A Phase I/II, Two-Part, Multicenter Study to Evaluate the Safety and Efficacy of M402 in Combination With Nab-Paclitaxel and Gemcitabine in Patients With Metastatic Pancreatic Cancer

People with primary metastatic pancreatic cancer will be treated with nab-paclitaxel and gemcitabine in combination with an investigational agent called necuparanib (M402). It is made from heparin, which is a well known blood thinner. Blood thinners have been shown in prior animal and human studies to have anti-cancer effects. Necuparanib has been re-engineered from heparin to have much lower blood thinning activity while keeping the anti-tumor activity. The investigators are testing whether necuparanib administered in combination with nab-paclitaxel and gemcitabine may be more effective than nab-paclitaxel and gemcitabine.

开始日期2012-05-01

申办/合作机构

Momenta Pharmaceuticals, Inc.

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100 项与 Necuparanib Sodium 相关的转化医学

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项与 Necuparanib Sodium 相关的文献（医药）

2020-06-01·European journal of cancer (Oxford, England : 1990)1区 · 医学

Randomised phase II trial of gemcitabine and nab-paclitaxel with necuparanib or placebo in untreated metastatic pancreas ductal adenocarcinoma

1区 · 医学

Article

作者: Yu, Kenneth H ; Krause, Silva ; Shao, Spencer H ; Barone, Diletta ; Roach, James M ; Richards, Donald A ; Ryan, David P ; Bekaii-Saab, Tanios ; Wolf, Julie ; Flaherty, Keith T ; O'Reilly, Eileen M ; Rosano, Molly ; Mahalingam, Devalingam

BACKGROUND:

Necuparanib, a rationally engineered low-molecular-weight heparin, combined with gemcitabine/nab-paclitaxel showed an encouraging safety and oncologic signal in a phase Ib trial. This randomised multicentre phase II trial evaluates the addition of necuparanib or placebo to gemcitabine/nab-paclitaxel in untreated metastatic pancreatic ductal adenocarcinoma (PDAC).

PATIENTS AND METHODS:

Eligibility included 18 years, histologically or cytologically confirmed metastatic PDAC, measurable disease and Eastern Co-Operative Oncology Group performance status of 0-1. Patients were randomly assigned to necuparanib (5 mg/kg subcutaneous injection once daily) or placebo (subcutaneous injection once daily) and gemcitabine/nab-paclitaxel on days 1, 8 and 15 of 28-day cycles. The primary end-point was median overall survival (OS), and secondary end-points included median progression-free survival, response rates and safety.

RESULTS:

One-hundred ten patients were randomised, 62 to necuparanib arm and 58 to placebo arm. The futility boundary was crossed at a planned interim analysis, and the study was terminated by the Data Safety Monitoring Board. The median OS was 10.71 months (95% confidence interval [CI]: 7.95-11.96) for necuparanib arm and 9.99 months (95% CI: 7.85-12.85) for placebo arm (hazard ratio: 1.12, 95% CI: 0.66-1.89, P-value: 0.671). The necuparanib arm had a higher incidence of haematologic toxicity relative to placebo patients (83% and 70%).

CONCLUSION:

The addition of necuparanib to standard of care treatment for advanced PDAC did not improve OS. Safety was acceptable. No further development of necuparanib is planned although targeting the coagulation cascade pathway remains relevant in PDAC. NCT01621243.

2019-02-01·Molecular cancer therapeutics2区 · 医学

Necuparanib, A Multitargeting Heparan Sulfate Mimetic, Targets Tumor and Stromal Compartments in Pancreatic Cancer

2区 · 医学

Article

作者: Farutin, Victor ; MacDonald, Amanda ; Lolkema, Martijn ; Zhang, Lynn ; Cochran, Edward ; Curran, Jennifer ; Schultes, Birgit C. ; Chu, Chia Lin ; Getchell, Kristen ; Krause, Silva ; Oosterom, Ilse ; Priess, Michelle ; Guess, Jamey

Abstract:

Pancreatic cancer has an abysmal 5-year survival rate of 8%, making it a deadly disease with a need for novel therapies. Here we describe a multitargeting heparin-based mimetic, necuparanib, and its antitumor activity in both in vitro and in vivo models of pancreatic cancer. Necuparanib reduced tumor cell proliferation and invasion in a three-dimensional (3D) culture model; in vivo, it extended survival and reduced metastasis. Furthermore, proteomic analysis demonstrated that necuparanib altered the expression levels of multiple proteins involved in cancer-driving pathways including organ development, angiogenesis, proliferation, genomic stability, cellular energetics, and invasion and metastasis. One protein family known to be involved in invasion and metastasis and altered by necuparanib treatment was the matrix metalloprotease (MMP) family. Necuparanib reduced metalloproteinase 1 (MMP1) and increased tissue inhibitor of metalloproteinase 3 (TIMP3) protein levels and was found to increase RNA expression of TIMP3. MMP enzymatic activity was also found to be reduced in the 3D model. Finally, we confirmed necuparanib's in vivo activity by analyzing plasma samples of patients enrolled in a phase I/II study in patients with metastatic pancreatic cancer; treatment with necuparanib plus standard of care significantly increased TIMP3 plasma protein levels. Together, these results demonstrate necuparanib acts as a broad multitargeting therapeutic with in vitro and in vivo anti-invasive and antimetastatic activity.

2017-12-01·The oncologist2区 · 医学

Safety, Pharmacokinetics, Pharmacodynamics, and Antitumor Activity of Necuparanib Combined with Nab-Paclitaxel and Gemcitabine in Patients with Metastatic Pancreatic Cancer: Phase I Results

2区 · 医学

Article

作者: O’Reilly, Eileen M. ; Nix, Darrell ; Avery, William ; Rosano, Molly ; Krause, Silva ; Miller, Paul ; Ryan, David P. ; Roach, James ; Flaherty, Keith ; Yu, Kenneth H. ; Wolf, Julie ; Tjan, Catherine

Abstract:

Lessons Learned:

Despite the compelling preclinical rationale of evaluating the genetically engineered heparin derivative, necuparanib, combined with standard therapy in metastatic pancreas adenocarcinoma, the results were ultimately disappointing. Safety was documented, although dose escalation was limited by the number of subcutaneous injections, the potential for skin toxicity (cellulitis), and low-level anticoagulant effect. Nonetheless, the hypothesis of targeting prothrombotic pathways in pancreas adenocarcinoma remains compelling.

Background:

Necuparanib is derived from unfractionated heparin and engineered for reduced anticoagulant activity while preserving known heparin-associated antitumor properties. This trial assessed the safety, pharmacokinetics (PK), pharmacodynamics, and initial efficacy of necuparanib combined with gemcitabine ± nab-paclitaxel in patients with metastatic pancreatic cancer.

Methods:

Patients received escalating daily subcutaneous doses of necuparanib plus 1,000 mg/m2 gemcitabine (days 1, 8, 15, and every 28 days). The protocol was amended to include 125 mg/m2 nab-paclitaxel after two cohorts (following release of the phase III MPACT data). The necuparanib starting dose was 0.5 mg/kg, with escalation via a modified 3 + 3 design until the maximum tolerated dose (MTD) was determined.

Results:

Thirty-nine patients were enrolled into seven cohorts (necuparanib 0.5, 1 mg/kg + gemcitabine; necuparanib 1, 2, 4, 6, and 5 mg/kg + nab-paclitaxel + gemcitabine). The most common adverse events were anemia (56%), fatigue (51%), neutropenia (51%), leukopenia (41%), and thrombocytopenia (41%). No deaths and two serious adverse events were potentially related to necuparanib. Measurable levels of necuparanib were seen starting at the 2 mg/kg dose. Of 24 patients who received at least one dose of necuparanib + nab-paclitaxel + gemcitabine, 9 (38%) achieved a partial response and 6 (25%) achieved stable disease (63% disease control rate). Given a cellulitis event and mild activated partial thromboplastin time increases at 6 mg/kg, the 5 mg/kg dose was considered the MTD and selected for further assessment in phase II.

Conclusion:

Acceptable safety and encouraging signals of activity in patients with metastatic pancreatic cancer receiving necuparanib, nab-paclitaxel, and gemcitabine were demonstrated.

项与 Necuparanib Sodium 相关的新闻（医药）

2024-10-09

·Pharmaceutical Technology

MSD ventures into fibroblast therapies with $1.9bn deal with Mestag

Mestag’s pipeline consists of antibody therapies based on fibroblast-immune interactions as a treatment for cancer and inflammatory diseases. Image credit: Sergiy Palamarchuk / Shutterstock. MSD ( Merck & Co) has signed a license and collaboration agreement with Mestag Therapeutics to develop new fibroblast therapies for inflammatory diseases – a deal potentially worth $1.9bn The companies did not disclose the particulars of the deal, noting that the agreement allows MSD the option to get exclusive development and marketing licences to “a prespecified number of potential targets.” The UK-based biotech in return will receive an upfront payment, and access fees and will be in line to receive option fees and “downstream payments”. Fibroblasts form the connective tissue and are responsible for synthesising extracellular matrix components and collagen, the structural framework of the body. They also play an important role in wound healing, inflammation, and tissue repair. Mestag’s pipeline consists of antibody therapies based on fibroblast-immune interactions as a treatment for cancer and inflammatory diseases. The company’s lead candidate, MST-0300, is a bispecific antibody. The therapy targets lymphotoxin beta receptor (LTBR) in the tumour on co-engagement of fibroblast activation protein (FAP), a tumour-specific marker expressed by cancer-associated fibroblasts, to induce the formation of tertiary lymphoid structures (TLSs) in solid tumours. The presence of these TLSs can be predictive of improved patient outcomes and better therapeutic response. Mestag plans to file an investigational new drug (IND) application in the second half of 2025. Another preclinical candidate in the company’s pipeline is M402, a stromal checkpoint agonist antibody. The therapy is designed to inhibit specific immune cell populations, including myeloid cells. Mestag states that M402 has the “potential to benefit patients across inflammatory diseases including rheumatoid arthritis, lupus, Sjogren’s, graft-versus-host disease and others.” See Also: Clinical Dose Companies in Contract Manufacturing for the Pharmaceutical Industry Innovent and ASK Pharm to commercialise limertinib for lung cancer MSD has been steadily investing in expanding its antibody therapies pipeline. In August, the company acquired Curon Biopharmaceutical , a Chinese biopharmaceutical company specialising in developing bispecific antibodies. The deal is worth approximately $1.3bn in upfront and milestone-based payments. Mestag had previously collaborated with Johnson & Johnson (J&J) in 2021. The licensing agreement allowed J&J the option of an exclusive license to develop and commercialise up to two therapies for the treatment of inflammatory disease.

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外链

KEGG	Wiki	ATC	Drug Bank
D11765	-	-	DB16251

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适应症	最高研发状态	国家/地区	公司	日期
胰腺导管腺癌	临床2期	-	Momenta Pharmaceuticals, Inc.	2013-04-15
胰腺继发性恶性肿瘤	临床2期	美国	Momenta Pharmaceuticals, Inc.	2012-05-01
胰腺继发性恶性肿瘤	临床2期	加拿大	Momenta Pharmaceuticals, Inc.	2012-05-01

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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


NCT01621243 (ASCO_GI2017)	临床2期	胰腺继发性恶性肿瘤	120	Necuparanib	窪鏇齋淵製鹽窪廠製窪(顧鬱鑰鬱顧觸繭遞餘選) = 餘壓積齋範願糧鏇壓範壓築獵製糧鑰廠鹹夢選 (壓夢網艱願鑰積膚構遞 ) 更多	不佳	2017-03-21
				Placebo	窪鏇齋淵製鹽窪廠製窪(顧鬱鑰鬱顧觸繭遞餘選) = 築艱艱鏇蓋壓製夢顧觸壓築獵製糧鑰廠鹹夢選 (壓夢網艱願鑰積膚構遞 ) 更多