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).

O'Reilly, Eileen Mary; Smith, Lon; Bendell, Johanna C.; Strickler, John H.; Zalupski, Mark M.; Gluck, William Larry; Kapoun, Ann M.; Yen, Wan-Ching; Xu, Lu; Hill, Dawn; Zhou, Lei; Dupont, Jakob; Cohn, Allen Lee

doi:10.1200/jco.2015.33.3_suppl.278

Cited by 11 publications

(11 citation statements)

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“…Preliminary results from the phase 1B trial demonstrated significant activity of a 15 mg/kg dose of tarextumab combined with standard doses of gemcitabine and nab-paclitaxel. The reported median time of progression-free survival was 5.6 months, and median time of overall survival was 11.6 months; 38% of this patient population had a response to the 3-drug combination, and response rate was even higher in the small number of patients whose tumors expressed high levels of NOTCH3 117 .…”

Section: Genetic Alterations As Therapeutic Targetsmentioning

confidence: 91%

Genetic Diversity of Pancreatic Ductal Adenocarcinoma and Opportunities for Precision Medicine

et al. 2016

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Patients with pancreatic ductal adenocarcinoma (PDA) have a poor prognosis-in spite of new treatments, approximately 7% survive for 5 years. Although there have been advances in systemic, primarily cytotoxic, therapies, it has been a challenge to treat patients with PDA using targeted therapies. Sequence analyses have provided a wealth of information about the genetic features of PDA and identified potential therapeutic targets. Preclinical and early-phase clinical studies have found specific pathways could be rationally targeted; it might also be possible to take advantage of the genetic diversity of PDAs to develop therapeutic agents. The genetic diversity and instability of PDA cells have long been thought of as obstacles to treatment, but now are considered exploitable features. We review the latest findings in pancreatic cancer genetics and the promise of targetedapproaches in pancreatic ductal adenocarcinoma therapy.Pancreatic ductal adenocarcinoma (PDA) is the most common type of pancreatic cancer 1 . The disease encompasses multiple histological subtypes, which affect patients' prognoses 2 . For example, patients with adenosquamous cancers have particularly poor outcomes, whereas mucinous neoplasms are generally lower grade and are considered to be a less aggressive form of the disease 3,4 . Irrespective, most cases of PDA are a challenge to treat, with 5 year rates of survival lower than 10% for patients with cancers of all stages 1 . To put * CORRESPONDENCE, Erik Knudsen, PHD, UTSW, Dallas TX, erik.knudsen@utsouthwestern.edu, Agnieszka Witkiewicz, UTSW, Dallas TX, agnes.witkiewicz@utsouthwestern.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. DISCLOSURES:EK: Research funding and advisory: Pfizer, Eli Lilly EO: Reseach funding: OncoMed, Celgene, Sanofi-Aventis, Astra-Zeneca, Bristol Myers Squibb, Incyte Pharmaceuticals JB: Advisory: Perthera AW: N/A HHS Public Access Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript this into perspective, it has been estimated that by 2020 that PDA will become the 2 nd leading cause of cancer-related death in the United States 5 .Most PDA is identified at a late stage, when surgical intervention is not possible. Even with complete resection and negative results from analyses of tumor margins, long-term survival after surgery is poor-tumors recur in virtually all patients 6 . Presumably, this is because micrometastases are present, even in patients whose disease appears confined to the pancreas. These features of the disease have driven the need for systemic treatments to control disseminated dise...

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Section: Genetic Alterations As Therapeutic Targetsmentioning

confidence: 91%

Genetic Diversity of Pancreatic Ductal Adenocarcinoma and Opportunities for Precision Medicine

et al. 2016

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“…In view of the encouraging preclinical findings, early phase trials were initiated in metastatic PDAC and extensive stage small cell lung cancer. Results from both phase Ib clinical trials were potentially promising, with reported response rates of 84% and 74% in the small cell lung and pancreatic cancer trials, respectively . Analysis of the phase Ib clinical trial in PDAC demonstrated a PFS of 5.6 months and OS of 11.6 months in patients treated with tarextumab in combination with gemcitabine and nab‐paclitaxel.…”

Section: Discussionmentioning

confidence: 99%

“…Diarrhea, fatigue, and anemia were the most common tarextumab‐related toxicities, and the events were mostly Grade 1 or 2. The overall response rate (CR + PR) was 29% . The median PFS and OS were 5.6 and 11.6 months, respectively.…”

Section: Introductionmentioning

confidence: 95%

A randomized phase II trial of nab‐paclitaxel and gemcitabine with tarextumab or placebo in patients with untreated metastatic pancreatic cancer

Bendell

Bullock

et al. 2019

Cancer Medicine

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Purpose Notch signaling dysregulation is implicated in the development of pancreatic adenocarcinoma (PDAC). Tarextumab is a fully human IgG2 antibody that inhibits Notch2/3 receptors. Patients and Methods Aphase 2, randomized, placebo‐controlled, multicenter trial evaluated the activity of tarextumab in combination with nab‐paclitaxel and gemcitabine in patients with metastatic PDAC. Patients were stratified based on ECOG performance score and Ca 19‐9 level and randomized 1:1 to nab‐paclitaxel, gemcitabine with either tarextumab or placebo. Based on preclinical and phase Ib results suggesting a positive correlation between Notch3 gene expression and tarextumab anti‐tumor activity, patients were also divided into subgroups of low, intermediate, and high Notch3 gene expression. Primary endpoint was overall survival (OS) in all and in patients with the three Notch3 gene expression subgroups (≥25th, ≥50% and ≥75% percentiles); secondary end points included progression‐free survival (PFS), 12‐month OS, overall response rate (ORR), and safety and biomarker investigation. Results Median OS was 6.4 months in the tarextumab group vs 7.9 months in the placebo group (HR = 1.34 [95% CI = 0.95, 1.89], P = .0985). No difference observed in OS in the Notch3 gene expression subgroups. PFS in the tarextumab‐treated group (3.7 months) was significantly shorter compared with the placebo group (5.5 months) (hazard ratio was 1.43 [95% CI = 1.01, 2.01]; P = .04). Grade 3 diarrhea and thrombocytopenia were more common in the tarextumab group. Conclusions The addition of tarextumab to nab‐paclitaxel and gemcitabine did not improve OS, PFS, or ORR in first‐line metastatic PDAC, and PFS was specifically statistically worse in the tarextumab‐treated patients. Clinical trial registry no NCT01647828.

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“…Table 2 outlines current new drug discovery efforts against these key signal transduction pathways [11,47,73,[89][90][91][92][93][94].…”

Section: Molecular Signaling In Cscsmentioning

confidence: 99%

Cancer stem cells: a challenging paradigm for designing targeted drug therapies

Khan

Alkarim

Bora

et al. 2015

Drug Discovery Today

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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).

Cited by 11 publications

References 0 publications

Genetic Diversity of Pancreatic Ductal Adenocarcinoma and Opportunities for Precision Medicine

Genetic Diversity of Pancreatic Ductal Adenocarcinoma and Opportunities for Precision Medicine

A randomized phase II trial of nab‐paclitaxel and gemcitabine with tarextumab or placebo in patients with untreated metastatic pancreatic cancer

Cancer stem cells: a challenging paradigm for designing targeted drug therapies

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