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. 2018 Apr 18;7(8):e1450710.
doi: 10.1080/2162402X.2018.1450710. eCollection 2018.

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

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Free PMC article

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

Maxim Kebenko et al. Oncoimmunology. .
Free PMC article

Abstract

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.

Keywords: AMG 110; BiTE®; CD3; EpCAM, phase 1; MT110; bispecific; immunotherapy; solid tumor; solitomab.

Figures

Figure 1.
Figure 1.
Treatment schema. Schedules A through C explored flat dosing and low-dose run-in schedules with and without a break in dosing. Treatment schedules D, Bx, and Bz1 explored various two-step run-in protocols with and without a break in dosing and optional extension weeks.
Figure 2.
Figure 2.
Immunohistochemical evaluation of duodenal biopsy tissue from a patient with lung adenocarcinoma treated with solitomab (3 µg/day for 8 days, 12 µg/day for 3 days). A, IHC staining of EpCAM expression shows EpCAM-positive epithelial cells in duodenal crypts and along villis (arrows) and EpCAM-negative cells of the mucosa and Brunner's cells (arrow heads). B, Infiltration of duodenal epithelium by CD3-positive (left) and T-cell restricted intracellular antigen (TIA)-positive (right; arrows) lymphocytes. Vacuolated tip enterocytes (arrow heads) are also present. C, HE staining showing damage to the crypt structure with villus collapse (arrow) and mucosal ulceration (double arrow). Vacuolated tip enterocytes (arrow heads) are visible along the villi.
Figure 3.
Figure 3.
Effect of treatment with muS110 on mouse duodenal tissue. A, IHC showing similar expression of EpCAM in enterocytes from animals treated with vehicle control (left) or muS110 (right). B, HE stain of mouse duodenal tissue from vehicle control-treated animal (left) showing normal, healthy crypt epithelium and villi; and from muS110-treated animals showing crypt elongation with enterocyte hyperplasia (arrow head), villous collapse and mucosal ulceration (arrow) as well as vacuolated tip enterocytes (open arrow head). C, IHC illustrating presence of CD3-positive lymphocytes as well as Granzyme B- and caspase-positive cells in animals treated with vehicle control or muS110. Ten animals per group received 0.05 mg/kg/day of muS110 once every day for two days. Images from representative animals are shown (200 × ).

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