A Phase 1b Dose Escalation Study of OMP-54F28 in Combination With Paclitaxel and Carboplatin in Patients With Recurrent Platinum-Sensitive Ovarian Cancer

This is an open-label Phase 1b dose-escalation study to assess the safety, tolerability, and PK of OMP-54F28 when combined with paclitaxel and carboplatin. OMP-54F28 will be administered IV on Days 1 of each 21-day cycle. Paclitaxel (175 mg/m2) and carboplatin (AUC = 5 mg/mL • min) will be administered IV on Day 1 of each cycle. A total of 6 cycles of paclitaxel and carboplatin will be given. Additional cycles may be given as per institutional standard of care after discussion with the Medical Monitor. Treatment with OMP-54F28 will continue after completion of treatment with paclitaxel and carboplatin. The planned dose levels of OMP-54F28 are 5 and 10 mg/kg.

开始日期2014-01-01

申办/合作机构

Mereo BioPharma 5, Inc.

NCT02069145

/ Completed临床1期

A Phase 1b Dose Escalation Study of OMP-54F28 in Combination With Sorafenib in Patients With Hepatocellular Cancer

This is an open-label Phase 1b dose-escalation study to assess the safety, tolerability, and PK of OMP-54F28 when combined with sorafenib. OMP-54F28 will be administered IV on Day 1 of each 21-day cycle. The planned dose levels of OMP-54F28 are 5 and 10 mg/kg. Depending on safety in this study, additional lower or intermediate dose levels may be evaluated.

开始日期2014-01-01

申办/合作机构

Mereo BioPharma 5, Inc.

NCT02050178

/ Completed临床1期

A Phase 1b Dose Escalation Study of OMP-54F28 in Combination With Nab-Paclitaxel and Gemcitabine in Patients With Previously Untreated Stage IV Pancreatic Cancer

This is an open-label Phase 1b dose-escalation study to assess the safety, tolerability, and PK of OMP-54F28 when combined with nab-paclitaxel and gemcitabine. OMP-54F28 will be administered IV on Days 1 and 15 of each 28-day cycle. Nab-paclitaxel (125 mg/m2) and gemcitabine (1000 mg/m2) will be administered IV on Days 1, 8, and 15 of each cycle. The planned dose levels of OMP-54F28 are 3.5 mg/kg and 7.0 mg/kg.

开始日期2013-11-01

申办/合作机构

Mereo BioPharma 5, Inc.

100 项与 Ipafricept 相关的临床结果

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100 项与 Ipafricept 相关的转化医学

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100 项与 Ipafricept 相关的专利（医药）

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项与 Ipafricept 相关的文献（医药）

2020-10-15·Clinical cancer research : an official journal of the American Association for Cancer Research1区 · 医学

Phase Ib Study of Wnt Inhibitor Ipafricept with Gemcitabine and nab-paclitaxel in Patients with Previously Untreated Stage IV Pancreatic Cancer

1区 · 医学

Article

作者: Weekes, Colin ; Cohen, Steven J. ; Cardin, Dana B. ; Shahda, Safi ; Brachmann, Rainer K. ; Dotan, Efrat ; Messersmith, Wells ; Denlinger, Crystal S. ; Kapoun, Ann M. ; Astsaturov, Igor ; Stagg, Robert J. ; Lenz, Heinz-Josef ; O'Neil, Bert ; Uttamsingh, Shailaja

Abstract:

Purpose::

The recombinant fusion protein ipafricept blocks Wnt signaling, and in combination with gemcitabine and nab-paclitaxel caused tumor regression in xenografts. This phase Ib study evaluated the combination of ipafricept with nab-paclitaxel + gemcitabine in patients with untreated metastatic pancreatic adenocarcinoma (mPDAC).

Patients and Methods::

Dose escalation started with standard dose nab-paclitaxel + gemcitabine and ipafricept (3.5 mg/kg days 1, 15). Because of fragility fractures seen with different anti-Wnt agents, following cohorts had ≥6 patients treated with ipafricept 3 to 5 mg/kg on day 1, and included bone marker monitoring and prophylactic bisphosphonates as indicated. On the basis of preclinical data, sequential dosing was evaluated in cohort 4 (ipafricept day 1 followed nab-paclitaxel + gemcitabine day 3). Objectives included safety, MTD, recommended phase II dose, pharmacokinetics, immunogenicity, pharmacodynamics, and efficacy.

Results::

A total of 26 patients were enrolled, five in cohort 1 and seven each in cohorts 2–4. ipafricept-related adverse events (AEs) of any grade included fatigue, nausea, vomiting, anorexia, and pyrexia. ipafricept-related AEs grade ≥3 included two events of aspartate aminotransferase elevation, and one each of nausea, rash, vomiting, and leucopenia. No dose-limiting toxicities or fragility fractures were observed. Nine patients (34.6%) had partial response, 12 (46.2%) stable disease as best response, with clinical benefit rate of 81%. Median progression-free survival was 5.9 m [95% confidence interval (CI), 3.4–18.4], median overall survival was 9.7 m (95% CI, 7.0–14). The study was terminated by the sponsor due to bone-related toxicity within this therapeutic program and concerns for commercial viability. One patient remains on therapy under compassionate use.

Conclusions::

Ipafricept can be administered with nab-paclitaxel + gemcitabine with reasonable tolerance. Wnt pathway remains a therapeutic target of interest in mPDAC.

2020-03-16·Oncology research2区 · 医学

Frizzled Receptors in Tumors, Focusing on Signaling, Roles, Modulation Mechanisms, and Targeted Therapies

2区 · 医学

Review

作者: Wang, Wei ; Zhao, Chenghai ; Sun, Yu

Wnt molecules play crucial roles in development and adult homeostasis through their receptors Frizzled proteins (Fzds). Fzds mediate canonical -catenin pathway and various noncanonical -catenin-independent pathways. Aberrant Fzd signaling is involved in many diseases including cancer. Wnt/-catenin is a well-established oncogenic pathway involved in almost every aspect of tumor development. However, Fzd-mediated noncanonical Wnt pathways function as both tumor promoters and tumor suppressors depending on cellular context. Fzd-targeted therapies have proven to be effective on cultured tumor cells, tumor cell xenografts, mouse tumor models, and patient-derived xenografts (PDX). Moreover, Fzd-targeted therapies synergize with chemotherapy in preclinical models. However, the occurrence of fragility fractures in patients treated with Fzd-targeted agents such as OMP-54F28 and OMP-18R5 limits the development of this combination. Along with new insights on signaling, roles, and modulation mechanisms of Fzds in human tumors, more Fzd-related therapeutic targets will be developed.

2019-03-01·Molecular carcinogenesis2区 · 医学

Wnt signaling dynamics in head and neck squamous cell cancer tumor‐stroma interactions

2区 · 医学

Article

作者: Gomez, Karina E. ; Keysar, Stephen B. ; Wang, Xiao‐Jing ; Jackson, Brian C. ; Jimeno, Antonio ; Miller, Bettina ; Somerset, Hilary L. ; Nieto, Cera ; Morton, John J. ; Reisinger, Julie ; Chimed, Tugs‐Saikhan ; Eagles, Justin R. ; Le, Phuong N.

Wnt pathway activation maintains the cancer stem cell (CSC) phenotype and promotes tumor progression, making it an attractive target for anti‐cancer therapy. Wnt signaling at the tumor and tumor microenvironment (TME) front have not been investigated in depth in head and neck squamous cell carcinoma (HNSCC). In a cohort of 48 HNSCCs, increased Wnt signaling, including Wnt genes (AXIN2, LGR6, WISP1) and stem cell factors (RET, SOX5, KIT), were associated with a more advanced clinical stage. Key Wnt pathway proteins were most abundant at the cancer epithelial‐stromal boundary. To investigate these observations, we generated three pairs of cancer‐cancer associated fibroblast (CAF) cell lines derived from the same HNSCC patients. 3D co‐culture of cancer spheres and CAFs mimicked these in vivo interactions, and using these we observed increased expression of Wnt genes (eg, WNT3A, WNT7A, WNT16) in both compartments. Of these Wnt ligands, we found Wnt3a, and less consistently Wnt16, activated Wnt signaling in both cancer cells and CAFs. Wnt activation increased CSC characteristics like sphere formation and invasiveness, which was further regulated by the presence of CAFs. Time lapse microscopy also revealed preferential Wnt activation of cancer cells. Wnt inhibitors, OMP‐18R5 and OMP‐54F28, significantly reduced growth of HNSCC patient‐derived xenografts and suppressed Wnt activation at the tumor epithelial‐stromal boundary. Taken together, our findings suggest that Wnt signaling is initiated in cancer cells which then activate CAFs, and in turn perpetuate a paracrine signaling loop. This suggests that targeting Wnt signaling in the TME is essential.

项与 Ipafricept 相关的新闻（医药）

2017-04-17

·BioSpace

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.

临床2期临床结果临床1期临床3期临床失败

2014-09-04

·BioSpace

Redwood City’s OncoMed Pharmaceuticals, Inc. Moves Forward On Drug Trials Halted Due To Side Effects

September 5, 2014 By Krystle Vermes , BioSpace.com Breaking News Staff California-based OncoMed Pharmaceuticals, Inc. announced today that the U.S. Food and Drug Administration has removed the partial hold on its ipafricept Phase 1 clinical trials. As a result, OncoMed will continue enrollment, and patients will begin participating in experiments within the next few weeks. “With important input from our clinical investigators and academic bone experts, the OncoMed team has developed modified study parameters intended to avoid potential risks while allowing us to evaluate the therapeutic impact of ipafricept for patients with pancreatic, hepatocellular and ovarian cancers in combination with standard therapy,” said Jakob Dupont , M.D., OncoMed’s Chief Medical Officer. “We appreciate the FDA’s prompt response to our submission and their acceptance of our proposed amendments to the trial protocols.” OncoMed gave the FDA a clinical safety and efficacy package for the drug. In turn, the FDA placed the partial clinical trial on hold. Modified dosing regimens, risk mitigation measures and modified enrollment criteria were the amendments of the Phase 1b trials. On June 13, OncoMed announced that it would voluntarily be halting enrollment in its Phase 1 vantictumab and ipafricept Wnt pathway programs. This came after reported incidents of mild-to-moderate bone adverse events. After the FDA looked at more data and amended study protocols given to it by OncoMed, it decided to remove the partial hold on the clinical trials. “We expect enrollment in our first-in-class Wnt pathway programs, ipafricept and vantictumab, to be back underway soon,” said Paul J. Hastings , Chairman and Chief Executive Officer of OncoMed. “The Wnt pathway represents a highly promising target for disrupting cancer stem cell activity and inducing tumor differentiation. As we advance ipafricept and vantictumab through clinical studies in combination with standard of care, we expect to generate key data from these Phase 1b studies that will support a potential opt-in by our partner Bayer as well as late-stage clinical development.” Ipafricept is a fusion protein that inhibits a signaling pathway in cancer called the Wnt pathway. It binds to ligands that are activators in Wnt signaling. Patients who received ipafricept in a Phase 1a study tolerated the treatment well, and experimentations showed that the fusion protein demonstrated on-target Wnt pathway modulation. OncoMed Pharmaceuticals is dedicated to discovering and developing therapeutics that target cancer stem cells. The company has five anti-cancer products in clinical development. var switchTo5x=true; stLight.options({publisher: "0341611e-38a4-415d-9e18-75e093ff27e0", doNotHash: false, doNotCopy: false, hashAddressBar: false});

临床1期

100 项与 Ipafricept 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D11758	-	-	DB15045

研发状态

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适应症	最高研发状态	国家/地区	公司	日期
铂敏感性卵巢癌	临床1期	美国	Mereo BioPharma 5, Inc.	2014-01-01
肝细胞癌	临床1期	美国	Mereo BioPharma 5, Inc.	2014-01-01
胰腺癌	临床1期	美国	Mereo BioPharma 5, Inc.	2013-11-01
前列腺癌	临床1期	美国	Bayer AG	2012-06-01
卵巢癌	临床1期	美国	Bayer AG	2012-06-01

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适应症

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT02050178 (Pubmed \| Clin Cancer Res) 人工标引	临床1期	胰腺癌一线	26	Gemcitabine+nab-paclitaxel+Ipafricept	鑰窪構鹽選遞糧衊艱襯(膚窪網壓廠壓膚醖廠壓) = 簾鬱憲築築淵壓餘觸願鏇願選餘觸壓構醖鹽鏇 (範範繭鏇夢鹽築鹽選簾, 3.4 ~ 18.4) 更多	不佳	2020-10-15
NCT02092363 (Pubmed \| Obstet Gynecol Surv) 人工标引	临床1期	铂敏感性卵巢癌	37	paclitaxel+carboplatin+ipafricept	襯襯蓋觸鹽餘憲製淵觸(鏇鏇獵膚簾鬱淵窪餘夢) = 鏇製淵積鏇構築窪鏇顧窪夢醖鬱衊鏇餘廠鑰觸 (網壓鏇鑰廠廠壓繭淵選 ) 更多	积极	2019-08-01
NCT02050178 (ASCO_GI2019)	临床1期	胰腺癌	26	Ipafricept + Nab-P/G	積範鏇鏇遞網醖獵廠襯(壓願製觸餘積糧顧範夢) = included 2 events of AST elevation, and 1 each of nausea, maculopapular rash, vomiting and WBC decrease 顧齋鹹鹹憲醖築壓積醖 (繭範獵製願遞繭艱鹹淵 ) 更多	积极	2019-01-29
NCT01608867 (Pubmed) 人工标引	临床1期	HR阳性/HER2低表达实体瘤	26	Ipafricept	顧獵觸顧夢齋觸襯齋製(窪獵簾鹹製衊觸淵衊積) = 15 mg/kg；Q3W 醖鬱鑰夢壓壓簾願壓膚 (窪膚鬱襯製艱構廠築膚 ) 更多	积极	2017-12-15
AACR2014	临床1期	肝细胞癌 \| 卵巢癌	-	OMP-54F28	選憲鬱簾網壓遞鹽窪顧(鬱製衊廠遞簾範願選觸) = induction 簾壓獵夢窪繭鹹蓋願醖 (遞壓醖鹽範簾製蓋製願 ) 更多	积极	2014-10-01
AACR2014	临床1期	肝细胞癌 \| 卵巢癌	-	OMP-54F28 + Sorafenib		积极	2014-10-01
NCT01608867 (ASCO2014)	临床1期	HR阳性/HER2低表达实体瘤	25	OMP-54F28	積構淵鬱網淵憲網獵積(鹽簾廠觸鑰築醖壓網膚) = 積製繭窪蓋顧選獵廠築製製築網廠夢襯獵鏇製 (醖廠齋範觸鬱襯糧衊鏇 ) 更多	-	2014-05-20