Tarextumab Research Articles

Results of a randomized phase II trial of an anti-notch 2/3, tarextumab (OMP-59R5, TRXT, anti-Notch2/3), in combination with nab-paclitaxel and gemcitabine (Nab-P+Gem) in patients (pts) with untreated metastatic pancreatic cancer (mPC).

279 Background: Tarextumab (TRXT), fully human IgG2 antibody inhibits signaling of Notch2/ 3 receptors. Tumor regression seen in Notch3 (N3) expressing pt-derived pancreatic cancer xenografts when TRXT combined with Nab-P+Gem. Phase 2, randomized, placebo-controlled trial conducted to evaluate efficacy, safety of combination in mPC. Methods: Pts randomized 1:1 to TRXT or placebo (PL). TRXT given IV at 15 mg/kg q 2wks (D 1, 15), nab-P 125 mg/m2, GEM 1000mg/m2 on D1, 8, 15 q 28 days. Tissue for N3 gene expression determination was required. Primary endpoints: overall survival (OS) in all and in 3 subgroups determined by Notch 3 gene expression. Secondary: safety, progression-free survival (PFS) and overall response rate (ORR). Results: N = 177 pts randomized. Performance status (0 or 1), CA19-9 stratum (0 – ULN, > ULN – 59ULN, ≥ 59ULN) balanced. Clinical trial information: NCT01647828. . Conclusions: Addition of TRXT to Nab-P+Gem did not improve OS in 1st line mPC. A potential detrimental effect on PFS and ORR was seen in subjects with N3 < 25%ile.[Table: see text]

Final results of phase Ib of tarextumab (TRXT, OMP-59R5, anti-Notch2/3) in combination with etoposide and platinum (EP) in patients (pts) with untreated extensive-stage small-cell lung cancer (ED-SCLC).

7508 Background: Notch signaling is implicated in cancer stem cell self-renewal and proliferation; thus being an appealing target in the treatment of SCLC. Tarextumab (TRXT), a fully human IgG2 ant...

Final results of phase Ib of anticancer stem cell antibody tarextumab (OMP-59R5, TRXT, anti-Notch 2/3) in combination with nab-paclitaxel and gemcitabine (Nab-P+Gem) in patients (pts) with untreated metastatic pancreatic cancer (mPC).

278 Background: Tarextumab (TRXT), fully human IgG2 antibody, inhibits signaling Notch 2, 3 receptors. Tumor regression seen in Notch 3 patient-derived PC xenografts when TRXT added to Nab-P+Gem. The maximum tolerated dose (MTD) of single agent TRXT was 7.5mg/kg every other week (Smith, EORTC 2012); the main dose limiting toxicity (DLT) was Grade 3 diarrhea. This study evaluates MTD, pharmacokinetics (PK), pharmacodynamics (PD) and early efficacy of TRXT + Nab-P+Gem in mPC. Methods: Cohorts of 3-6 pts treated at 6 dose levels of TRXT. TRXT IV Days 1 + 15 with GEM 1000mg/m2 alone (first two cohorts) or nab-P 125 mg/m2 and GEM 1000mg/m2on Days 1, 8, 15 of every 28-day cycle. Biomarker analysis of surrogate tissue and tumor undertaken. Results: By 08/22/14, N= 40 treated. TRXT 15 mg/kg selected as Phase 2 dose. 1 DLT Grade 3 diarrhea in 15 mg/kg cohort. Frequently reported (≥15%) TRXT adverse events(AEs) were: diarrhea(60%), fatigue(43%), anemia(28%), decreased appetite (18%) and nausea(15%); most grade 1 or 2 and managed supportively. Other AEs (≥ 30%) were: cytopenia, alopecia, vomitng and peripheral edema. GEM or Nab-P+Gem did not alter PK of TRXT. Notch pathway-related genes, HEYL, HES2, NOTCH2 and cancer stem cell markers were altered in hair follicles at TRXT > 7.5 mg/kg combined with Nab-P+Gem. Plasma, blood RNA biomarkers were also modulated by TRXT + Nab-P+Gem. Conclusions: TRXT + Nab-P+ Gem is well tolerated. 15 mg/kg is the selected Phase 2 dose of TRXT. Encouraging anti-tumor activity was observed. Final safety, efficacy, PK and PD results in surrogate and serial tumor tissues will be presented. The Phase 2 randomized, placebo-controlled ALPINE study is underway. Clinical trial information: NCT01647828. [Table: see text]

465 Biomarker analysis in Phase 1b study of anti-cancer stem cell antibody Tarextumab (TAR) in combination with nab-paclitaxel and gemcitabine (Nab-P+Gem) demonstrates pharmacodynamic (PD) modulation of the Notch pathway in patients (pts) with untreated metastatic pancreatic cancer (mPC)

a whole genome gene expression array as well as different technologies for protein expression and protein phosphorylation with an emphasis on the epidermal growth factor receptor (EGFR)-pathway. Results: In this study, we demonstrated that surgery, vascular clamping and subsequent processing had a significant impact on the expression of genes and the expression and the phosphorylation status of proteins. The gene expression profiling showed a high variability between patients. Significant changes of expression in individual patients occurred in up to 690 genes in normal tissue (mean 118 genes) and in up to 4,116 genes in primary cancer tissue (mean 1,553 genes) comparing presurgery and ischemia time points postsurgery. Clinically highly relevant was the finding that expression of EGFR-pathway proteins and, in particular, their phosphorylation status is affected by surgery and postsurgical tissue processing. For example, the expression level of EGFR changed more then 2-fold in cancer tissue of 30% of the patients. Conclusion: An understanding of tissue data variability in relation to processing techniques during and postsurgery is mandatory when testing surgical specimens in the context of clinical diagnostics, drug development, or identification of predictive biomarkers. To obtain reliable expression data, tissue processing for research and diagnostic purposes needs to be highly standardized. Alterations in molecular patterns due to ischemia, identified in this study have to be analyzed with caution in research and development programs.