Delving into the Latest Updates on Tarextumab with Synapse

The study consists of a Phase1b lead-in portion to determine the maximum tolerated dose (MTD) of OMP-59R5 in combination with nab-paclitaxel and gemcitabine followed by a Phase 2, multicenter, randomized, placebo-controlled portion to evaluate the efficacy and safety of OMP-59R5 in combination with nab-paclitaxel and gemcitabine in subjects with previously untreated stage IV pancreatic cancer.

Start Date01 Oct 2012

Sponsor / Collaborator

Mereo BioPharma 5, Inc.

NCT01859741

/ TerminatedPhase 1/2

A Phase 1b/2 Study of OMP-59R5 in Combination With Etoposide and Platinum Therapy in Subjects With Untreated Extensive Stage Small Cell Lung Cancer (PINNACLE)

The study consists of a Phase1b lead-in portion to determine the maximum tolerated dose (MTD) of OMP-59R5 (tarextumab) in combination with etoposide (EP) for 6 cycles followed a Phase 2, multi center, randomized, placebo-controlled portion comparing the efficacy and safety of OMP-59R5 in combination with EP for 6 cycles followed by single agent OMP-59R5 relative to EP alone for 6 cycles in subjects receiving first-line therapy for extensive stage small cell lung cancer.

Start Date07 Jan 2012

Sponsor / Collaborator-

NCT01277146

/ CompletedPhase 1

A Phase 1 Dose Escalation Study of OMP-59R5 in Subjects With Solid Tumors

This is an open-label Phase 1 dose escalation study of OMP-59R5 in subjects with previously treated solid tumors for which there is no remaining standard curative therapy and no therapy with a demonstrated survival benefit. Up to 44 subjects will be enrolled at up to 2 centers. Subjects will be assessed for safety, immunogenicity, pharmacokinetics, biomarkers, and efficacy. No formal interim analyses will be performed.
Prior to enrollment, subjects will undergo screening to determine study eligibility. Upon enrollment, subjects will receive intravenous (IV) infusions of OMP-59R5 at a assigned dosing schedule for 56 days. After 56 days, subjects will be assessed for disease status. If there is no evidence of disease progression or if the tumor is smaller, then subjects may continue to receive IV infusions of OMP-59R5 every week until disease progression.
Dose escalation will be conducted to determine the maximum tolerated dose (MTD). No dose escalation or reduction will be allowed within a dose cohort. The first 2 subjects enrolled in a cohort will not be treated on the same day. The dose may be administered at any time during the day. Three subjects will be treated at each dose level if no dose-limiting toxicities (DLTs) are observed. The first 2 subjects in each cohort will not be started on OMP-59R5 on the same day. If 1 of 3 subjects experiences a DLT, that dose level will be expanded to 6 subjects. If 2 or more subjects experience a DLT, no further subjects will be dosed at that level and 3 additional subjects will be added to the preceding dose cohort unless 6 subjects have already been treated at that dose level. Subjects will be assessed for DLTs from the time of the first dose through 28 days. Dose escalation for newly enrolled subjects, if appropriate, will occur after all subjects in a cohort have completed their Day 28 DLT assessment. Subjects with stable disease or a response at Day 56 will be allowed to continue to receive weekly doses of OMP-59R5 until disease progression. An additional 14 subjects will be enrolled at the highest dose level that result in <2 of the 6 subjects experiencing a DLT.

Start Date01 Dec 2010

Sponsor / Collaborator

Mereo BioPharma 5, Inc.

100 Clinical Results associated with Tarextumab

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100 Translational Medicine associated with Tarextumab

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100 Patents (Medical) associated with Tarextumab

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8

Literatures (Medical) associated with Tarextumab

01 Sep 2019·Cancer Medicine

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

Article

Author: Leach, Joseph W. ; LoConte, Noelle K. ; O'Reilly, Eileen M. ; Kapoun, Ann M. ; Holmgren, Eric ; Dupont, Jakob ; Yu, Kenneth H. ; Bendell, Johanna C. ; Strickler, John ; Patel, Ravindranath ; Hool, Hugo ; Hu, Zishuo Ian ; Ritch, Paul ; Sahai, Vaibhav ; Firdaus, Irfan ; Sanchez, James ; Sohal, Davendra P. S. ; Zhou, Lei ; Bullock, Andrea ; Wang‐Gillam, Andrea ; Hatoum, Hassan ; Picozzi, Vincent

AbstractPurposeNotch 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 MethodsAphase 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.ResultsMedian 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.ConclusionsThe 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 noNCT01647828.

15 Aug 2019·Investigational New DrugsQ3 · MEDICINE

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

Q3 · MEDICINE

Article

Author: Wang, Min ; Dupont, Jakob ; Kapoun, Ann M ; Stagg, Robert J ; Tolcher, Anthony ; Smith, David C ; Papadopoulos, Kyriakos P ; Patnaik, Amita ; Chugh, Rashmi ; Xu, Lu

SummaryPurpose 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.

01 May 2019·Clinical Cancer ResearchQ1 · MEDICINE

EGFR/Notch Antagonists Enhance the Response to Inhibitors of the PI3K-Akt Pathway by Decreasing Tumor-Initiating Cell Frequency

Q1 · MEDICINE

Article

Author: Li, Tian ; Yang, Yongji ; Shen, Yafeng ; Liu, Shuowu ; Ye, Xuting ; Fu, Wenyan ; Yu, Yue ; Lin, Fangxing ; Lei, Changhai ; Hu, Shi ; Tang, Ying ; Fan, Xiaoyan ; Ding, Min

AbstractPurpose:Both EGFR and PI3K-Akt signaling pathways have been used as therapeutically actionable targets, but resistance is frequently reported. In this report, we show that enrichment of the cancer stem cell (CSC) subsets and dysregulation of Notch signaling underlie the challenges to therapy and describe the development of bispecific antibodies targeting both HER and Notch signaling.Experimental Design:We utilized cell-based models to study Notch signaling in drug-induced CSC expansion. Both cancer cell line models and patient-derived xenograft tumors were used to evaluate the antitumor effects of bispecific antibodies. Cell assays, flow cytometry, qPCR, and in vivo serial transplantation assays were employed to investigate the mechanisms of action and pharmacodynamic readouts.Results:We found that EGFR/Notch targeting bispecific antibodies exhibited a notable antistem cell effect in both in vitro and in vivo assays. Bispecific antibodies delayed the occurrence of acquired resistance to EGFR inhibitors in triple-negative breast cancer cell line–based models and showed efficacy in patient-derived xenografts. Moreover, the EGFR/Notch bispecific antibody PTG12 in combination with GDC-0941 exerted a stronger antitumor effect than the combined therapy of PI3K inhibitor with EGFR inhibitors or tarextumab in a broad spectrum of epithelial tumors. Mechanistically, bispecific antibody treatment inhibits the stem cell–like subpopulation, reduces tumor-initiating cell frequency, and downregulates the mesenchymal gene expression.Conclusions:These findings suggest that the coblockade of EGFR and Notch signaling has the potential to increase the response to PI3K inhibition, and PTG12 may gain clinical efficacy when combined with PI3K blockage in cancer treatment.

1

News (Medical) associated with Tarextumab

17 Apr 2017

·www.biospace.com

When It Rains, It Pours: Bay Area’s OncoMed Tanks Again as Lung Cancer Med Fails Phase II, Discontinues Phase I Study

April 17, 2017 By Alex Keown , BioSpace.com Breaking News Staff REDWOOD CITY, Calif. – Shares of OncoMed Pharmaceuticals are down more than 18 percent this morning after the company announced its mid-stage combination lung cancer treatment failed to meet endpoints. OncoMed said tarextumab (anti-Notch2/3, OMP-59R5) in combination with etoposide and a chemotherapy drug to treat patients with extensive-stage small cell lung cancer showed results that were “undifferentiated from those of chemotherapy plus placebo.” As a result, the company said the trial did not meet primary endpoints of progression-free survival, nor secondary endpoints of overall survival. The median progression-free survival for tarextumab plus chemotherapy was 5.6 months versus 5.5 months for chemotherapy plus placebo. Overall response rates were 68.5 percent and 70.8 percent in the tarextumab and placebo arms respectively, the company said. Tarextumab (anti-Notch2/3, OMP-59R5) is a fully human monoclonal antibody that targets the Notch2 and Notch3 receptors. The drug is part of OncoMed’s collaboration with GlaxoSmithKline . Small cell lung cancer is expected to make up between 10 and 15 percent of the 224,390 newly diagnosed lung cancer cases and the 158,080 deaths estimated to occur in the U.S. Current standard of care in treating small cell lung cancer is the chemotherapeutic etoposide in combination with either cisplatin or carboplatin. “Small cell lung cancer is a very difficult-to-treat disease and unfortunately, tarextumab did not show benefit over placebo in this Phase 2 trial,” Paul Hastings , OncoMed’s chairman and chief executive officer said in a statement. Additionally, OncoMed said it will discontinue enrollment in the Phase 1b clinical trial of brontictuzumab (anti-Notch1, OMP-52M51) in combination with trifluridine/tipiracil (Lonsur) in third-line colorectal cancer patients. The combination of brontictuzumab plus chemotherapy was not tolerable in this patient population. April has not been kind to OncoMed. On April 10, the company announced its partnership with Bayer to develop two drugs, vantictumab and ipafricept , both Wnt pathway inhibitors, had ended due to “strategic reasons.” With Bayer’s withdrawal, OncoMed retains worldwide rights to both drugs. Also on April 10, the company announced it was terminating a Phase II trial testing demcizumab in combination with Abraxane as a first-line treatment in metastic pancreatic cancer after the drug failed to meet endpoints. Due to the events announced today and last week, Hastings said the company will undergo an immediate comprehensive portfolio prioritization review. “The immediate task ahead is to thoroughly examine the available data, our resources and the opportunities to re-focus our efforts. We ended the first quarter of 2017 with $156.9 million in cash and short-term investments,” Hastings said.

Phase 2Clinical ResultPhase 1Phase 3Clinical Trial Failure

100 Deals associated with Tarextumab

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D11775	Tarextumab	-	DB12104

R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Pancreatic Cancer	Phase 2	-	GSK Plc	-
Small Cell Lung Cancer	Phase 2	-	GSK Plc	-
Extensive stage Small Cell Lung Cancer	Preclinical	United States	-	07 Jan 2012

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT01647828 (ALPINE, CTgov)	Phase 1/2	Pancreatic Cancer	217	OMP-59R5+Gem (P1B: OMP-59R5 2.5 mg/kg + Gem)	ackuwkohtz(sgdrlsvbyk) = sxdrdasubz yiejetyski (ukgaxrzhab, vacahausvi - cjvjxxnsnb) View more	-	15 Feb 2023
				OMP-59R5+Gem (P1B: OMP-59R5 5 mg/kg + Gem)	ackuwkohtz(sgdrlsvbyk) = vkaeymjgsq yiejetyski (ukgaxrzhab, abiatfugts - xabzgjbhnm) View more
NCT01647828 (Pubmed) Manual	Phase 2	Metastatic Pancreatic Cancer First line	-	nab-paclitaxel+gemcitabine+tarextumab	(jrqdsdfohz) = zlrpaiqpys odslpyvmfu (ocbfppbesl ) View more	Negative	01 Sep 2019
				nab-paclitaxel+gemcitabine+Placebo	(jrqdsdfohz) = evmrpdcpjo odslpyvmfu (ocbfppbesl ) View more
NCT01277146 (Pubmed \| Invest New Drugs)	Phase 1	Solid tumor	42	Tarextumab 0.5 mg/kg	vuvyegrxbc(dcqvcikuyo) = tzyhzuumyc htplfrhiyq (ecckukcntz ) View more	-	01 Aug 2019
				Tarextumab 1 mg/kg	vuvyegrxbc(dcqvcikuyo) = tpcxyjlhme htplfrhiyq (ecckukcntz ) View more
NCT01859741 (PINNACLE, CTgov)	Phase 1/2	Extensive stage Small Cell Lung Cancer	172	ETO+OMP-59R5 (P1B: OMP-59R5 5mg/kg + ETO + CIS)	adjwoyoymt(etiwcfrscu) = eidwhxspdk cshtmiioyx (gwmcbhzpfo, qvypgzchgl - ewakfexbiv) View more	-	01 May 2019
				ETO+OMP-59R5 (P1B: OMP-59R5 7.5 mg/kg + ETO + CIS)	adjwoyoymt(etiwcfrscu) = iwgydenmxq cshtmiioyx (gwmcbhzpfo, cvrudwuyad - dupfnrvikw) View more
NCT01859741 (PINNACLE, GlobeNewswire) Manual	Phase 2	Small Cell Lung Cancer First line	145	Chemotherapy+Tarextumab	(rhcmgcmqtg) = umiwxbkami valcnyhvbb (oejuvekfrj ) View more	Negative	17 Apr 2017
				Chemotherapy+Placebo	(rhcmgcmqtg) = urbtlouess valcnyhvbb (oejuvekfrj ) View more
NCT01859741 (ASCO2016)	Phase 1	Extensive stage Small Cell Lung Cancer	27	Tarextumab + Etoposide + Cisplatin	etcyjbrega(hbnvpdgzbu) = 22.2% dxmqvcnvfn (mhsmuezefp ) View more	Positive	20 May 2016
				Tarextumab + Etoposide + Carboplatin
NCT01859741 (ASCO2015)	Phase 1/2	Extensive stage Small Cell Lung Cancer	27	Tarextumab (TRXT) with EP	(sohmwqekuo) = ifmcdiloll xqsdtctomt (awrbbiiiuk ) View more	-	20 May 2015
NCT01647828 (ASCO_GI2015)	Phase 1/2	Metastatic Pancreatic Cancer	40	Tarextumab 15 mg/kg	(ksypopedif) = yozmczzzce lmzmfpsyww (iuzzpzqccy ) View more	-	20 Jan 2015
NCT01647828 (ASCO_GI2014)	Phase 1/2	Metastatic Pancreatic Cancer	24	OMP-59R5	(zpzqkiwaqm) = ihopxqkbmc zbemvyttvn (xkdqjyewdw ) View more	-	20 Jan 2014
				Nab-P+Gem	(ltevcpccwh) = tfckzcuzwp lwwciccann (itdsqmnvkc )

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