Phase 1 Dose Escalation Study of MEDI-565, a Bispecific T-Cell Engager that Targets Human Carcinoembryonic Antigen, in Patients With Advanced Gastrointestinal Adenocarcinomas

Pishvaian, Michael J.; Morse, Michael A.; McDevitt, Jennifer; Norton, Jonathan; Ren, Song; Robbie, Gabriel J.; Ryan, Patricia C.; Soukharev, Serguei; Bao, Haifeng; Denlinger, Crystal S.

doi:10.1016/j.clcc.2016.07.009

Cited by 76 publications

(54 citation statements)

References 6 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…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%

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

133

106

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

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

133

106

View full text Add to dashboard Cite

show abstract

“…In fact, dexamethasone at clinically relevant concentrations could blunt the increase in cytokine levels with minimal impact on proliferation or killing of ALL cells 46. This provided a rationale for coadministering blinatumomab with dexamethasone in clinical trials, a practice that has continued with other BiTE® antibody constructs 47, 48. However, it is not clear if the differential sensitivity of effector functions to dexamethasone can be generalized across the BiTE® platform.…”

Section: Mechanism Of Action and Key Characteristics Of Bite® Antibodmentioning

confidence: 99%

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

Yuraszeck

Kasichayanula

Benjamin

2017

Clin Pharma and Therapeutics

View full text Add to dashboard Cite

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.

show abstract

“…Although risk factors for neurotoxicity associated with Tcell therapy have been investigated, none are established for decision-making in patients. Other CD3 bispecifics targeting CD20 (Schuster et al 2015), carcinoembryonic antigen (Pishvaian et al 2016), EpCAM (Sebastian et al 2007), and HER2 (Kiewe et al 2006;Haense et al 2016) have been associated mostly with headache and not with severe neurotoxicity (Bannerji et al 2017), but detailed information is limited. The etiology may be related to cytokines, since a similar toxicity is manifest in patients treated with agents that stimulate T-cell cytokine production independent of CD19 (e.g.…”

Section: Session 7: Clinical Experiencementioning

confidence: 99%

Summary of a workshop on preclinical and translational safety assessment of CD3 bispecifics

Kamperschroer

Shenton

Lebrec

et al. 2020

Journal of Immunotoxicology

View full text Add to dashboard Cite

Currently, there is a multitude of CD3 bispecifics with different molecular designs and binding properties in preclinical and clinical development for the treatment of liquid or solid tumors. The key safety concerns with CD3 bispecifics are excessive release of cytokines, which may translate to potentially life-threating cytokine release syndrome (CRS), target organ toxicity due to redirection of T-cells to normal tissues expressing the tumor-associated antigen (TAA) (off-tumor/on-target cytotoxicity), and, in some instances, neurotoxicity. Another key challenge is to arrive at a safe clinical starting dose and an efficient escalating strategy that allows patients in early dose cohorts the potential for clinical benefit in Phase 1 trials. To expand the therapeutic index and bring more treatment options to patients, there are intense efforts to overcome these challenges through improvements in molecular design, preclinical safety assessment strategies, and clinical management practices. A recent workshop at the U.S. Food and Drug Administration (FDA) with industry, academic, and regulatory agency representation was held to discuss the challenges and explore where such improvements to the development of CD3 bispecifics can be implemented. Here, the content of the presentations and the discussion that occurred during this workshop are summarized. ARTICLE HISTORY

show abstract

Phase 1 Dose Escalation Study of MEDI-565, a Bispecific T-Cell Engager that Targets Human Carcinoembryonic Antigen, in Patients With Advanced Gastrointestinal Adenocarcinomas

Cited by 76 publications

References 6 publications

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

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

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

Summary of a workshop on preclinical and translational safety assessment of CD3 bispecifics

Contact Info

Product

Resources

About