Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multicentre, single-arm, phase 2 study

Topp, Max S.; Gökbuget, Nicola; Stein, Anthony S.; Zugmaier, Gerhard; O’Brien, Susan; Bargou, Ralf C.; Dombret, Hervé; Fielding, Adele K.; Heffner, Leonard T.; Larson, Richard A.; Neumann, Svenja; Foà, Robin; Litzow, Mark R.; Ribera, Josep‐Marǐa; Rambaldi, Alessandro; Schiller, Gary J.; Brüggemann, Monika; Horst, Heinz A.; Holland, Christopher P.; Jia, Catherine; Maniar, Tapan; Huber, Birgit; Nagorsen, Dirk; Forman, Stephen J.; Kantarjian, Hagop M.

doi:10.1016/s1470-2045(14)71170-2

Cited by 1,043 publications

(1,091 citation statements)

References 26 publications

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“…70, 74, 75 Three dosing regimens were tested in the first 18 subjects enrolled into MT103‐206: a flat dose of 15 μg/m 2 /d, step dosing from 5 μg/m 2 /d × 7 d to 15 μg/m 2 /d, and step dosing from 5–15–30 μg/m 2 /d, all for a total infusion duration of 28 days. Dose selection was based on results from previous studies with blinatumomab (MT103‐104 and MT103‐202) with step dosing implemented to mitigate adverse events.…”

Section: Clinical Experience With Blinatumomabmentioning

confidence: 99%

Translation and Clinical Development of Bispecific T‐cell Engaging Antibodies for Cancer Treatment

Yuraszeck

Kasichayanula

Benjamin

2017

Clin Pharma and Therapeutics

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Bispecific T‐cell Engagers (BiTE®) antibody constructs enable a polyclonal T‐cell response to cell‐surface tumor‐associated antigens, bypassing the narrow specificities of T‐cell receptors and the need for antigen presentation through the major histocompatibility complex pathways. Blinatumomab, a CD19xCD3 BiTE® antibody construct, received accelerated approval for the treatment of relapsed/refractory Philadelphia chromosome negative acute lymphoblastic leukemia. Herein we review the pharmacology, safety, and efficacy observed in studies of blinatumomab and other BiTE® antibody constructs. Quantitative systems pharmacology is envisioned as a means to optimize dosing decisions for trials in which BiTE® antibody constructs are administered as monotherapy or in combination with other immunotherapies.

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Section: Clinical Experience With Blinatumomabmentioning

confidence: 99%

Translation and Clinical Development of Bispecific T‐cell Engaging Antibodies for Cancer Treatment

Yuraszeck

Kasichayanula

Benjamin

2017

Clin Pharma and Therapeutics

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“…Proof of concept was shown early with blinatumomab in the setting of hematologic malignancies; 12 , 14 , 15 however, information on the applicability of BiTE® antibody constructs to the solid tumor setting remains very limited. 18 We report here the final results of the first-in-human phase 1 study of solitomab, a BiTE® antibody construct immunotherapy against EpCAM, in solid tumors.…”

Section: Discussionmentioning

confidence: 99%

“…13 Blinatumomab was the first BiTE® antibody construct to be clinically evaluated, focusing on hematologic malignancies. Blinatumomab has demonstrated efficacy in patients with Philadelphia chromosome-negative relapsed/refractory acute lymphoblastic leukemia (ALL) 14 and antilymphoma activity in patients with relapsed/refractory diffuse large B-cell lymphoma. 15 …”

Section: Introductionmentioning

confidence: 99%

A multicenter phase 1 study of solitomab (MT110, AMG 110), a bispecific EpCAM/CD3 T-cell engager (BiTE®) antibody construct, in patients with refractory solid tumors

Kebenko

Goebeler

Wolf³

et al. 2018

OncoImmunology

117

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We assessed the tolerability and antitumor activity of solitomab, a bispecific T-cell engager (BiTE®) antibody construct targeting epithelial cell adhesion molecule (EpCAM). Patients with relapsed/refractory solid tumors not amenable to standard therapy received solitomab as continuous IV infusion in a phase 1 dose-escalation study with six different dosing schedules. The primary endpoint was frequency and severity of adverse events (AEs). Secondary endpoints included pharmacokinetics, pharmacodynamics, immunogenicity, and antitumor activity. Sixty-five patients received solitomab at doses between 1 and 96 µg/day for ≥28 days. Fifteen patients had dose-limiting toxicities (DLTs): eight had transient abnormal liver parameters shortly after infusion start or dose escalation (grade 3, n = 4; grade 4, n = 4), and one had supraventricular tachycardia (grade 3); all events resolved with solitomab discontinuation. Six patients had a DLT of diarrhea: four events resolved (grade 3, n = 3; grade 4, n = 1), one (grade 3) was ongoing at the time of treatment-unrelated death, and one (grade 3) progressed to grade 5 after solitomab discontinuation. The maximum tolerated dose was 24 µg/day. Overall, 95% of patients had grade ≥3 treatment-related AEs, primarily diarrhea, elevated liver parameters, and elevated lipase. Solitomab half-life was 4.5 hours; serum levels plateaued within 24 hours. One unconfirmed partial response was observed. In this study of a BiTE® antibody construct targeting solid tumors, treatment of relapsed/refractory EpCAM-positive solid tumors with solitomab was associated with DLTs, including severe diarrhea and increased liver enzymes, which precluded dose escalation to potentially therapeutic levels.

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“…Blinatumomab proved highly efficient in adult BCP-ALL and B-cell lymphoma patients as well as in pediatric BCP-ALL. 2 , 21 , 22 It has been approved by the FDA for the treatment of relapsed or refractory adult and pediatric ALL patients and current trials are in planning employing blinatumomab in the upfront non-relapsed setting in pediatric ALL also. Likewise, impressive effects in both adults and children were achieved by administration of genetically modified T cells which express a CD19 specific CAR consisting typically of a CD19 scFv fused to intracellular signal transduction domain of CD3ζ for activation and at least one costimulatory domain, e.g.…”

Section: Cd19 Targeting With Fc Engineered Antibodies Optimized For Ementioning

confidence: 99%

Perspectives of Fc engineered antibodies in CD19 targeting immunotherapies in pediatric B-cell precursor acute lymphoblastic leukemia

et al. 2018

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Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multicentre, single-arm, phase 2 study

Cited by 1,043 publications

References 26 publications

Translation and Clinical Development of Bispecific T‐cell Engaging Antibodies for Cancer Treatment

Translation and Clinical Development of Bispecific T‐cell Engaging Antibodies for Cancer Treatment

A multicenter phase 1 study of solitomab (MT110, AMG 110), a bispecific EpCAM/CD3 T-cell engager (BiTE®) antibody construct, in patients with refractory solid tumors

Perspectives of Fc engineered antibodies in CD19 targeting immunotherapies in pediatric B-cell precursor acute lymphoblastic leukemia

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