A phase 1 dose escalation and expansion study of Tarextumab (OMP-59R5) in patients with solid tumors

Abstract

Purpose This Phase I trial evaluated the maximum tolerated dose, safety, pharmacokinetics, pharmacodynamics and preliminary efficacy of tarextumab (OMP-5948), a novel cross-reactive antibody which binds and selectively inhibits signaling via both Notch2 and Notch3, in adult patients with advanced malignancies. Methods Standard 3 + 3 design with tarextumab 0.5, 1, 2.5, or 5 mg/kg weekly, or 5, 7.5, or 10 mg/kg every other week, or 7.5 mg every 3 weeks. Dose-limiting toxicities (DLT) were assessed during the first 28 days. Results Forty-two patients received tarextumab (21 weekly, 15 every other week, 6 every three weeks). 2/6 subjects at the 5 mg/kg weekly dose, 2/3 at 10 mg/kg every other week, and 0/6 at 7.5 mg/kg every three weeks had a DLT. The maximum tolerated dose (MTD) was 2.5 mg/kg weekly, and 7.5 mg/kg on the every other and every three week schedules. Gastrointestinal (GI) toxicity was the most common adverse event with diarrhea (81%), fatigue (48%), nausea (45%), anorexia (38%), and vomiting (38%) and abdominal pain and constipation (24% each). Biomarker analysis showed regulation of stem cell and Notch gene signaling. Conclusion Tarextumab was generally well-tolerated at doses <2.5 mg weekly and 7.5 mg/kg every other and every third week. Diarrhea was dose-limiting above these levels, but relatively easily managed at lower doses. Inhibition of Notch pathway signaling was demonstrated at these doses. ClinicalTrials.gov Identifier: NCT01277146.

Keywords: Notch inhibition; Phase 1; Tarextumab.

Conflict of interest statement

At the time of the study Drs. Wang, Kapoun, Xu, Dupont and Stagg were employees of OncoMed. Dr. Dupont is currently employed by Genentech. Drs. Smith and Chugh are employees of the University of Michigan which has licensed intellectual property to OncoMed Pharmaceuticals and may receive royalties. Drs. Smith, Chugh, Patnaik, Papadopoulos and Tolcher reported that the research was funded at their institutions by OncoMed.

Figures

Fig. 1

Group mean concentration-time profiles. Data organized by nominal time; sample tested below LLOQ (lower limit of quantitation) were imputed to 1 μg/mL

Fig. 2

Stem cell and differentiation genes regulated in hair follicles by tarextumab treatment. Tarextumab significantly affected genes associated with cellular fate (KITLG, RGS14, ADAM23). RNAs were isolated from hair follicles (n = 19 pt). The y-axis represents gene expression at baseline and 28 days following treatment initiation. The pts. represented were dosed as follows: 0.5 mg/kg QW (n = 3), 1.0 mg/kg QW (n = 3), 2.5 mg/kg QW (n = 5), 5.0 mg/kg QW (n = 8)

Fig. 3

Effects of tarextumab treatment on Notch target gene expression in whole blood. Tarextumab significantly down-regulated expression of Notch pathway genes, HES1 and NEURL in whole blood. RNAs were isolated from whole blood from each of 38 patients. The y-axis represents gene expression at baseline (Day 0) and at various time points following treatment initiation (indicated along x-axis). The patients represented were dosed as follows: 0.5 mg/kg QW (n = 3), 1.0 mg/kg QW (n = 3), 2.5 mg/kg QW (n = 6), 5.0 mg/kg QW (n = 9)

Fig. 4

Tarextumab reduced Notch and stem cell signatures in biopsied tumors. Gene Set Enrichment Analysis (GSEA) showed tarextumab significantly affected gene expression associated with Notch signaling and stem cell genes in 3 paired tumor biopsies. a Heat map of fold change of gene expression ratios comparing post-treatment (day 35) with pre- treatment (day 0) samples. Gene set enrichment analysis demonstrated that (b) Notch target and (c) consensus cancer stem cell genes (CSC, Pubmed#21169407) were significantly down-regulated in the treated tumors post tarextumab treatment