scholarly journals Very-High Dose Dexamethasone Mobilizes Endogenous Bi-Specific Gamma Delta+ NKT Cells

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4557-4557
Author(s):  
Janet R Rea ◽  
Theresa Deisher ◽  
Peter A. Jarzyna ◽  
Yumna Zahid ◽  
Kathleen Suwito ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Flow Cytometry ◽  
Single Dose ◽  
B Cell ◽  
Dose Escalation ◽  
Drug Product ◽  
Single Patient ◽  
Gamma Delta ◽  
Nkt Cell ◽  
The Past

Abstract Dexamethasone has been widely used since its initial approval by the FDA in 1958, either individually or as part of a therapeutic regimen for a variety of diseases and disorders, including lymphoma and leukemia and most recently, COVID-19 mediated disease. During a preclinical experiment with A20 B-cell lymphoma bearing mice, a suprapharmacologic dose of dexamethasone phosphate, equivalent to a Human (Equivalent) Dose of 17.5 mg/kg, was inadvertently administered. Blood samples were collected and analyzed by flow cytometry, revealing the presence of a new cell 48 hours after dosing. Subsequent experiments confirmed this finding following a single dose of AVM0703. This cell has since been identified as a bi-specific gamma-delta+ NKT cell, or AVM-NKT cell. One of the challenges of being able to deliver suprapharmacologic dexamethasone doses was the drug product itself. These limitations led to the development of a new drug product, AVM0703, which permits the safe administration of the doses necessary to mobilize these cells. AVM0703 is supplied as a sterile, single-use 50 mL, 24 mg/mL solution for infusion, without preservatives. The ability to rapidly mobilize and activate these cells following a single dose of AVM0703 in as little as 6 hours is the subject of an on-going clinical trial, in patients with lymphoid malignancies (NCT04329728), specifically no-option, R/R ALL, MCL, DLBCL, Primary Mediastinal Large B-cell, Burkitt, CLL/SLL and B-or T-ALL. The study consists of 2-parts, dose-escalation to determine the Phase 2 dose, followed by an adaptive-design, expansion cohort study in the same patient population. Concurrently, clinical data has also been obtained from Expanded Access-Single Patient INDs. Based on the murine model, a theoretically effective HED was determined to be at least 18 mg/kg. Because the maximum dose approved for generic injectable dexamethasone is 6 mg/kg, the starting dose for the clinical trial was set at 6 mg/kg. The dose escalation study design is a 3 x 3 design, originally consisting of cohorts escalating by 3 mg/kg to 21 mg/kg (6, 9, 12, 15, 18 and 21 mg/kg). Since that time and based on safety data (see below), the FDA has permitted a revision to the study, in which the 12 and 15 mg/kg cohorts are skipped. Table 1 provides the original and current study design, with the corresponding total dose for a 70 kg patient. For example, 18 mg/kg is 1.26 g for a 70 kg patient. The trial also incorporates a validated Quality of Life questionnaire and a 12-month follow-up period. In Expanded Use, Single-Patient IND setting, 4 patients received at least one AVM0703 dose: glioblastoma: one 6 mg/kg; B-cell ALL: one 18 mg/kg dose; and two prostate cancer patients: one 18 mg/kg dose and patient #2: repeat doses for the past year as depicted in Table 2. Figure 1 depicts the flow cytometry analysis 24 hours following an 18 mg/kg AVM0703 dose. From a safety perspective, there have been no reports of drug-related or treatment emergent SAE's. The murine model safety findings correlate to the human experience. Adverse events reported to date have been self-limiting and mild to moderate. Frequent AEs include slight elevations of blood pressure, glucose and BUN that resolve without treatment in < 1 week post dose. Leukocytosis and lymphocytosis were reported 24 hours post infusion from the B-cell ALL patient but resolved by 7-days without reported intervention. Because a single AVM0703 dose triggers the rapid mobilization and activation of an endogenous bi-specific gamma-delta+ NKT cell with a favorable emerging safety profile, AVM0703 shows promise as a therapeutic agent in treating this serious disease. Figure 1 Figure 1. Disclosures Rea: AVM Biotechnology, LLC: Current Employment. Deisher: AVM Biotechnology, LLC: Current Employment. Jarzyna: AVM Biotechnology, LLC: Current Employment. Zahid: AVM Biotechnology, LLC: Ended employment in the past 24 months. Suwito: AVM Biotechnology, LLC: Current Employment. Poulin: AVM Biotechnology, LLC: Current Employment.

scholarly journals Phase I clinical trial using escalating single-dose infusion of chimeric anti-CD20 monoclonal antibody (IDEC-C2B8) in patients with recurrent B-cell lymphoma

Blood ◽  
1994 ◽  
Vol 84 (8) ◽  
pp. 2457-2466 ◽  
Author(s):  
DG Maloney ◽  
TM Liles ◽  
DK Czerwinski ◽  
C Waldichuk ◽  
J Rosenberg ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Single Dose ◽  
B Cells ◽  
Phase I ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Chimeric Antibody ◽  
Cd20 Antibody ◽  
Anti Cd20

The B-cell antigen CD20 is expressed on normal B cells and by nearly all B-cell lymphomas. This nonmodulating antigen provides an excellent target for antibody-directed therapies. A chimeric anti-CD20 antibody (IDEC-C2B8), consisting of human IgG1-kappa constant regions and variable regions from the murine monoclonal anti-CD20 antibody IDEC- 2B8, has been produced for clinical trials. It lyses CD20+ cells in vitro via complement and antibody-dependent cell-mediated lysis. Preclinical studies have shown that the chimeric antibody selectively depletes B cells in blood and lymph nodes in macaque monkeys. In this phase I clinical trial, 15 patients (3 per dose level) with relapsed low-grade B-cell lymphoma were treated with a single dose (10, 50, 100, 250, or 500 mg/m2) of antibody administered intravenously. Treatment- related symptoms correlated with the number of circulating CD20 cells and grade II events consisted of fever (5 patients); nausea (2), rigor (2), orthostatic hypotension (2), bronchospasm (1), and thrombocytopenia (1). No significant toxicities were observed during the 3 months of follow-up. Serum C3, IgG, and IgM levels, neutrophils, and T cells were largely unchanged. At the three higher dose levels, pharmacokinetics of the free antibody showed a serum half-life of 4.4 days (range, 1.6 to 10.5). Levels greater than 10 micrograms/mL persisted in 6 of 9 patients for more than 14 days. No quantifiable immune responses to the infused antibody have been detected. CD20+ B cells were rapidly and specifically depleted in the peripheral blood at 24 to 72 hours and remained depleted for at least 2 to 3 months in most patients. Two-week postinfusion tumor biopsies showed the chimeric antibody bound to tumor cells and a decrease in the percentage of B cells. Tumor regressions occurred in 6 of 15 patients (2 partial and 4 minor responses). The results of this single-dose trial have been used to design a multiple-dose phase I/II study.

scholarly journals Phase I clinical trial using escalating single-dose infusion of chimeric anti-CD20 monoclonal antibody (IDEC-C2B8) in patients with recurrent B-cell lymphoma

Blood ◽  
1994 ◽  
Vol 84 (8) ◽  
pp. 2457-2466 ◽  
Author(s):  
DG Maloney ◽  
TM Liles ◽  
DK Czerwinski ◽  
C Waldichuk ◽  
J Rosenberg ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Single Dose ◽  
B Cells ◽  
Phase I ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Chimeric Antibody ◽  
Cd20 Antibody ◽  
Anti Cd20

Abstract The B-cell antigen CD20 is expressed on normal B cells and by nearly all B-cell lymphomas. This nonmodulating antigen provides an excellent target for antibody-directed therapies. A chimeric anti-CD20 antibody (IDEC-C2B8), consisting of human IgG1-kappa constant regions and variable regions from the murine monoclonal anti-CD20 antibody IDEC- 2B8, has been produced for clinical trials. It lyses CD20+ cells in vitro via complement and antibody-dependent cell-mediated lysis. Preclinical studies have shown that the chimeric antibody selectively depletes B cells in blood and lymph nodes in macaque monkeys. In this phase I clinical trial, 15 patients (3 per dose level) with relapsed low-grade B-cell lymphoma were treated with a single dose (10, 50, 100, 250, or 500 mg/m2) of antibody administered intravenously. Treatment- related symptoms correlated with the number of circulating CD20 cells and grade II events consisted of fever (5 patients); nausea (2), rigor (2), orthostatic hypotension (2), bronchospasm (1), and thrombocytopenia (1). No significant toxicities were observed during the 3 months of follow-up. Serum C3, IgG, and IgM levels, neutrophils, and T cells were largely unchanged. At the three higher dose levels, pharmacokinetics of the free antibody showed a serum half-life of 4.4 days (range, 1.6 to 10.5). Levels greater than 10 micrograms/mL persisted in 6 of 9 patients for more than 14 days. No quantifiable immune responses to the infused antibody have been detected. CD20+ B cells were rapidly and specifically depleted in the peripheral blood at 24 to 72 hours and remained depleted for at least 2 to 3 months in most patients. Two-week postinfusion tumor biopsies showed the chimeric antibody bound to tumor cells and a decrease in the percentage of B cells. Tumor regressions occurred in 6 of 15 patients (2 partial and 4 minor responses). The results of this single-dose trial have been used to design a multiple-dose phase I/II study.

A Phase I/II Trial of Combination Gemcitabine and Bortezomib (VELCADE®) for Relapsed/Refractory T-Cell Non-Hodgkin Lymphoma (NHL) and Aggressive B-Cell NHL

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1646-1646
Author(s):  
Andrew M. Evens ◽  
Steven T. Rosen ◽  
Leo I. Gordon ◽  
Irene Helenowski ◽  
Justin Kline ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cell ◽  
Phase I ◽  
B Cell ◽  
Dose Escalation ◽  
Research Funding ◽  
Treatment Cycle ◽  
Treatment Schedule ◽  
Dosing Schedule ◽  
Grade 3

Abstract Abstract 1646 Background: NF-κB has been shown to be deregulated in B-NHL and T-NHL subtypes. The proteasome inhibitor, bortezomib, has the capacity to reverse the downstream consequences of NF-κB, while gemcitabine has documented single-agent activity in relapsed/refractory NHL. Further, in vitro and murine xenograft tumor models have demonstrated synergy between these two agents. Based on these data, and the continued unmet clinical need for patients with relapsed/refractory aggressive NHL either ineligible for or relapsed after stem cell transplant (SCT), we conducted a phase I/II trial utilizing this novel combination. Methods: This was a phase I/II investigator-initiated clinical trial conducted through two centers. The phase I design was a classic 3+3 with dose escalation of bortezomib (1.3 mg/m2 to 1.6 mg/m2 given day (D) 1 and D8) with static gemcitabine dosing (800 mg/m2 D1 and D8) given on q 21 day cycles. The definition of dose limiting toxicity (DLT) was: a) grade 3 or 4 non-hematologic toxicity (other than grade 3 nausea or vomiting); b) grade 4 vomiting despite maximal anti-emetic support; c) grade 4 neutropenia on D1 of a treatment cycle (despite growth factor support); and d) grade 4 thrombocytopenia on D1 of a treatment cycle. Following completion of bortezomib escalation, a planned phase II expansion of the study was planned. The null hypothesis was that the true success was less than or equal to 15% and the alternate hypothesis was that the true success was 40% or higher; type I error of 5% and a power of 80% was assumed. Results: From April 2006 to December 2010, we enrolled 32 relapsed/refractory NHL pts onto this phase I/II clinical trial. Sixteen pts had T-NHL (n=12 peripheral T-NHL NOS and n=1 each with angioimmunoblastic T-NHL, NK-/T-NHL, transformed large cell [from pre-existing cutaneous T-cell], and hepatosplenic) and 16 had B-NHL (all relapsed/refractory DLBCL). There were 16 women and 16 men with a median age of 61 years (range, 37–85 years). The median ECOG performance status was 1 (range, 0–2), median prior therapies were 2.5 (range, 1–5), while 35% had failed prior autologous SCT. During the initial phase I dose escalation, 2 DLTs were noted (grade 3 hypertension and grade 3 elevation of liver function tests), while a maximally tolerated dose was not identified. However, among the first 18 pts treated on the D1+D8 (q21 day) dosing schedule, 67% experienced grade 3/4 neutropenia and/or grade 3/4 thrombocytopenia, primarily on D8 of treatment cycles. These recurrent D8 cytopenias resulted in repeated treatment delay(s). The median number of cycles delivered for these 18 pts were 1.0 (due to hematotoxicity), which was associated with a low (59%) median normalized dose-intensity. Thus, in early 2009, the clinical trial was amended instituting a modified treatment schedule of gemcitabine 800 mg/m2 and bortezomib 1.6 mg/m2 to both be administered on D1 and D15 of a 28-day schedule for an additional 22 patients. Treatment-related toxicity was markedly reduced using this modified treatment schedule; only one grade 3 event each of anemia and thrombocytopenia were recorded. However, after 14 pts had accrued to the modified treatment schedule, efficacy data were analyzed by the Northwestern University Data Monitoring Committee (DMC). Among all 32 patients, the ORR was 16% (complete remission (CR) 13%). Further, the ORR for all B-NHL pts was 6% (no CR) and 25% for T-NHL (19% CR). On the modified D1+D15 treatment schedule, the ORR for B-NHL was 0% (0/8); while among T-NHL, the ORR was 50% (3/6) with each of these latter pts remaining in continued remission at 29+, 26+, and 19+ months. Nevertheless, an analysis performed by the DMC for the overall study conduct recommended premature study closure; thus the final planned 8 pts did not enroll. Conclusions: We determined in this phase I/II study for pts with relapsed/refractory, aggressive T-NHL and B-NHL that combined bortezomib/gemcitabine using a dosing schedule of D1+8 q21 days was not tolerated and is not recommended for further study. Modification of bortezomib/gemcitabine dosing to D1+15 q28 days was tolerated markedly better, allowing consistent treatment delivery. Altogether, clinical efficacy of gemcitabine plus bortezomib in aggressive B-NHL was low (with either schedule), while there was a potential signal of activity with durable responses in a small number of pts in the T-NHL population utilizing the modified treatment schedule. Disclosures: Evens: Millennium: Research Funding, advisory board. Off Label Use: Velcade in T-cell and aggressive (non-MCL) B-cell NHL. Winter:Millennium: Research Funding. Smith:Millennium: Research Funding.

scholarly journals A phase 1 clinical trial of the selective BTK inhibitor ONO/GS-4059 in relapsed and refractory mature B-cell malignancies

Blood ◽  
2016 ◽  
Vol 127 (4) ◽  
pp. 411-419 ◽  
Author(s):  
Harriet S. Walter ◽  
Simon A. Rule ◽  
Martin J. S. Dyer ◽  
Lionel Karlin ◽  
Ceri Jones ◽  
...  
Keyword(s):  
Clinical Trial ◽  
B Cell ◽  
Dose Escalation ◽  
Phase 1 ◽  
B Cell Malignancies ◽  
Dose Escalation Study ◽  
Phase 1 Clinical Trial ◽  
Human Dose ◽  
Key Points ◽  
Btk Inhibitor

Key Points We report a first-in-human dose-escalation study in relapsed/refractory B-cell malignancies with the potent BTK inhibitor ONO/GS-4059. ONO/GS-4059 induced clinically durable responses in relapsed/refractory B-cell malignancies without significant toxicities.

Single dose high-dose-rate brachytherapy with focal dose escalation for prostate cancer: Mature results of a phase 2 clinical trial

2021 ◽  
Vol 159 ◽  
pp. 67-74
Author(s):  
Shreya Armstrong ◽  
Stephanie Brown ◽  
May Stancliffe ◽  
Peter Ostler ◽  
Robert Hughes ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Trial ◽  
Single Dose ◽  
Dose Rate ◽  
Dose Escalation ◽  
High Dose Rate ◽  
High Dose ◽  
Phase 2 ◽  
High Dose Rate Brachytherapy ◽  
Phase 2 Clinical Trial

Phase I/II, first in human trial of the Bruton’s tyrosine kinase inhibitor (BTKi) M7583 in patients with B cell malignancies.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e14101-e14101 ◽  
Author(s):  
Simon Rule ◽  
David Tucker ◽  
Anup Kalapur ◽  
Barbara Sarholz ◽  
Jürgen Scheele ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Tyrosine Kinase ◽  
Phase I ◽  
B Cell ◽  
Dose Escalation ◽  
Cell Lymphoma ◽  
Objective Response ◽  
B Cell Lymphoma ◽  
B Cell Malignancies ◽  
Cell Functions

e14101 Background: BTK is a cytoplasmic tyrosine kinase expressed in cells of hematopoietic origin that is involved in innate and adaptive immunity. BTK inhibition blocks B-cell functions including proliferation, antigen presentation, antibody production, and cell migration. The B-cell receptor pathway is implicated in the pathogenesis of B-cell malignancies such as diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), and B-cell chronic lymphocytic leukemia (CLL). Small molecule BTKis are a new class of agent against B-cell malignancies; ibrutinib has recently been approved for the treatment of resistant/refractory CLL, MCL, and Waldenström’s macroglobulinemia (WM). This ongoing phase I/II clinical trial (NCT02825836) is designed to determine the safety, tolerability, PK, BTK occupancy, and preliminary antitumor activity of the highly selective BTKi M7583 in patients (pts) with refractory/resistant B cell malignancies. Methods: The trial is in two parts: a dose-escalation part for which pts with refractory/resistant B cell malignancies are eligible; and a dose-expansion part for which pts with DLBCL (ABC subtype) or MCL who have failed 1-3 prior lines of therapy are eligible. Pts in the dose-escalation part will be enrolled to sequential dose escalation, with ascending once-daily M7583 doses starting at 80 mg (3 initial days)/160 mg (full 28-day cycle) and increasing according to an adaptive Bayesian design. Results: Three pts have been enrolled to treatment with M7583 80/160 mg (Table). All 3 patients have had an objective response or stable disease and relevant clinical benefit.Conclusions: M7583 appears to have a favorable benefit:risk profile, with an efficacy signal at a dose of 80 mg (3 initial days)/160 mg (full cycle) with objective response or clinical benefit. Clinical trial information: NCT02825836. [Table: see text]

Results of a phase I study of bispecific anti-CD19, anti-CD20 chimeric antigen receptor (CAR) modified T cells for relapsed, refractory, non-Hodgkin lymphoma.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 2510-2510 ◽  
Author(s):  
Nirav Niranjan Shah ◽  
Fenlu Zhu ◽  
Dina Schneider ◽  
Carolyn Taylor ◽  
Winfried Krueger ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Hodgkin Lymphoma ◽  
Dose Escalation ◽  
Phase 1 ◽  
Expansion Phase ◽  
Non Hodgkin Lymphoma ◽  
Car T

2510 Background: Anti-CD19 CAR-T cell therapy is a breakthrough treatment (tx) for patients (pts) with relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (NHL). Despite impressive outcomes, non-response and relapse with CD19 negative disease remain challenges. Through dual B-cell antigen targeting of CD20 and CD19, with a first-in-human bispecific lentiviral CAR-T cell (LV20.19CAR), we aim to improve response rates while limiting CD19 negative relapse. Methods: Pts were treated on a Phase 1 dose escalation + expansion trial (NCT03019055) to demonstrate safety of a 41BB/CD3z LV20.19CAR T cell for adults with R/R B-cell NHL. Safety was assessed by incidence of dose limiting toxicities (DLTs) within 28 days post-infusion. Starting dose was 2.5 x 10^5 cells/kg with a target dose of 2.5 x 10^6 cells/kg. All pts received fludarabine+cyclophosphamide for lymphodepletion. Results: 11 pts have completed tx to date. 9 pts in dose escalation and 2 pts in expansion phase. Median age was 54 years (46-67) and histology included DLBCL = 5 pts, MCL = 4 pts, and CLL = 2 pts. In dose escalation, 3 pts were treated at 2.5 x 10^5 cells/kg, 3 pts at 7.5 x 10^5 cells/kg, and 3 pts at 2.5 x 10^6 cells/kg with no DLTs. As a result, 2.5 x 10^6 cells/kg was selected for expansion. In terms of safety, 6 pts developed Grade 1-2 cytokine release syndrome (CRS) and 3 pts had Grade 1-2 neurotoxicity (NTX). No patient had grade 3-4 CRS or NTX and none required ICU level care. 4 pts required 1-2 doses of tocilizumab for CRS. The day 28 overall response rate (ORR) for all pts was 82% (6/11 = complete response (CR) and 3/11 = partial response). All CR pts remain in remission, the longest > 1 year. All progressing pts underwent repeat biopsy, and all retained either CD19 or CD20 positivity. Additional pts are being enrolled in the expansion phase and updated data will be presented. Conclusions: Phase 1 results from the LV20.19 CAR T clinical trial demonstrate that infusion of 2.5 x 10^6 cells/kg is safe for further investigation with no DLTs among treated pts. Down-regulation of target antigens was not identified as a mechanism of resistance in progressing pts. With limited toxicity and encouraging ORR, dual targeted LV20.19CAR T cells merits further investigation. Clinical trial information: NCT03019055.

Veliparib (ABT-888), Bendamustine, and Rituximab (VBR) Is Well Tolerated and Efficacious in Patients with Lymphoma: Final Analysis of a Phase 1b Clinical Trial of VB and a Cohort Expansion of Vbr in Patients with B-Cell Lymphoma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2691-2691
Author(s):  
Jacob D Soumerai ◽  
Andrew D Zelenetz ◽  
Craig H Moskowitz ◽  
Anas Younes ◽  
Maria Lia Palomba ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Multiple Myeloma ◽  
B Cell ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
B Cell Lymphomas ◽  
Phase 1B ◽  
Grade 3

Abstract Background: PARP is overexpressed in many malignancies and protects against chemotherapy-induced genetic damage. The PARP inhibitor veliparib enhances the cytotoxicity of alkylating agents. Bendamustine is an alkylator with activity in several lymphoid malignancies, multiple myeloma, and solid tumors. Bendamustine plus rituximab (BR) is highly active in indolent B-cell lymphomas, with overall (ORR) and complete response rates (CRR) of 90-92% and 41-60%, respectively. We therefore completed a phase 1b trial of veliparib plus bendamustine (VB) in patients with solid tumors, lymphoma and myeloma, as well as a cohort expansion of veliparib, bendamustine and rituximab (VBR) in patients with CD20+ B-cell lymphomas. We report here final response data with 10.5 months (median) of follow up for all patients with lymphoma included in this trial. Methods: Patients with relapsed solid tumors, lymphoma and multiple myeloma with no standard curative options were eligible for the dose escalation portion of this trial. We have previously reported the results of the dose escalation portion, wherein MTD was established at level 6 (veliparib 300mg PO BID plus bendamustine 90 mg/m2). In the cohort expansion, patients with CD20+ B-cell lymphoma (excluding Burkitt and Burkitt-like lymphoma) were treated with bendamustine 90mg/m2 IV days 1 and 2, veliparib 300 mg PO bid on days 1-7 and rituximab 375 mg/m2 on day 1 of each 28-day cycle, for a total 6 cycles. Results: Lymphoma histologies (n=15) were FL (7), DLBCL, transformed FL, or Richter's transformation (4), classical Hodgkin lymphoma (3) and MCL (1). Eight patients received VB in the dose escalation portion and 7 received VBR in the cohort expansion (all CD20+ NHL). Fourteen patients were evaluable for response. One patient with FL in the dose escalation cohort was withdrawn for inability to swallow study drug. Median age was 66 (26-82), median number of prior therapies was 3 (1-10), 7 were refractory to prior therapy, 3 received prior bendamustine, and all patients with CD20+ disease received prior rituximab. Among 7 patients who received VB in the dose escalation cohort, ORR and CRR were 5/7 (71%) and 4/7 (57%). Median PFS is 6.9 months (range 1.6 - 31.3), and 4 of 5 responding patients have progressed. Among 7 patients who received VBR in the cohort expansion, ORR and CRR were 6/7 (86%) and 5/7 (71%). Median PFS is not yet reached at 12.4 months (range 2.0-17.1), and 2 of 6 responding patients have progressed. All patients with FL achieved CR (including 1 VB, 5 VBR). Toxicities in the cohort expansion are similar to those from the dose escalation study. DLTs were grade 4 anemia and grade 3 nausea, hypertension and hyperhidrosis. No DLTs were seen in the cohort expansion. Among all 42 patients treated on study with either VB or VBR, grade ≥3 toxicities were lymphopenia (85.7%), anemia (19%), neutropenia (11.9%), thrombocytopenia (9.5%), leukopenia (7.1%), fatigue (4.8%), nausea (4.8%), sepsis (4.8%), anorexia (2.4%), transaminitis (2.4%), duodenal hemorrhage (2.4%) and hyperhidrosis (2.4%). Conclusions: VBR is tolerated and efficacious in patients with B-cell lymphoma, particularly among patients with follicular lymphoma. These data warrant further investigation of VBR in a phase II clinical trial. Disclosures No relevant conflicts of interest to declare.

scholarly journals AVM0703 Tumor Debulking Enhances Cy/Flu Efficacy

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4498-4498
Author(s):  
Theresa Deisher ◽  
Spencer Sawas ◽  
Kathleen Suwito ◽  
Colleen Rylatt ◽  
Peter A. Jarzyna ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Clinical Trials ◽  
Tumor Growth ◽  
Natural Killer ◽  
Nkt Cells ◽  
Secondary Malignancies ◽  
Gamma Delta ◽  
The Past ◽  
Natural Killer T

Abstract AVM0703 is a high concentration (24 mg/mL) dexamethasone phosphate drug product that permits the safe administration of the doses necessary to mobilize gamma delta+, bi-specific natural killer T (NKT) cells. AVM0703 is in clinical trials as a stand-alone treatment for relapsed/refractory (R/R) Non-Hodgkin's Lymphoma (NHL). Even more exciting is the potential combination of AVM0703 with standard chemotherapy to reduce the number of treatment cycles while maintaining efficacy. A therapeutic solution that reduces the number of chemotherapy cycles could lower the risk of secondary malignancies, decrease long-term toxicities, and limit costs associated with management of chemotherapy toxicities. AVM0703 has been well tolerated to date, with mild to moderate and self-limiting side effects. This indicates the use of AVM0703 in combination therapies may greatly improve quality of life for patients during treatment. AVM0703 has been tested in an aggressive mouse B-cell lymphoma model (A20) alone and in combination with cyclophosphamide/fludarabine (CyFlu). The tumor killing effect of AVM0703 on A20 cells in Matrigel TM embedded tumors is evident as early as 3 hours after dosing, assessed by flow cytometry. Maximum A20 cell death is observed 24 hours after treatment in blood (Figure 1) and between 3- and 24-hours in tumors (Figure 2). Treatment with AVM0703 alone was compared with Cy/Flu alone and with a combination of single dose AVM0703 followed by one Cy/Flu cycle. Tumor growth was monitored by caliper measurements and blood and tumors were analyzed by flow cytometry at the end point, 7-days after Cy/Flu dosing. AVM0703 alone was superior to one cycle of Cy/Flu and the combination of a dose of AVM0703 followed by Cy/Flu was the most effective (Figure 3). Of the mice treated with the combination, 33% had no visible tumor 7-days post-dose. We are currently testing AVM0703 administered between 6- and 24-hours before a single Cy/Flu dose and predict that A20 eradication should be more complete in all compartments. Acute 7 day studies will be followed by long-term studies to evaluate A20 tumor escape or recurrence. In previous studies with long term monitoring of tumor growth, AVM0703 administered 3 days before one cycle of Cy/Flu induced long-term stable disease up to 50 days in tumor bearing mice (Figure 4a) compared to two cycles of Cy/Flu where 33% of the tumors escaped (Figure 4b). Additional studies in combination with R-CHOP are underway. AVM0703 has the ability to debulk the tumor by mobilizing gamma delta+, bi-specific natural killer T (NKT) cells. When added to a chemotherapeutic regimen, the chemotherapy may be more effective due to the lower tumor burden in the body. As cancer survivors live longer, the late term consequences of chemotherapy have become apparent, which include secondary malignancies. The challenge for new treatments is to reduce toxicities without sacrificing efficacy. AVM0703 has the potential to be one solution when used in combination with chemotherapy. Future clinical trials will determine if debulking with AVM0703 results in a reduction of the number of necessary R-CHOP cycles while maintaining or enhancing the efficacy rate. Figure 1 Figure 1. Disclosures Deisher: AVM Biotechnology, LLC: Current Employment. Sawas: AVM Biotechnology, LLC: Current Employment. Suwito: AVM Biotechnology, LLC: Current Employment. Rylatt: AVM Biotechnology, LLC: Current Employment. Jarzyna: AVM Biotechnology, LLC: Current Employment. Zahid: AVM Biotechnology, LLC: Ended employment in the past 24 months. Parthasarathy: AVM Biotechnology, LLC: Consultancy, Ended employment in the past 24 months. Poulin: AVM Biotechnology, LLC: Current Employment. Lee-Diaz: AVM Biotechnology, LLC: Current Employment.

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