In:
Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 14, No. 12_Supplement_2 ( 2015-12-01), p. C42-C42
Abstract:
Background: The Notch pathway plays a key role in embryonic development, the regulation of stem and progenitor cells, and is implicated in human cancer. Notch-1 (N1) signaling is activated by various mechanisms including N1 activating mutations in certain solid tumors. Brontictuzumab (BRON) is a humanized IgG2 antibody that inhibits the signaling function of N1. As such, BRON is a novel anti-cancer agent that inhibits tumor growth through direct actions on tumor cells, including CSCs, and effects on tumor angiogenesis. Materials and methods: A phase I dose escalation and expansion study was initiated in patients (pts) with certain advanced solid tumors (cholangiocarcinoma, breast (BC), colorectal (CRC), esophageal, gastric, pancreatic, small cell lung cancers (SCLC), and adenoid cystic carcinomas (ACC)) that have rates of N1 activation between 12-50%. BRON was administered intravenously to study safety, pharmacokinetics (PK), pharmacodynamics, preliminary efficacy, and to determine the maximum tolerated dose. The trial has a biomarker (Notch1 intracellular domain (NICD)) selected expansion cohort. Results: 44 pts have been enrolled in 8 dose escalation cohorts at doses of 0.25, 0.5, 1, and 2.5mg/kg every 4 weeks (Q4W), and then 1.0, 1.5, 2.0, 2.5 mg/kg every 3 weeks (Q3W) with a dose expansion cohort at the MTD of 1.5 mg/kg Q3W. Tumor types included CRC (12), ACC (11), cholangiocarcinoma (7), BC (6),, esophageal (3), pancreatic (2), SCLC (2), and one pt with gastric cancer. 3 pts experienced dose-limiting toxicity (DLTs) AEs with gr 3 fatigue (2.5 mg/kg Q4W), and gr 3 diarrhea (2.5 mg/kg Q3W and 2.0 mg/kg Q3W). The most frequent adverse events (AE) were: diarrhea (73%), fatigue (61%), and nausea (45%). Common grade 3 or higher AEs included diarrhea (29%) and fatigue (7%). One pt with a N1 activating mutation in ACC had partial response after 2 doses. Another patient with an inactivating FBXW7 mutation and high NICD had stable disease for more than 290 days. 5 pts had stable disease: 2 with BC, 2 with ACC, and 1 with CRC. In the dose expansion cohort (7 efficacy evaluable pts, all NICD high), 3 SDs were observed. CSC and Notch pathway markers were reduced with BRON treatment. Conclusions: BRON is generally well tolerated. Diarrhea is the primary toxicity of this antibody. Potential early efficacy consistent with the predictive biomarker hypothesis is noted. MTD has been established and the recommended phase 2 dose is 1.5 mg/kg Q3W. Enrollment continues in the dose expansion cohort. Updated efficacy, safety, and PK results will be presented. Clinical trial information: NCT01778439. Citation Format: Pamela Munster, S. Gail Eckhardt, Amita Patnaik, Anthony F. Shields, Anthony W. Tolcher, S. Lindsey Davis, John V. Heymach, Lu Xu, Ann M. Kapoun, Leonardo Faoro, Jakob Dupont, Renata Ferrarotto. Safety and preliminary efficacy results of a first-in-human phase I study of the novel cancer stem cell (CSC) targeting antibody brontictuzumab (OMP-52M51, anti-Notch1) administered intravenously to patients with certain advanced solid tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C42.
Type of Medium:
Online Resource
ISSN:
1535-7163
,
1538-8514
DOI:
10.1158/1535-7163.TARG-15-C42
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2015
detail.hit.zdb_id:
2062135-8
SSG:
12
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