Srikanth Ambati - Academia.edu (original) (raw)

Papers by Srikanth Ambati

Clinical and Translational Science

Odronextamab is a fully-human IgG4-based CD20xCD3 bispecific antibody that binds to CD3 on T cell... more Odronextamab is a fully-human IgG4-based CD20xCD3 bispecific antibody that binds to CD3 on T cells and CD20 on B cells, triggering T-cell-mediated cytotoxicity independent of T-cell-receptor recognition. Adequate safety, tolerability, and encouraging durable complete responses have been observed in an ongoing first-in-human (FIH) study of odronextamab in patients with relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL; NCT02290951). We retrospectively evaluated the pharmacokinetic, pharmacodynamic, and antitumor characteristics of odronextamab in a series of in vitro/in vivo preclinical experiments, to assess their translational value to inform dose escalation for the FIH study. Half-maximal effective concentration values from in vitro cytokine release assays (range: 0.05-0.08 mg/L) provided a reasonable estimate of odronextamab concentrations in patients associated with cytokine release at a 0.5 mg dose (maximum serum concentration: 0.081 mg/L) on week 1/day 1, which could therefore be used to determine the week 1 clinical dose. Odronextamab concentrations resulting in 100% inhibition of tumor growth in a Raji xenograft tumor mouse model (1-10 mg/L) were useful to predict efficacious concentrations in patients and inform dose-escalation strategy. Although predicted human pharmacokinetic parameters derived from monkey data overestimated projected odronextamab exposure, they provided a conservative estimate for FIH starting doses. With step-up dosing, the highest-tested weekly odronextamab dose in patients (320 mg) exceeded the 1 mg/kg single dose in monkeys without step-up dosing. In conclusion, combination of odronextamab in vitro cytokine data, efficacious concentration data from mouse tumor models, and pharmacokinetic evaluations in monkeys has translational value to inform odronextamab FIH study design in patients with R/R B-NHL.

Blood, 2020

BACKGROUND: Odronextamab (REGN1979) is a first-in-class, hinge-stabilized, fully human CD20 x CD3... more BACKGROUND: Odronextamab (REGN1979) is a first-in-class, hinge-stabilized, fully human CD20 x CD3 IgG4-based bispecific antibody that binds to CD20-expressing cells and CD3 on T cells, targeting CD20+ cells via T-cell-mediated cytotoxicity independent of T-cell receptor recognition. Patients with relapsed/refractory B-cell non-Hodgkin lymphoma were treated with odronextamab in a first-in-human, Phase 1 study (NCT02290951). Patient biopsies were analyzed to investigate the association of clinical response and relapse with B- and T-cell markers. METHODS: Tumor biopsies collected at baseline and at disease progression were analyzed by semi-quantitative CD20 chromogenic immunohistochemistry (IHC). B-cell antigen and immune cell multiplex immunofluorescence was also performed. Bulk tumor tissue nucleic acid isolates were analyzed by whole exome DNA sequencing. Peripheral blood mononuclear cells isolated from baseline samples were analyzed by highly multiplexed flow cytometry T-cell immun...

Clinical Lymphoma, Myeloma & Leukemia, 2021

Context Limited published SLRs exist on third-line and greater (3L+) treatment of R/R DLBCL, desp... more Context Limited published SLRs exist on third-line and greater (3L+) treatment of R/R DLBCL, despite recent approvals of newer therapies. Objective To conduct an SLR evaluating the efficacy, safety, and PROs of therapies for 3L+ R/R DLBCL. Design SLR in accordance with the Cochrane Handbook for Systematic Reviews of Interventions and European Union Health Technology Assessment requirements; publications prior to November 2020 in MEDLINE, MEDLINE In-Process, Embase, and Cochrane Library databases; supplemented by a gray literature search. Main Outcome Measures Efficacy, safety, and PROs. Results Post-screening of 9,901 records, 143 publications covering 40 studies were identified. Seven studies were reported as interventions of interest: chimeric antigen receptor T-cell therapy (CAR-T: 3), antibody–drug conjugates (ADC: 2), nuclear export inhibitor (S: 1), aza-anthracenedione analogue (P: 1), and chemo/chemoimmunotherapy (Ch: 2). Wide ranges of efficacy outcomes were reported. CAR-T ...

Clinical Lymphoma, Myeloma & Leukemia, 2021

Context There is no well-defined standard of care in 3L+ R/R FL. Recently, novel treatments were ... more Context There is no well-defined standard of care in 3L+ R/R FL. Recently, novel treatments were evaluated in trials or approved by regulators. Objective To conduct an SLR evaluating efficacy, safety, and PROs of treatments for 3L+ R/R FL. Design The SLR included publications prior to November 2020 in MEDLINE, MEDLINE In-Process, Embase, and Cochrane Library databases, with a supplemental gray literature search. Main Outcome Measures Efficacy, safety, and PROs. Results Post-screening of 7,330 records, 73 publications covering 28 studies were identified. Studies identified were characterized by line of treatment and response/survival rates; safety and PROs observed from the studies were described. Seven studies on 3L+ were reported as interventions of interest: anti-CD20 monoclonal antibodies (R: 1), PI3K inhibitors (PI3K: 4), EZH2 inhibitors (EZH2: 1), and chimeric antigen receptor T-cell therapy (CAR-T: 1). Efficacy varied. For R: Overall response rate (ORR) 38%; median duration of...

Blood

BACKGROUND: Relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL) remains an area of high... more BACKGROUND: Relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL) remains an area of high unmet patient need and no curative options are currently available. Odronextamab (REGN1979) is a first-in-class, hinge-stabilized, fully human IgG4-based bispecific antibody that binds to CD20-expressing cells and CD3 on T cells, targeting CD20+ cells via T-cell-mediated cytotoxicity independent of T-cell receptor recognition. The safety, tolerability, and anti-tumor activity of odronextamab monotherapy was evaluated in a global, multicenter, Phase 1 study in heavily pretreated patients with R/R B-NHL (NCT02990951; Bannerji et al, ASH 2019). Intravenous infusion of odronextamab has demonstrated an acceptable safety profile at doses up to 320 mg weekly (QW), and the maximum tolerated dose was not reached. Broad and durable anti-tumor responses were observed in both indolent and aggressive lymphomas, including in patients who progressed after prior CAR T-cell therapy. An assessment of pha...

Cell

Highlights d Proteomic profiles of extracellular vesicles and particles (EVPs) from 426 human sam... more Highlights d Proteomic profiles of extracellular vesicles and particles (EVPs) from 426 human samples d Identification of pan-EVP markers d Characterization of tumor-derived EVP markers in human tissues and plasma d EVP proteins can be useful for cancer detection and determining cancer type

Journal of Clinical Oncology

e19351 Background: CAR T, approved in the US as of October 2017, impacted the treatment landscape... more e19351 Background: CAR T, approved in the US as of October 2017, impacted the treatment landscape for patients with relapsed or refractory (R/R) DLBCL after ≥2 lines of therapy, but there is little known about real-world (RW) treatment patterns in patients who fail or do not respond to CAR T. No treatments of proven benefits are available after CAR T treatment failure. The objective of this study was to describe RW treatment patterns after CAR T. Methods: From MarketScan Commercial/Medicare claims databases (2017‒2018) we identified adult DLBCL patients who received approved CD19-directed CAR T (treatment date = index date). Eligible patients had ≥6 months continuous health plan enrollment prior to index date (i.e. baseline period) and were followed until plan disenrollment or December 31, 2018. Patients with a diagnosis of acute lymphoblastic leukemia over the baseline period were excluded. We identified the first and second treatments after CAR T with systemic chemotherapy, target...

Journal of Clinical Oncology

3101 Background: Heat shock protein (HSP) 90 regulates the disposition and activity of a large nu... more 3101 Background: Heat shock protein (HSP) 90 regulates the disposition and activity of a large number of deregulated proteins in Ewing sarcoma. We have shown pre-clinical efficacy of PU-H71, a novel HSP90 inhibitor developed at MSKCC, in Ewing sarcoma. Unfolded proteins as a result of HSP90 inhibition are degraded via the ubiquitin-proteasome pathway or the autophagy pathway. We investigated the effects of combined inhibition of HSP90 and the proteasome pathway. Methods: We studied the effects of PU-H71 and bortezomib alone and in combination on cell proliferation and viability in multiple Ewing cell lines, benign stromal cells and hematopoietic stem cells. We performed cell cycle analysis, clonogenic assay, immunoblot analysis, reverse phase protein array and in vivo experiments in NOD/SCID IL2R gamma null (NSG) mice using the A673 cell line transduced with GFP luciferase. Using A673 metastatic model in NSG mice, we investigated the disease burden when treated with PU-H71, bortezom...

Blood

Background REGN1979 is an anti-CD20 x anti-CD3 bispecific IgG4 antibody (Ab) modified to reduce F... more Background REGN1979 is an anti-CD20 x anti-CD3 bispecific IgG4 antibody (Ab) modified to reduce Fc binding. Engaging both targets results in CD20-specific, local T-cell activation and cytotoxicity, a mechanism of action distinct from standard anti-CD20 Abs. Dose escalation is complete and a recommended Ph 2 dose has been determined. We report Ph 1 safety and efficacy results of REGN1979 in patients (pts) with R/R B-NHL previously treated with anti-CD20 Abs, including pts with progressive disease after anti-CD19 CAR T-cell (CAR T) therapy. Methods Primary objectives are to determine safety, tolerability, and occurrence of dose limiting toxicities (DLTs). Other objectives are to assess antitumor activity, pharmacokinetics (PK), and pharmacodynamics. Eligible pts with R/R B-NHL must have received prior CD20-directed therapy. Treatment consists of 12 weekly intravenous doses of REGN1979 followed by every 2-week dosing for 12 doses (36 weeks total). Results As of June 3, 2019, 96 pts (di...

Journal of Clinical Oncology

10533Background: Treatment for ES in North America has evolved to include cycles of VDC and IE. A... more 10533Background: Treatment for ES in North America has evolved to include cycles of VDC and IE. A regimen including these 5 agents with interval dose compression has achieved 5 year EFS of 73% for ...

Blood

Background NHL is the most common hematological malignancy. Among a heterogeneous group of NHLs, ... more Background NHL is the most common hematological malignancy. Among a heterogeneous group of NHLs, 85-90% are of B-cell origin and include follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), and several other B-NHLs. Anti-CD20 Abs in combination with chemotherapy are the standard of care for the treatment of B-NHLs; however, despite initial responses, many patients relapse, often with progressively shorter response durations in subsequent lines of therapy and poor outcome. REGN1979 is a CD20 x CD3 bispecific IgG4 Ab that binds to CD3+ T-cells and CD20+ B-cells, targeting CD20+ tumor cells via T-cell-mediated cytotoxicity. An ongoing Phase 1 study in patients with B-cell malignancies is evaluating the safety, tolerability, and efficacy of REGN1979 as monotherapy (NCT02290951). Preliminary data from the Phase 1 study showed broad antitumor activity with REGN1979 in heavily pretreated R/R B-NHL patients, including som...

Blood

Introduction REGN1979 is an anti-CD20 x anti-CD3 bispecific IgG4 antibody (Ab) modified to reduce... more Introduction REGN1979 is an anti-CD20 x anti-CD3 bispecific IgG4 antibody (Ab) modified to reduce Fc binding. Engaging both targets results in CD20-specific, local T-cell activation and cytotoxicity, a mechanism of action distinct from standard anti-CD20 Abs. We report updated promising efficacy results of a Phase 1 trial of REGN1979 in patients (pts) with relapsed/refactory (R/R) B-NHL previously treated with anti-CD20 Abs. Methods The primary objectives of the study are to determine safety, tolerability, and occurrence of dose limiting toxicities (DLTs). Other objectives include assessment of preliminary antitumor activity, pharmacokinetics (PK), and pharmacodynamics. Eligible pts with R/R NHL must have received at least 1 prior CD20-directed therapy. Treatment consists of 12 weekly doses of REGN1979 followed by every 2 week dosing for 12 doses for a total of 36 weeks. Guidelines are provided for management of cytokine release syndrome (CRS) and include steroids and/or tocilizumab...

Journal of Clinical Oncology

11050 Background: DSRCT is a rare tumor with a dismal prognosis in the setting of current treatme... more 11050 Background: DSRCT is a rare tumor with a dismal prognosis in the setting of current treatment options. Preclinical data suggested that VEGF-dependent angiogenesis is important for DSRCT tumor biology and that targeting angiogenesis with bevacizumab in combination with irinotecan was more effective than treatment with irinotecan alone. This pilot study was designed to explore the safety and feasibility of adding ITB to the existing “P6- like” regimen used to treat DSRCT. Methods: Fifteen patients with newly diagnosed DSRCT were enrolled onto this single-institution study. They began treatment with 2 cycles of irinotecan (20 mg/m2/dose x 10 days) and temozolomide (100 mg/m2/dose x 5 days). Bevacizumab 10 mg/kg q2 weeks was added after sufficient time had passed from initial biopsy or surgery. Patients were then treated with cycles of alkylator based chemotherapy (3 cycles of cyclophosphamide, doxorubicin, vincristine and 3 cycles of ifosfamide, etoposide). An initial surgical re...

Blood

Many patients with B-cell lymphomas, including mantle cell lymphoma (MCL) and diffuse large B-cel... more Many patients with B-cell lymphomas, including mantle cell lymphoma (MCL) and diffuse large B-cell lymphoma (DLBCL), are not cured by conventional chemo-immunotherapy. One reason for this is because these drugs, while effective, are limited by their narrow therapeutic window and significant toxicities. B-cell lymphomas are highly dependent on DNA damage checkpoints, and hence are biologically responsive to drugs that trigger these checkpoints. Hence, In order to identify superior DNA damaging anti-lymphoma drugs we evaluated a series of novel, third generation, DNA-directed alkylating agents that have DNA specific binding domains chemically linked via urea, carbamate or hydrazinecarboxamide to N-mustard pharmacophores. The chemically favorable water-soluble ureidomustine (BO-1055) was evaluated for activity against 23 human lymphoma cell lines including MCL, DLBCL (GCB and ABC subtype) and a spontaneous murine B-cell lymphoma. Fifty % of these MCL and DLBCL cell lines exhibited BO-1...

Blood

2051 Background: Beta-thalassemia patients on regular transfusions develop progressive iron overl... more 2051 Background: Beta-thalassemia patients on regular transfusions develop progressive iron overload. The introduction of noninvasive measures of hepatic and cardiac iron loading (MRI T2*) has made the monitoring of iron excess in regularly transfused thalassemia patients more accessible and annual assessments are now feasible to assist in chelation management and dose adjustments. Methods: We have retrospectively reviewed 46 beta-thalassemia major patients, 37 female (F) and 20 male (M), with a mean age 30.1yr (range 9–59yr). All received regular transfusions to maintain pre transfusion Hb levels of 9 to10 gm/dl and had 2 or more annual MRI T2* studies. All 46 patients were treated with deferasirox. Each patient was monitored yearly for iron concentration by hepatic and cardiac magnetic resonance imaging (MRI) T2*. They were also assessed with monthly evaluations for liver and renal function (Bili, AST, ALT, BUN, Creatinine), serum ferritin, CBC, and urinalysis. Annual EKG, ECHO, h...

Blood

Some B-cell lymphoma including mantle cell lymphoma (MCL) and diffuse large B-cell lymphoma (DLBC... more Some B-cell lymphoma including mantle cell lymphoma (MCL) and diffuse large B-cell lymphoma (DLBCL) remain incurable using conventional chemotherapeutic approaches. Therefore it is important that new treatment strategies be developed. We have evaluated the efficacy of a number of novel, third generation, DNA-directed alkylating agents that have DNA specific binding domain by linking DNA-affinic molecules to N-mustard pharmacophore via a urea, carbamate or hydrazinecarboxamide linker (Kapuriya et al. Bioorganic & Medicinal Chem. 19:471–485; 2011). One of these, the water-soluble ureidomustine BO-1055, was screened for toxicity against a panel of human lymphoma cell lines including MCL (JEKO-1, Z-138, HBL-2), DLBCL (OCILy10, OCILy19) and a spontaneous murine B-cell lymphoma. We also screened BO1055 against a panel of normal human cells including mesenchymal stromal cells (IC50 >10uM), bone marrow-derived endothelium (IC50 >10uM) lung basal epithelium, bronchial epithelium and my...

Journal of Clinical Oncology

10569Background: Survival rates for children and young adults with relapsed and/or refractory sar... more 10569Background: Survival rates for children and young adults with relapsed and/or refractory sarcomas remain poor. Cytotoxic salvage options for these patients are limited and associated with sign...

British Journal of Cancer

Clinical and Translational Science

Odronextamab is a fully-human IgG4-based CD20xCD3 bispecific antibody that binds to CD3 on T cell... more Odronextamab is a fully-human IgG4-based CD20xCD3 bispecific antibody that binds to CD3 on T cells and CD20 on B cells, triggering T-cell-mediated cytotoxicity independent of T-cell-receptor recognition. Adequate safety, tolerability, and encouraging durable complete responses have been observed in an ongoing first-in-human (FIH) study of odronextamab in patients with relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL; NCT02290951). We retrospectively evaluated the pharmacokinetic, pharmacodynamic, and antitumor characteristics of odronextamab in a series of in vitro/in vivo preclinical experiments, to assess their translational value to inform dose escalation for the FIH study. Half-maximal effective concentration values from in vitro cytokine release assays (range: 0.05-0.08 mg/L) provided a reasonable estimate of odronextamab concentrations in patients associated with cytokine release at a 0.5 mg dose (maximum serum concentration: 0.081 mg/L) on week 1/day 1, which could therefore be used to determine the week 1 clinical dose. Odronextamab concentrations resulting in 100% inhibition of tumor growth in a Raji xenograft tumor mouse model (1-10 mg/L) were useful to predict efficacious concentrations in patients and inform dose-escalation strategy. Although predicted human pharmacokinetic parameters derived from monkey data overestimated projected odronextamab exposure, they provided a conservative estimate for FIH starting doses. With step-up dosing, the highest-tested weekly odronextamab dose in patients (320 mg) exceeded the 1 mg/kg single dose in monkeys without step-up dosing. In conclusion, combination of odronextamab in vitro cytokine data, efficacious concentration data from mouse tumor models, and pharmacokinetic evaluations in monkeys has translational value to inform odronextamab FIH study design in patients with R/R B-NHL.

Blood, 2020

BACKGROUND: Odronextamab (REGN1979) is a first-in-class, hinge-stabilized, fully human CD20 x CD3... more BACKGROUND: Odronextamab (REGN1979) is a first-in-class, hinge-stabilized, fully human CD20 x CD3 IgG4-based bispecific antibody that binds to CD20-expressing cells and CD3 on T cells, targeting CD20+ cells via T-cell-mediated cytotoxicity independent of T-cell receptor recognition. Patients with relapsed/refractory B-cell non-Hodgkin lymphoma were treated with odronextamab in a first-in-human, Phase 1 study (NCT02290951). Patient biopsies were analyzed to investigate the association of clinical response and relapse with B- and T-cell markers. METHODS: Tumor biopsies collected at baseline and at disease progression were analyzed by semi-quantitative CD20 chromogenic immunohistochemistry (IHC). B-cell antigen and immune cell multiplex immunofluorescence was also performed. Bulk tumor tissue nucleic acid isolates were analyzed by whole exome DNA sequencing. Peripheral blood mononuclear cells isolated from baseline samples were analyzed by highly multiplexed flow cytometry T-cell immun...

Clinical Lymphoma, Myeloma & Leukemia, 2021

Context Limited published SLRs exist on third-line and greater (3L+) treatment of R/R DLBCL, desp... more Context Limited published SLRs exist on third-line and greater (3L+) treatment of R/R DLBCL, despite recent approvals of newer therapies. Objective To conduct an SLR evaluating the efficacy, safety, and PROs of therapies for 3L+ R/R DLBCL. Design SLR in accordance with the Cochrane Handbook for Systematic Reviews of Interventions and European Union Health Technology Assessment requirements; publications prior to November 2020 in MEDLINE, MEDLINE In-Process, Embase, and Cochrane Library databases; supplemented by a gray literature search. Main Outcome Measures Efficacy, safety, and PROs. Results Post-screening of 9,901 records, 143 publications covering 40 studies were identified. Seven studies were reported as interventions of interest: chimeric antigen receptor T-cell therapy (CAR-T: 3), antibody–drug conjugates (ADC: 2), nuclear export inhibitor (S: 1), aza-anthracenedione analogue (P: 1), and chemo/chemoimmunotherapy (Ch: 2). Wide ranges of efficacy outcomes were reported. CAR-T ...

Clinical Lymphoma, Myeloma & Leukemia, 2021

Context There is no well-defined standard of care in 3L+ R/R FL. Recently, novel treatments were ... more Context There is no well-defined standard of care in 3L+ R/R FL. Recently, novel treatments were evaluated in trials or approved by regulators. Objective To conduct an SLR evaluating efficacy, safety, and PROs of treatments for 3L+ R/R FL. Design The SLR included publications prior to November 2020 in MEDLINE, MEDLINE In-Process, Embase, and Cochrane Library databases, with a supplemental gray literature search. Main Outcome Measures Efficacy, safety, and PROs. Results Post-screening of 7,330 records, 73 publications covering 28 studies were identified. Studies identified were characterized by line of treatment and response/survival rates; safety and PROs observed from the studies were described. Seven studies on 3L+ were reported as interventions of interest: anti-CD20 monoclonal antibodies (R: 1), PI3K inhibitors (PI3K: 4), EZH2 inhibitors (EZH2: 1), and chimeric antigen receptor T-cell therapy (CAR-T: 1). Efficacy varied. For R: Overall response rate (ORR) 38%; median duration of...

Blood

BACKGROUND: Relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL) remains an area of high... more BACKGROUND: Relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL) remains an area of high unmet patient need and no curative options are currently available. Odronextamab (REGN1979) is a first-in-class, hinge-stabilized, fully human IgG4-based bispecific antibody that binds to CD20-expressing cells and CD3 on T cells, targeting CD20+ cells via T-cell-mediated cytotoxicity independent of T-cell receptor recognition. The safety, tolerability, and anti-tumor activity of odronextamab monotherapy was evaluated in a global, multicenter, Phase 1 study in heavily pretreated patients with R/R B-NHL (NCT02990951; Bannerji et al, ASH 2019). Intravenous infusion of odronextamab has demonstrated an acceptable safety profile at doses up to 320 mg weekly (QW), and the maximum tolerated dose was not reached. Broad and durable anti-tumor responses were observed in both indolent and aggressive lymphomas, including in patients who progressed after prior CAR T-cell therapy. An assessment of pha...

Cell

Highlights d Proteomic profiles of extracellular vesicles and particles (EVPs) from 426 human sam... more Highlights d Proteomic profiles of extracellular vesicles and particles (EVPs) from 426 human samples d Identification of pan-EVP markers d Characterization of tumor-derived EVP markers in human tissues and plasma d EVP proteins can be useful for cancer detection and determining cancer type

Journal of Clinical Oncology

e19351 Background: CAR T, approved in the US as of October 2017, impacted the treatment landscape... more e19351 Background: CAR T, approved in the US as of October 2017, impacted the treatment landscape for patients with relapsed or refractory (R/R) DLBCL after ≥2 lines of therapy, but there is little known about real-world (RW) treatment patterns in patients who fail or do not respond to CAR T. No treatments of proven benefits are available after CAR T treatment failure. The objective of this study was to describe RW treatment patterns after CAR T. Methods: From MarketScan Commercial/Medicare claims databases (2017‒2018) we identified adult DLBCL patients who received approved CD19-directed CAR T (treatment date = index date). Eligible patients had ≥6 months continuous health plan enrollment prior to index date (i.e. baseline period) and were followed until plan disenrollment or December 31, 2018. Patients with a diagnosis of acute lymphoblastic leukemia over the baseline period were excluded. We identified the first and second treatments after CAR T with systemic chemotherapy, target...

Journal of Clinical Oncology

3101 Background: Heat shock protein (HSP) 90 regulates the disposition and activity of a large nu... more 3101 Background: Heat shock protein (HSP) 90 regulates the disposition and activity of a large number of deregulated proteins in Ewing sarcoma. We have shown pre-clinical efficacy of PU-H71, a novel HSP90 inhibitor developed at MSKCC, in Ewing sarcoma. Unfolded proteins as a result of HSP90 inhibition are degraded via the ubiquitin-proteasome pathway or the autophagy pathway. We investigated the effects of combined inhibition of HSP90 and the proteasome pathway. Methods: We studied the effects of PU-H71 and bortezomib alone and in combination on cell proliferation and viability in multiple Ewing cell lines, benign stromal cells and hematopoietic stem cells. We performed cell cycle analysis, clonogenic assay, immunoblot analysis, reverse phase protein array and in vivo experiments in NOD/SCID IL2R gamma null (NSG) mice using the A673 cell line transduced with GFP luciferase. Using A673 metastatic model in NSG mice, we investigated the disease burden when treated with PU-H71, bortezom...

Blood

Background REGN1979 is an anti-CD20 x anti-CD3 bispecific IgG4 antibody (Ab) modified to reduce F... more Background REGN1979 is an anti-CD20 x anti-CD3 bispecific IgG4 antibody (Ab) modified to reduce Fc binding. Engaging both targets results in CD20-specific, local T-cell activation and cytotoxicity, a mechanism of action distinct from standard anti-CD20 Abs. Dose escalation is complete and a recommended Ph 2 dose has been determined. We report Ph 1 safety and efficacy results of REGN1979 in patients (pts) with R/R B-NHL previously treated with anti-CD20 Abs, including pts with progressive disease after anti-CD19 CAR T-cell (CAR T) therapy. Methods Primary objectives are to determine safety, tolerability, and occurrence of dose limiting toxicities (DLTs). Other objectives are to assess antitumor activity, pharmacokinetics (PK), and pharmacodynamics. Eligible pts with R/R B-NHL must have received prior CD20-directed therapy. Treatment consists of 12 weekly intravenous doses of REGN1979 followed by every 2-week dosing for 12 doses (36 weeks total). Results As of June 3, 2019, 96 pts (di...

Journal of Clinical Oncology

10533Background: Treatment for ES in North America has evolved to include cycles of VDC and IE. A... more 10533Background: Treatment for ES in North America has evolved to include cycles of VDC and IE. A regimen including these 5 agents with interval dose compression has achieved 5 year EFS of 73% for ...

Blood

Background NHL is the most common hematological malignancy. Among a heterogeneous group of NHLs, ... more Background NHL is the most common hematological malignancy. Among a heterogeneous group of NHLs, 85-90% are of B-cell origin and include follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), and several other B-NHLs. Anti-CD20 Abs in combination with chemotherapy are the standard of care for the treatment of B-NHLs; however, despite initial responses, many patients relapse, often with progressively shorter response durations in subsequent lines of therapy and poor outcome. REGN1979 is a CD20 x CD3 bispecific IgG4 Ab that binds to CD3+ T-cells and CD20+ B-cells, targeting CD20+ tumor cells via T-cell-mediated cytotoxicity. An ongoing Phase 1 study in patients with B-cell malignancies is evaluating the safety, tolerability, and efficacy of REGN1979 as monotherapy (NCT02290951). Preliminary data from the Phase 1 study showed broad antitumor activity with REGN1979 in heavily pretreated R/R B-NHL patients, including som...

Blood

Introduction REGN1979 is an anti-CD20 x anti-CD3 bispecific IgG4 antibody (Ab) modified to reduce... more Introduction REGN1979 is an anti-CD20 x anti-CD3 bispecific IgG4 antibody (Ab) modified to reduce Fc binding. Engaging both targets results in CD20-specific, local T-cell activation and cytotoxicity, a mechanism of action distinct from standard anti-CD20 Abs. We report updated promising efficacy results of a Phase 1 trial of REGN1979 in patients (pts) with relapsed/refactory (R/R) B-NHL previously treated with anti-CD20 Abs. Methods The primary objectives of the study are to determine safety, tolerability, and occurrence of dose limiting toxicities (DLTs). Other objectives include assessment of preliminary antitumor activity, pharmacokinetics (PK), and pharmacodynamics. Eligible pts with R/R NHL must have received at least 1 prior CD20-directed therapy. Treatment consists of 12 weekly doses of REGN1979 followed by every 2 week dosing for 12 doses for a total of 36 weeks. Guidelines are provided for management of cytokine release syndrome (CRS) and include steroids and/or tocilizumab...

Journal of Clinical Oncology

11050 Background: DSRCT is a rare tumor with a dismal prognosis in the setting of current treatme... more 11050 Background: DSRCT is a rare tumor with a dismal prognosis in the setting of current treatment options. Preclinical data suggested that VEGF-dependent angiogenesis is important for DSRCT tumor biology and that targeting angiogenesis with bevacizumab in combination with irinotecan was more effective than treatment with irinotecan alone. This pilot study was designed to explore the safety and feasibility of adding ITB to the existing “P6- like” regimen used to treat DSRCT. Methods: Fifteen patients with newly diagnosed DSRCT were enrolled onto this single-institution study. They began treatment with 2 cycles of irinotecan (20 mg/m2/dose x 10 days) and temozolomide (100 mg/m2/dose x 5 days). Bevacizumab 10 mg/kg q2 weeks was added after sufficient time had passed from initial biopsy or surgery. Patients were then treated with cycles of alkylator based chemotherapy (3 cycles of cyclophosphamide, doxorubicin, vincristine and 3 cycles of ifosfamide, etoposide). An initial surgical re...

Blood

Many patients with B-cell lymphomas, including mantle cell lymphoma (MCL) and diffuse large B-cel... more Many patients with B-cell lymphomas, including mantle cell lymphoma (MCL) and diffuse large B-cell lymphoma (DLBCL), are not cured by conventional chemo-immunotherapy. One reason for this is because these drugs, while effective, are limited by their narrow therapeutic window and significant toxicities. B-cell lymphomas are highly dependent on DNA damage checkpoints, and hence are biologically responsive to drugs that trigger these checkpoints. Hence, In order to identify superior DNA damaging anti-lymphoma drugs we evaluated a series of novel, third generation, DNA-directed alkylating agents that have DNA specific binding domains chemically linked via urea, carbamate or hydrazinecarboxamide to N-mustard pharmacophores. The chemically favorable water-soluble ureidomustine (BO-1055) was evaluated for activity against 23 human lymphoma cell lines including MCL, DLBCL (GCB and ABC subtype) and a spontaneous murine B-cell lymphoma. Fifty % of these MCL and DLBCL cell lines exhibited BO-1...

Blood

2051 Background: Beta-thalassemia patients on regular transfusions develop progressive iron overl... more 2051 Background: Beta-thalassemia patients on regular transfusions develop progressive iron overload. The introduction of noninvasive measures of hepatic and cardiac iron loading (MRI T2*) has made the monitoring of iron excess in regularly transfused thalassemia patients more accessible and annual assessments are now feasible to assist in chelation management and dose adjustments. Methods: We have retrospectively reviewed 46 beta-thalassemia major patients, 37 female (F) and 20 male (M), with a mean age 30.1yr (range 9–59yr). All received regular transfusions to maintain pre transfusion Hb levels of 9 to10 gm/dl and had 2 or more annual MRI T2* studies. All 46 patients were treated with deferasirox. Each patient was monitored yearly for iron concentration by hepatic and cardiac magnetic resonance imaging (MRI) T2*. They were also assessed with monthly evaluations for liver and renal function (Bili, AST, ALT, BUN, Creatinine), serum ferritin, CBC, and urinalysis. Annual EKG, ECHO, h...

Blood

Some B-cell lymphoma including mantle cell lymphoma (MCL) and diffuse large B-cell lymphoma (DLBC... more Some B-cell lymphoma including mantle cell lymphoma (MCL) and diffuse large B-cell lymphoma (DLBCL) remain incurable using conventional chemotherapeutic approaches. Therefore it is important that new treatment strategies be developed. We have evaluated the efficacy of a number of novel, third generation, DNA-directed alkylating agents that have DNA specific binding domain by linking DNA-affinic molecules to N-mustard pharmacophore via a urea, carbamate or hydrazinecarboxamide linker (Kapuriya et al. Bioorganic & Medicinal Chem. 19:471–485; 2011). One of these, the water-soluble ureidomustine BO-1055, was screened for toxicity against a panel of human lymphoma cell lines including MCL (JEKO-1, Z-138, HBL-2), DLBCL (OCILy10, OCILy19) and a spontaneous murine B-cell lymphoma. We also screened BO1055 against a panel of normal human cells including mesenchymal stromal cells (IC50 >10uM), bone marrow-derived endothelium (IC50 >10uM) lung basal epithelium, bronchial epithelium and my...

Journal of Clinical Oncology

10569Background: Survival rates for children and young adults with relapsed and/or refractory sar... more 10569Background: Survival rates for children and young adults with relapsed and/or refractory sarcomas remain poor. Cytotoxic salvage options for these patients are limited and associated with sign...

British Journal of Cancer