On April 20, 2016 Deciphera Pharmaceuticals, a clinical-stage biotechnology company focused on developing advanced kinase inhibitor treatments targeting the tumor cell and the tumor microenvironment, reported that its highly-selective small molecule CSF1R inhibitor, DCC-3014, has demonstrated highly-specific inhibition of the colony stimulating factor 1 receptor (CSFIR), a key target across many cancer indications (Press release, Deciphera Pharmaceuticals, APR 20, 2016, View Source [SID:1234511141]). In addition, DCC-3014, which was designed as a highly-specific macrophage immunomodulatory agent based on the company’s Switch Control Inhibitor platform, demonstrated significantly enhanced anti-tumor activity when used in combination with an anti-PD-1 checkpoint inhibitor in preclinical cancer models. Based on these data, which were presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2016, on April 20, 2016 in New Orleans, Deciphera plans to initiate a Phase 1 clinical trial with DCC-3014 in the second half of 2016.

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"DCC-3014’s robust inhibition of the CSF1R kinase, as demonstrated by these data presented at the AACR (Free AACR Whitepaper) Annual Meeting, provide encouraging evidence of its potential as a immunomodulatory agent through its action on tumor-associated macrophages (TAMs), both as a single agent and in combination with other immune checkpoint inhibitors, across a number of cancer models," said Michael D. Taylor, Ph.D., Deciphera’s President and Chief Executive Officer. "We look forward to initiating the first-in-human Phase 1 trial with DCC-3014 later this year."

In a poster titled, "The highly specific CSF1R inhibitor DCC-3014 exhibits immunomodulatory and anti-invasive activities in cancer models," Deciphera researchers presented preclinical data demonstrating DCC-3014’s robust inhibition of CSF1R kinase, and potential utility as a macrophage immunomodulatory agent in combination with other immune checkpoint inhibitors or chemotherapeutic agents. Highlights of the data include:

DCC-3014 exhibited nanomolar potency for inhibition of CSF1R, sparing highly related kinases such as KIT, PDGFR and FLT3 by greater than 100-fold, and sparing other kinases by more than 1,000-fold.
DCC-3014 showed sustained in vivo inhibition of CSF1R, offering greater than 90% inhibition more than 24 hours after dosing, in a murine PK/PD model.
DCC-3014 demonstrated significant single agent activity and additive effects in combination with a murine anti-PD1 antibody in a murine model of colorectal cancer.
DCC-3014 blocked tumor growth, invasion and bone degradation in a prostate cancer model and exhibited optimized biopharmaceutical properties.
About DCC-3014

DCC-3014, a highly-selective small molecule colony stimulating factor 1 receptor (CSFIR), was designed as a highly-specific macrophage immunomodulatory agent based on the company’s Switch Control Inhibitor platform. In preclinical studies, DCC-3014 has demonstrated highly-specific inhibition of CSF1R, a key target across many cancer indications, as well as significantly enhanced anti-tumor activity when used in combination with an anti-PD-1 checkpoint inhibitors. Based on these data, Deciphera plans to initiate a Phase 1 clinical trial with DCC-3014 in the second half of 2016.

To examine the effect on cognitive function of adjuvant ovarian function suppression (OFS) for breast cancer.
The Suppression of Ovarian Function (SOFT) trial randomised premenopausal women with hormone receptor-positive breast cancer to 5 years adjuvant endocrine therapy with tamoxifen+OFS, exemestane+OFS or tamoxifen alone. The Co-SOFT substudy assessed objective cognitive function and patient reported outcomes at randomisation (T0), and 1 year later (T1); the primary endpoint was change in global cognitive function, measured by the composite objective cognitive function score. Data were compared for the pooled tamoxifen+OFS and exemestane+OFS groups vs the tamoxifen alone group using the Wilcoxon rank-sum test.
Of 86 participants, 74 underwent both T0 and T1 cognitive testing; 54 randomised to OFS+ either tamoxifen (28) or exemestane (26) and 20 randomised to tamoxifen alone. There was no significant difference in the changes in the composite cognitive function scores between the OFS+ tamoxifen or exemestane groups and the tamoxifen group (mean±s.d., -0.21±0.92 vs -0.04±0.49, respectively, P=0.71, effect size=-0.20), regardless of prior chemotherapy status, and adjusting for baseline characteristics.
The Co-SOFT study, although limited by small samples size, provides no evidence that adding OFS to adjuvant oral endocrine therapy substantially affects global cognitive function.British Journal of Cancer advance online publication 19 April 2016; doi:10.1038/bjc.2016.71 www.bjcancer.com.

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More than 50 monoclonal antibodies (mAbs), including several antibody-drug conjugates, are in advanced clinical development, forming an important part of the many molecularly targeted anticancer therapeutics currently in development. Drug development is a relatively slow and expensive process, limiting the number of drugs that can be brought into late-stage trials. Development decisions could benefit from quantitative biomarkers, enabling visualization of the tissue distribution of (potentially modified) therapeutic mAbs to confirm effective whole-body target expression, engagement, and modulation and to evaluate heterogeneity across lesions and patients. Such biomarkers may be realized with positron emission tomography imaging of radioactively labeled antibodies, a process called immunoPET. This approach could potentially increase the power and value of early trials by improving patient selection, optimizing dose and schedule, and rationalizing observed drug responses. In this review, we summarize the available literature and the status of clinical trials regarding the potential of immunoPET during early anticancer drug development.
© 2015 by American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper).

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On April 20, 2016 Emergent BioSolutions Inc. (NYSE:EBS) reported that it presented preclinical data on its bispecific ADAPTIRTM (modular protein technology) molecule, ES425, at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in New Orleans, Louisiana. The ES425 molecule is being developed as a potential therapeutic for triple-negative breast cancer (TNBC) (Press release, Emergent BioSolutions, APR 20, 2016, View Source;p=RssLanding&cat=news&id=2158702 [SID:1234511142]). This product candidate was constructed using the ADAPTIR platform technology and will be further developed by Emergent’s planned spin-off company Aptevo Therapeutics.

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ES425 is a bispecific immunotherapeutic protein that redirects T-cell cytotoxicity to tumor cells expressing ROR1 (receptor tyrosine kinase-like orphan receptor 1), an oncofetal antigen expressed on TNBC and other solid tumor and hematologic malignancies.
The presentation, "Anti-ROR1 x Anti-CD3 ADAPTIRTM Molecule, ES425, Redirects T-Cell Cytotoxicity and Inhibits Tumor Growth in Preclinical Models of Triple-Negative Breast Cancer," shared results of preclinical studies examining in vitro and in vivo activity of ES425. Results showed that ES425 efficiently redirected T-cell cytotoxicity against ROR1(+) cell lines at low picomolar concentrations in vitro. T cells were activated and proliferated in response to ES425 in the presence of ROR1(+) target cells. In vivo, pharmacokinetic analysis showed inhibition of tumor growth and an improvement in overall survival in preclinical models of TNBC.

"The encouraging preclinical data demonstrate that ES425 effectively redirects T-cell cytotoxicity in preclinical TNBC models and merits investigation as a potential therapeutic in TNBC and other malignancies," said Scott C. Stromatt, M.D., chief medical officer of Emergent BioSolutions. "Effective treatment of metastatic, triple-negative breast cancer remains a highly unmet medical need and we look forward to continuing development of this molecule to enable filing an Investigational New Drug application in the next year."

About the ADAPTIR Platform

ADAPTIR bispecific proteins are modular, single chain polypeptides that are comprised of two separate binding domains, a hinge segment, and an effector domain. They have a differentiated structure from monoclonal antibodies and can generate a unique signaling response. Some ADAPTIR molecules may mediate T-cell cytotoxicity by redirecting T cells against tumor cells and some by targeted cytokine delivery. In addition, other ADAPTIR proteins may mediate complement dependent cytotoxicity and Fc dependent cytotoxicity, similar to monoclonal antibodies. ADAPTIR and any and all Emergent BioSolutions Inc. brand, product, service and feature names, logos, and slogans are trademarks or registered trademarks of Emergent BioSolutions Inc. or its subsidiaries in the United States or other countries. All rights reserved.

Joint modelling of longitudinal and survival data is increasingly used in clinical trials on cancer. In prostate cancer for example, these models permit to account for the link between longitudinal measures of prostate-specific antigen (PSA) and time of clinical recurrence when studying the risk of relapse. In practice, multiple types of relapse may occur successively. Distinguishing these transitions between health states would allow to evaluate, for example, how PSA trajectory and classical covariates impact the risk of dying after a distant recurrence post-radiotherapy, or to predict the risk of one specific type of clinical recurrence post-radiotherapy, from the PSA history. In this context, we present a joint model for a longitudinal process and a multi-state process, which is divided into two sub-models: a linear mixed sub-model for longitudinal data and a multi-state sub-model with proportional hazards for transition times, both linked by a function of shared random effects. Parameters of this joint multi-state model are estimated within the maximum likelihood framework using an EM algorithm coupled with a quasi-Newton algorithm in case of slow convergence. It is implemented under R, by combining and extending mstate and JM packages. The estimation program is validated by simulations and applied on pooled data from two cohorts of men with localized prostate cancer. Thanks to the classical covariates available at baseline and the repeated PSA measurements, we are able to assess the biomarker’s trajectory, define the risks of transitions between health states and quantify the impact of the PSA dynamics on each transition intensity. Copyright © 2016 John Wiley & Sons, Ltd.
Copyright © 2016 John Wiley & Sons, Ltd.

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