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MabVax Therapeutics Initiates Phase I Trial of HuMab-5B1 for Treatment of Pancreatic Cancer

On March 21, 2016 MabVax Therapeutics Holdings, Inc. (OTCQB: MBVX), a clinical-stage oncology drug development company, reported the initiation of a phase I clinical trial of HuMab-5B1 for patients with locally advanced or metastatic adenocarcinoma of the pancreas (PDAC) or other CA19-9 positive malignancies (Press release, MabVax, MAR 21, 2016, View Source [SID:1234509768]).

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The CA19-9 target is expressed on more than 90% of pancreatic cancers and is a validated biomarker for the disease. The Company filed an Investigational New Drug (IND) application for this product on November 30, 2015 and received U.S. Food and Drug Administration (FDA) authorization to proceed with the study on December 24, 2015.

The study is a phase I, open-label, multi-center, dose-escalation clinical trial. The primary objectives are to determine the safety, maximum tolerated dose (MTD), and the pharmacokinetics (PK) of HuMab-5B1. The phase I trial will also evaluate the tumor response rate based on RECIST 1.1 and the duration of response of HuMab-5B1 as a single agent or in combination with a standard of care chemotherapy regimen. The study will enroll up to approximately 60 patients at multiple centers in the United States.

On January 28, 2016 MabVax received authorization from FDA to proceed with a second phase I clinical trial with [Zr-89]-HuMab-5B1 as a new generation PET imaging agent in patients with pancreatic cancer. [Zr-89]-HuMab-5B1 combines a well-established PET imaging radiolabel [Zr-89] with the targeting specificity of the HuMab-5B1 antibody. Preclinical xenograft animal models demonstrated high image resolution of tumors, making [Zr-89]-HuMab-5B1 attractive as a potential diagnostic agent for use with the HuMab-5B1 therapeutic product. Some of the data was previously published in the Journal of Nuclear Medicine, Bioconjugate Chemistry, and the Proceedings of the National Academy of Sciences.

David Hansen, President and CEO, said, "Data generated in the early portions of these two Phase I trials could demonstrate important initial safety, PK and targeting specificity data of the antibody and signal the potential utility of the HuMab-5B1 antibody in the diagnosis and treatment of patients with this devastating disease. We anticipate reporting interim-study data from both trials in mid-year 2016. Additionally, we are excited about the potential applicability of our dual-product development approach in other cancers with HuMab-5B1, as well as with follow-on antibodies under development at MabVax."

About HuMab-5B1:

MabVax’s HuMab-5B1 antibody is fully human and was discovered from the immune response of cancer patients vaccinated with an antigen-specific vaccine during a Phase I trial at Memorial Sloan Kettering Cancer Center. In preclinical research, the 5B1 antibody has demonstrated high specificity and affinity, and has shown potent cancer cell killing capacity and efficacy in animal models of pancreatic, colon and small cell lung cancers. The antigen the antibody targets is expressed on more than 90% of pancreatic cancers making the antibody potentially broadly applicable to most patients suffering from this type of cancer.

AVEO and CANbridge Life Sciences Announce Exclusive Licensing Agreement for AV-203 Outside of North America

On March 21, 2016 AVEO Oncology (NASDAQ:AVEO) and CANbridge Life Sciences, a biopharmaceutical company focused on developing Western drug candidates in China and North Asia, reported an exclusive collaboration and license agreement in which AVEO has granted CANbridge Life Sciences worldwide rights, excluding the United States, Canada, and Mexico, to AV-203, AVEO’s clinical-stage ErbB3 (HER3) inhibitory antibody candidate (Press release, AVEO, MAR 21, 2016, View Source [SID:1234509764]).

CANbridge plans to develop AV-203 first in esophageal squamous cell cancer (ESCC), the most prevalent form of esophageal cancer. According to the World Health Organization, esophageal cancer is the eighth most common cancer globally, with over 450,000 cases diagnosed each year. To date, AVEO has completed a Phase 1, open-label, dose-escalation study of AV-203 in patients with advanced solid tumors. In this study, AV-203 was found to be generally safe and well-tolerated, with an early signal of activity consistent with preclinical data showing the potential for heregulin, the only known ligand for ErbB3, to serve as a biomarker predictive of AV-203 anti-tumor activity.

Under the terms of the agreement, CANbridge Life Sciences is obligated to pay AVEO an upfront payment of $1 million plus up to $133 million in potential reimbursement and milestone payments, assuming the successful achievement of specified development, regulatory and commercialization objectives. AVEO is also eligible for a tiered royalty, with a percentage range in the low double digits, on net sales of AV-203 in the agreement’s territories.

CANbridge Life Sciences will be responsible for costs associated with the execution of a development plan that includes additional manufacturing requirements as well as pre-clinical and clinical studies necessary to demonstrate proof-of-concept for AV-203 as a treatment for squamous cell esophagus cancer, including a Phase IIa proof-of-concept study meeting mutually agreed upon criteria. Following completion of the proof-of-concept studies, AVEO and CANbridge will negotiate a possible agreement under which they may co-develop AV-203, with each party bearing a percentage of the cost of global development activities based on respective geographic rights. If the parties fail to reach such an agreement, CANbridge may continue the development of AV-203 on its own in markets outside of the United States, Canada and Mexico.

"With an exclusive license to AV-203 outside of North America, CANbridge will be expanding outside of Asia for the first time," said James Xue, CANbridge Chairman and CEO. "Pre-clinical work shows that AV-203 has the potential to treat ESCC, the most common type of esophageal cancer in Asia, with fifty percent of worldwide diagnoses occurring in China. Esophageal cancer is also prevalent in other parts of the world, particularly developing countries. As part of our globalization strategy, we plan to develop AV-203 in Asia first, then bring it to other territories where patients with this form of disease have few treatment options."

"There is a growing body of clinical data which suggests that heregulin-driven ErbB3 signaling drives resistance to standard therapy in a variety of tumors overexpressing HER3," said Michael Bailey, president and chief executive officer of AVEO. "This agreement allows us to further advance AV-203 development by leveraging the resources of a motivated partner in CANbridge, which is led by a deeply experienced team hailing from Genzyme, Synageva and other life sciences innovators. Importantly, it also allows us to retain North American rights for future development for a third clinical stage drug candidate, providing AVEO with a robust portfolio of oncology therapeutics."

Non-alcoholic steatohepatitis-associated hepatic fibrosis and hepatocellular carcinoma in a combined mouse model of genetic modification and dietary challenge.

Experimental models of non-alcoholic steatohepatitis (NASH) are still required for understanding pathophysiology of NASH. This study aimed to examine whether disease progression is accelerated by combining dyslipidemic genetic modification and dietary challenges and develop NASH-associated hepatic fibrosis, cirrhosis, and carcinoma in a short period.
Low-density lipoprotein receptor knockout (LDLR-/-) mouse was fed with choline-deficient amino acid-defined (CDAA) diet including 1 w/w% cholesterol and 41 kcal% fat, a modified CDAA (mCDAA) diet, was comprehensively profiled over 1 year.
Microvesicular and macrovesicular steatosis in the liver was observed from 1(st) week after the start of mCDAA-feeding. Macrovesicular steatosis was exacerbated with time and was observed in almost all hepatocytes at 8(th) week, but slightly decreased at 16(th) week. Infiltration of macrophages and neutrophils, and up-regulation of hepatic inflammatory cytokines such as TNF-α and IL-1β were also observed from 1(st) week. Plasma hepatic transaminase activities were increased at 1(st) week, reached a peak at 4(th) week, and gradually decreased thereafter. In parallel with increases in hepatic gene expression of collagen-I, hepatic fibrosis area were expanded after 4(th) week and massively spread all over the liver by 8(th) week. Hepatocellular hyperplasia was observed from 24(th) week. Hepatocellular adenoma and carcinoma were observed from 31(st) and 39(th) week, respectively.
These results suggest that in a rodent NASH model with combination of genetic modification and dietary challenges, following hepatic steatosis, inflammatory cell infiltration and hepatic injury, hepatic fibrosis, hepatocellular hyperplasia, adenoma, and carcinoma can be developed in a relatively short period. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.

Evaluating the Impact of a Switch to Nilotinib on Imatinib-Related Chronic Low-Grade Adverse Events in Patients With CML-CP: The ENRICH Study.

Many patients with chronic myeloid leukemia in chronic phase experience chronic treatment-related adverse events (AEs) during imatinib therapy. These AEs can impair quality of life and lead to reduced treatment adherence, which is associated with poor clinical outcomes.
In the phase II ENRICH (Exploring Nilotinib to Reduce Imatinib Related Chronic Adverse Events) study (N = 52), the effect of switching patients with imatinib-related chronic low-grade nonhematologic AEs from imatinib to nilotinib was evaluated.
Three months after switching to nilotinib, 84.6% of the patients had overall improvement in imatinib-related AEs (primary endpoint). Of 210 imatinib-related AEs identified at baseline, 62.9% had resolved within 3 months of switching to nilotinib. Of evaluable patients, most had improvements in overall quality of life after switching to nilotinib. At screening, 65.4% of evaluable patients had a major molecular response (BCR-ABL1 ≤ 0.1% on the International Scale). After switching to nilotinib, the rate of the major molecular response was 76.1% at 3 months and 87.8% at 12 months. Treatment-emergent AEs reported with nilotinib were typically grade 1 or 2; however, some patients developed more serious AEs, and 8 patients discontinued nilotinib because of new or worsening AEs.
Overall, results from the ENRICH study demonstrated that switching to nilotinib can mitigate imatinib-related chronic low-grade nonhematologic AEs in patients with chronic myeloid leukemia in chronic phase, in conjunction with acceptable safety and achievement of molecular responses. This trial was registered at www.clinicaltrials.gov as NCT00980018.
Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Antigen Selection for Enhanced Affinity T-Cell Receptor-Based Cancer Therapies.

Evidence of adaptive immune responses in the prevention of cancer has been accumulating for decades. Spontaneous T-cell responses occur in multiple indications, bringing the study of de novo expressed cancer antigens to the fore and highlighting their potential as targets for cancer immunotherapy. Circumventing the immune-suppressive mechanisms that maintain tumor tolerance and driving an antitumor cytotoxic T-cell response in cancer patients may eradicate the tumor or block disease progression. Multiple strategies are being pursued to harness the cytotoxic potential of T cells clinically. Highly promising results are now emerging. The focus of this review is the target discovery process for cancer immune therapeutics based on affinity-matured T-cell receptors (TCRs). Target cancer antigens in the context of adoptive cell transfer technologies and soluble biologic agents are discussed. To appreciate the impact of TCR-based technology and understand the TCR discovery process, it is necessary to understand key differences between TCR-based therapy and other immunotherapy approaches. The review first summarizes key advances in the cancer immunotherapy field and then discusses the opportunities that TCR technology provides. The nature and breadth of molecular targets that are tractable to this approach are discussed, together with the challenges associated with finding them.
© 2016 Society for Laboratory Automation and Screening.