients at each dose level, while 2 (33%) at 70 and 3 (50%) at 90 mg/m2 achieved clearance of MRD at all sites including bone marrow aspirate by flow cytometry. No patient in CR has relapsed after 8–14 (median 11) months of follow-up. Of 4 patients evaluable by clone-specific real-time PCR, previously reported sensitive to 1 HCL cell in 106 normal, 3 patients at 90 mg/m2/dose were negative. Conclusions: BR can achieve responses including CRs in multiply relapsed HCL, and its safety profile permits comparison of BR with DCFR using the more common dose level of bendamustine, 90 mg/m2 days 1 and 2. Additional patients and follow-up will be required to access durability of response and long-term eradication of MRD, and to compare BR with DCFR (Supported in part by NCI, intramural research program, NIH, Genentech, Inc, and Cephalon, Inc). Disclosures: Kreitman: Cephalon: Research Funding; Genentech: Research Funding. Off Label Use: Use of bendamustine and rituximab for HCL. Arons:Genentech: Research Funding.

Final Results and Follow-up of a Phase I Study of the Fc Engineered CD19 Antibody XmAb®5574 (aka MOR00208) in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1993-1993
Author(s):  
Jennifer A. Woyach ◽  
Farrukh Awan ◽  
Ian Flinn ◽  
Jesus G. Berdeja ◽  
Elizabeth A Wiley ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Trial ◽  
Nk Cell ◽  
Physical Exam ◽  
Hematologic Toxicity ◽  
Efficacy Data ◽  
Cell Counts ◽  
Infusion Reactions ◽  
Dose Levels

Abstract CD19 is an attractive target in lymphoid malignancies as it is highly expressed in nearly all CLL and non-Hodgkin’s lymphomas. While development of CD19 directed antibodies (abs) had previously been limited by antigen internalization, improved ab modification technology has restored this potential target. XmAb5574 (MOR00208) is a novel humanized IgG1 CD19 monoclonal ab with an engineered Fc region to enhance Fc gamma receptor binding affinity. We have previously presented safety and efficacy data from a first in human trial of this ab in relapsed or refractory (R/R) CLL, and now update these results along with results of a maintenance therapy cohort, follow-up efficacy data on all patients (pts), and correlative studies. This study was a multi-institutional phase I trial of XmAb5574 in pts with R/R CLL. An accelerated titration design was used, with dose levels of 0.3, 1, 3, 6, 9, and 12 mg/kg with an expansion to a total of 16 pts at the maximal tolerated dose (MTD). Patients received 9 intravenous infusions of XmAb5574: days 1, 4, 8, 15, and 22 of cycle 1, and days 1, 8, 15, and 22 of cycle 2. Once 5 patients were treated in the maximal dose cohort, additional patients who had at least stable disease after 2 cycles had the option to receive Xmab5574 every 28 days for an additional 4 infusions. Toxicity was assessed using the National Cancer Institute’s Common Criteria for Adverse Events v4.0 for non-hematologic toxicity, and IWCLL 2008 guidelines for hematologic toxicity. Disease response assessment by physical exam was performed on C1D28, C2D28, and 4, 8, and 12 weeks after the end of Cycle 2. CT assessment was performed C2D28. 27 pts were enrolled, with a median age of 66 years (range 40-84). The pts were generally high risk: 14 had high-risk disease by Rai stage, 8 had del(11q22.3) and 10 had del(17p13.1) by FISH, and 24 had IgVH unmutated disease. The median number of prior therapies was 4 (range 1-13). Toxicity with this agent was modest with no MTD identified. 5 pts experienced grade 3 or 4 treatment-related toxicity, which included neutropenia (3 pts), thrombocytopenia (2 pts), increased aspartate aminotransferase (AST; 1 pt), febrile neutropenia (1 pt), and tumor lysis syndrome (1 pt). Grade 1 and 2 toxicities assessed as possibly related to XmAb5574 that occurred in more than 10% of pts included infusion reactions, increased AST, increased alanine aminotransferase, neutropenia, thrombocytopenia, fever, chills, and peripheral neuropathy. Infusion reactions occurred in 67% of patients, however, all were grade 1 or 2, and no reactions were seen following the first infusion. On the basis of physical exam and laboratory studies, 18 patients (66.7%) achieved a partial response (PR), and the remaining 9 patients (33.3%) achieved stable disease (SD). Adding CT criteria, 8 patients (29.6%) achieved a PR with an additional 16 patients (59.3%) achieving SD. Two patients had progressive disease by CT criteria. No patient dosed below 3 mg/kg had an objective response. Of the 16 pts treated at the maximum dose, 12 patients (75%) had a PR by physical exam criteria and 6 patients (37.5%) had a PR by CT criteria, with 2 of these pts achieving a PR during the maintenance phase. Median progression free survival (PFS) for all patients was 199 days (95% CI: 168-299 days). For patients on all dose levels who received 9 doses or less, PFS was 189 days, and for the 8 patients on the extended treatment cohort, PFS was 420 days (95% CI: 168 days-not reached). Flow cytometry was performed for absolute T and NK cell counts as well as activation. During the first 12 weeks, there was no significant change in T or NK cell counts; however, from cycle 1 day 1 pre to end of infusion there was a significant decrease in both T and NK cell number. There was no significant change in T or NK cell activation at any point. PK was best modeled by a two-compartment model. Half-life was 14 days, with clearance 5mL/day/kg that was not dose-dependent. A steady-state was reached at or before infusion 9. In conclusion, this Phase I trial demonstrates safety and preliminary efficacy of a novel Fc engineered CD19 monoclonal antibody XmAb5574 (MOR00208) and justifies movement into the Phase II setting. The modest toxicity combined with preliminary efficacy as a single agent will likely allow for successful combination therapies, and current studies in CLL are investigating XmAb5574 in combination with other active agents. Disclosures Foster: Xencor, Inc: Employment.

scholarly journals The Safety and Efficacy of a CRISPR/Cas9-Engineered Universal CAR-T Cell Product (CTA101) in Patients with Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 52-52 ◽  
Author(s):  
Yongxian Hu ◽  
Yali Zhou ◽  
Mingming Zhang ◽  
Wengang Ge ◽  
Yi Li ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Dose Level ◽  
Gene Editing ◽  
Private Company ◽  
Safety And Efficacy ◽  
Car T Cells ◽  
Car T

Introduction Although autologous CAR-T therapy targeting CD19+ B-cell has proven efficacy in hematological malignancies. The challenges such as undesirable waiting time, possible manufacturing failures and high cost, remain to be solved. In addition, antigen-loss/downregulation leads to treatment failure after single-target CAR-T therapy. To tackle these issues, we developed a universal CD19/CD22-targeting CAR-T cell with the TRAC region and CD52 gene disrupted using CRISPR/Cas9 technology. Pre-clinical data demonstrated the safety of CRISPR gene editing and the anti-leukemia ability of CTA101. Method Pts with CD19+ or CD22+ r/r B-ALL received a single dose of CTA101 with traditional 3+3 dose escalation (dose level: 1, 3 and 6×106 CAR+ T cells/kg). Prior to CTA101 infusion, pts received pre-conditioning chemotherapy regimen consisting of cyclophosphamide, fludarabine and alemtuzumab. The primary endpoint is the frequency of DLTs and AEs and secondary endpoints including ORR, OS, cellular PK, etc. (NCT04227015) Results Characteristics of CTA101 CTA101 was manufactured by electroporation of ribonucleoprotein complexes (RNP) comprising Cas9 loaded with sgRNA targeting TRAC and CD52 followed by lentiviral transduction of the CAR transgene. All products were expanded above 100-folds after 10-12 days manufacturing (Fig.1a). CAR expression was detected by FCM staining, ranging from 40~80% (Fig.1b). The frequency of editing as determined by flow cytometry was consistently above 85% (88%-97%) for TRAC and above 65% (68%-83%) for CD52 (Fig.1c, 1d). The CD19/CD22 dual targeting universal CAR-T cells showed potent antigen specific cytotoxicity, and mitigated tumor antigen escape (Fig.1e). Whole genome sequencing was carried out to assess the on-target and off-target editing events. While most mutations were on target, a few off-target mutations were identified, which needed further investigation (Fig.2). QPCR assays identified no detectable rearrangements occurred with the simultaneous editing of four loci: TRAC and CD52 (TRAC-CD52) during the manufacture process. Residual Cas9 protein was quantified during the manufacturing process, showing declining levels that were 0.195 fg/cell (detection limit of sensitive ELISA) in the final product. Clinical result As of August 5th 2020, 8 adult pts were screened, and 6 adult pts were enrolled. All of 6 patients received one infusion of CTA101 (DL1: 3 pts; DL2: 3 pts), with no more than 8 days between enrollment and infusion. The median age of 6 pts was 49 years (range, 26 to 56), the median prior lines of therapies were 5 (range, 2 to 8), and the median marrow blast percentage was 52% (range, 1 to 82). 3 pts had hyperleukocytosis prior to enrollment with difficulties in apheresis for autologous CAR-T, 1 relapsed after autologous CD22 CAR-T, and 3 had high-risk genomic lesions (Table 1). All 6 pts were available for evaluation of safety and efficacy. No DLTs, GvHD, ICANS and death occurred to date. All pts experienced CRS (3 G1, 2 G2, 1 G3), and the G3 CRS recovered within 7 days with one dose of tocilizumab and glucocorticoids. Other common AEs were prolonged cytopenia (3 G3), virus reactivation/infections (CMV 1 G2, 2 G3; ADV 1 G1), bacterial pneumonia (1 G3), and fungal sepsis (1 G3). The majority of events recovered to date. No replication competent lentivirus (RCL) has been detected. On D28 after CTA101 infusion, 5/6 (83.3%) pts achieved CR/CRi, and 5/5 (100%) pts achieved MRD-. With a median follow-up of 85 days (range, 53 to 202), 4/5 pts remained MRD-, 1/5 had MRD+ CR (Fig. 3). Only 1 pt received HSCT in remission on D60. Expansion had been observed in all pts and peaked from D10 to D14 (Fig.4). The correlation among dose level, donor difference, tumor burden and degree of expansion could not be identified. The median duration of persistence was 42 days. The lowest peak expansion was detected by qPCR in the pt without response and whose T lymphocyte recovered within D7, while FCM did not detect CTA101 expansion in the pt. Conclusions CTA101 demonstrates manageable safety profile and deep response of high MRD- CR/CRi rate. No GvHD and CRISPR/Cas9 genome editing associated AEs occurred. Early data of cellular PK and efficacy illustrate that CRISPR gene editing does not curtail the expansion and anti-leukemia capacity of CAR-T. Updated data, including long term gene editing-related AEs, will be presented after further follow-up. Disclosures Zhou: Nanjing Bioheng Biotech Co., Ltd: Current Employment. Ge:Nanjing Bioheng Biotech Co., Ltd: Current Employment. Han:Nanjing Bioheng Biotech Co., Ltd: Current equity holder in private company. Wang:Nanjing Bioheng Biotech Co., Ltd: Current Employment. Zhang:Nanjing Bioheng Biotech Co., Ltd: Current Employment. Ren:Nanjing Bioheng Biotech Co., Ltd: Current equity holder in private company.

scholarly journals Preliminary Results from a Phase I Study of HMPL-523, a Selective Oral Syk Inhibitor, in Patients with Relapsed or Refractory Lymphoma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2432-2432
Author(s):  
Paolo Strati ◽  
Dominik Chraniuk ◽  
Eva González-Barca ◽  
Michal Taszner ◽  
Rathi Pillai ◽  
...  
Keyword(s):  
T Cell ◽  
Phase I ◽  
B Cell ◽  
Phase I Study ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Publicly Traded ◽  
Grade 3 ◽  
Dose Levels ◽  
Anti Tumor Activity

Abstract Background: Spleen tyrosine kinase (Syk) plays an integral role in B-cell receptor signaling critical in the development and survival of several subtypes of lymphoma. HMPL-523 is a selective, oral Syk inhibitor that has shown strong anti-tumor efficacy in xenograft models of B-cell and T-cell lymphoma. HMPL-523 had a manageable safety profile and demonstrated anti-tumor activity in a phase I study of lymphoma patients in China (NCT02857998). Here, we report the safety and preliminary anti-tumor activity of HMPL-523 in the dose escalation phase of a phase 1 study of relapsed/refractory lymphoma patients in the United States and Europe (NCT03779113). Methods: The primary objectives of the phase I study were to evaluate the safety and tolerability of HMPL-523 and to determine the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D). Secondary objectives were to assess the pharmacokinetics (PK) and evaluate the preliminary efficacy of HMPL-523. Eligible patients had histologically confirmed lymphoma, exhausted all approved therapy options, and had good organ function, including creatinine clearance ≥ 40 ml/min by Cockcroft-Gault, absolute neutrophil count ≥ 1000/µL, platelet count ≥ 50,000/µL, and hemoglobin ≥ 8.0 g/dL. Dose escalation was performed according to a 3+3 study design. Treatment emergent adverse events (AEs) were assessed per NCI CTCAE v5.0. Treatment responses were assessed by Lugano criteria at weeks 8, 16, and 24, and then every 12 weeks. Patients received HMPL-523 treatment daily in 28-day cycles until disease progression or unacceptable toxicity. Results: As of July 15, 2021, 21 patients had been enrolled and dosed with HMPL-523 at one of six dose levels (100 to 800 mg once daily). Baseline tumor subtypes included Hodgkin lymphoma (HL; n=5); diffuse large B-cell lymphoma (DLBCL; n=4); follicular lymphoma (FL; n=4); marginal zone lymphoma (MZL; n=2); and 1 patient each with mantle cell lymphoma (MCL), small lymphocytic lymphoma (SLL), peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma (CTCL), mixed HL/DLBCL, and Richter's transformation. Patients were predominantly Caucasian (90.5%) and male (71.4%). The median age was 61 years (range 27 to 89 years) and 71.4% had an ECOG performance status of 1. The median lines of prior therapy was 4 (range 2 to 17). The majority of patients had prior anti-CD20 antibody exposure (71.4%), and four patients (19%) received prior Bruton tyrosine kinase inhibitors. Five patients continue to receive study treatment. The most frequently reported treatment emergent AEs were aspartate aminotransferase increase (23.8%), anemia (23.8%), neutropenia (19%), hyponatremia (19%), creatinine increase (19%), and nausea (19%). The most common grade ≥ 3 AEs were neutropenia (14.3%), hyponatremia (14.3%), and anemia (9.5%). Three dose limiting toxicities were observed: 1 in the 100 mg cohort (grade 3 confusion) and 2 in the 800 mg cohort (grade 3 fever and grade 3 alanine aminotransferase increase). The dose was deescalated to 700 mg, which was determined to be the MTD and RP2D. Among 17 efficacy evaluable patients, 2 patients (1 HL, 1 FL) dosed at 600 mg and 800 mg (reduced to 600 mg due to toxicity) achieved complete response, and 1 patient (dose increased from 400 to 600 mg) achieved partial response (FL). Stable disease was observed in 5 (29.4%) patients (2 DLBCL, 1 MCL, 1 SLL, 1 PTCL). At steady state, HMPL-523 showed approximately dose proportional PK over the daily dose range of 100 to 700 mg. Conclusions: HMPL-523 was well tolerated at all dose levels within the range of 100 mg to 700 mg and demonstrated proof of activity at dose levels of 400 mg or higher in heavily pre-treated patients. The dose expansion phase of the study will evaluate safety and efficacy in patients with multiple subtypes of B-cell and T-cell lymphoma at the RP2D of 700 mg. Updated safety, PK, and anti-tumor activity will be presented. Disclosures Strati: Astrazeneca-Acerta: Research Funding; Roche-Genentech: Consultancy. González-Barca: Roche: Honoraria, Other: Travel; Kyowa Kirin: Consultancy; EUSA Pharma: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Travel; Takeda. Abbvie: Honoraria. Taszner: Roche, Takeda: Consultancy, Other: Travel. Pillai: HUTCHMED: Current Employment. Chien: HUTCHMED: Current Employment, Current equity holder in publicly-traded company. Nanda: HUTCHMED: Current Employment, Current equity holder in publicly-traded company, Other: Travel. Rudinski: HUTCHMED: Current Employment. Jayaprakash: HUTCHMED, Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Ended employment in the past 24 months; Astrazeneca: Current equity holder in publicly-traded company. Hahka-Kemppinen: HUTCHMED: Current Employment, Current holder of individual stocks in a privately-held company; Eli Lilly: Current holder of individual stocks in a privately-held company. Kania: HUTCHMED: Current Employment, Current equity holder in publicly-traded company.

Reduced-Intensity Stem Cell Transplantation (RIST) for Non-Hodgkin Lymphoma (NHL): A Single-Institute Experience of 52 Patients.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 5145-5145
Author(s):  
Kyoko Sugimoto ◽  
Yasushi Onishi ◽  
Shigeru Kusumoto ◽  
Sung-Won Kim ◽  
Masahiro Kami ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
B Cell ◽  
Cell Transplantation ◽  
Nk Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Large B Cell

Abstract Since allogeneic hematopoietic stem cell transplantation (HSCT) is reported to have a high mortality rate for advanced lymphoma patients, less toxic technique has been expected. We evaluated the safety and preliminary efficacy of RIST in patients with advanced NHL on the basis of the WHO classification. We retrospectively reviewed the medical records of 52 patients with NHL who underwent RIST from February 2000 to April 2004 at National Cancer Center Hospital. The median age of the patients at the time of RIST was 50 years (range, 26 to 67 years). Eighteen patients had indolent B-cell lymphoma (follicular 16, lymphoplasmacytic 1, chronic lymphocytic leukemia 1), 11 had aggressive B-cell lymphoma (diffuse large B cell 8, mediastinal large B cell 2, mantle cell 1), and 23 had T-cell and NK-cell lymphoma (adult T-cell leukemia/lymphoma 12, peripheral T-cell, unspecified 8, extranodal NK/T-cell 1, enteropathy-type T-cell 1, anaplastic large cell 1). The median number of prior chemotherapy regimens was 3 (range, 1–8), and 17 (33%) patients had experienced autologous HSCT before RIST. Thirty (58%) patients had progressive/refractory disease at the time of transplantation. The RIST regimens were fludarabine- (n=47) and cladribine-based (n=5), of whom 9 patients received additional anti-thymocyte globulin. Stem cell sources were related peripheral blood (n=36), unrelated bone marrow (n=8), and unrelated cord blood (n=8). GVHD prophylaxis was cyclosporin alone (n=36) or cyclosporin and short-term methotrexate (n=16). The median duration of follow-up after transplantation was 309 days (range, 2 to 1492 days). Except for one patient who died early on day 2, all patients showed sustained engraftment. Acute GVHD gradeII–IV developed in 32 patients (62%), gradeIII–IV developed in 12 (23%) and chronic GVHD developed in 29 (56%). The day-100 TRM rate was 6%, including sepsis (n=2) and liver failure (n=1). The estimated one-year overall-survival and estimated progression-free survival rates were 75% and 63%, respectively, for all patients; 94% and 94% for indolent B cell, 76% and 58% for T or NK cell and 42% and 21% for aggressive B cell, as shown in Figures 1 and 2. (P = 0.0037 and, 0.0004 by log-rank test). In our analysis, GVHD did not clearly affect the clinical response or survival. Sustained engraftment and the low TRM rate indicate that RIST is feasible in patients with relapsed or refractory NHL. Although this is a preliminary study with a heterogeneous population and a short follow-up, the results suggest that RIST might be a promising procedure in relapsed or refractory NHL, especially in indolent B-, T- and NK-NHL. Further large-scale prospective studies are warranted.

Sign in / Sign up

Export Citation Format

Share Document