A phase 1 study was conducted to evaluate the safety, pharmacokinetics (PK), efficacy and pharmacogenetic characteristics of clofarabine in seven Japanese pediatric patients with relapsed/refractory acute lymphoblastic leukemia (ALL). Patients in Cohort 1 received clofarabine 30 mg/m(2)/day for 5 days, followed by 52 mg/m(2)/day for 5 days in subsequent cycles. Cohort 2 patients were consistently treated with 52 mg/m(2)/day for 5 days. No more than six cycles were performed. Every patient had at least one ≥Grade 3 adverse event (AE). AEs (≥Grade 3) related to clofarabine were anaemia, neutropenia, febrile neutropenia, thrombocytopenia, alanine aminotransferase increased, aspartate aminotransferase increased, haemoglobin decreased, and platelet (PLT) count decreased. C max and AUC of clofarabine increased in a dose-dependent fashion, but its elimination half-life (T 1/2) did not appear to be dependent on dose or duration of treatment. Clofarabine at 52 mg/m(2)/day shows similarly tolerable safety and PK profiles compared to those in previous studies. No complete remission (CR), CR without PLT recovery, or partial remission was observed. Since clofarabine is already used as a key drug for relapsed/refractory ALL patients in many countries, the efficacy of clofarabine in Japanese pediatric patients should be evaluated in larger study including more patients, such as by post-marketing surveillance.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

On April 18, 2016 AstraZeneca reported new data from multiple molecules in its industry-leading DNA Damage Response (DDR) pipeline at the 2016 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in New Orleans, LA (Press release, AstraZeneca, APR 18, 2016, View Source [SID:1234511011]). These agents use a variety of different pathways to disrupt tumour cells’ natural ability to repair themselves as they replicate, eventually causing the tumour cells to die.7,8 Illustrating the unique breadth of AstraZeneca’s approaches to DDR, presentations at AACR (Free AACR Whitepaper) featured molecules that disrupt multiple tumour cell repair processes, including single-strand break repair, double-strand break repair, and cell cycle regulation.1-6

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

Susan Galbraith, Head of AstraZeneca’s Oncology Innovative Medicines Unit said, "Taken together with the positive Phase II results of olaparib in patients with metastatic, castration-resistant prostate cancer published early this year,9 we are encouraged by the potential of PARP inhibition in multiple tumour types beyond ovarian cancer. The breadth of our pipeline showcases DDR monotherapies and combinations that could attack cancer in a multitude of novel ways – our first priority, as demonstrated here at AACR (Free AACR Whitepaper), is to follow the science to identify and quickly advance those molecules that have the potential to address the greatest unmet medical needs."

PARP Inhibition and Lynparza (olaparib): Beyond Ovarian Cancer

The PARP inhibitor olaparib is the cornerstone of AstraZeneca’s pipeline of personalised treatments targeting DDR mechanisms in cancer cells. Olaparib was combined with the investigational AKT inhibitor AZD5363 in a new Phase I trial of germline (g) BRCA and non-BRCA mutant (m) advanced cancer patients with ovarian, breast, prostate and bile duct cancers.1 Results showed that the olaparib-AZD5363 combination was well-tolerated with multiple responses, including 10 RECIST complete or partial responses (out of 37 evaluable patients) in both gBRCA and non-BRCAm tumours, as well as prior PARP inhibitor-treated cancers.1

Olaparib disrupts the repair of single-strand DNA breaks, a mode of action that has potential to work in a range of tumour types beyond ovarian cancer.10 AstraZeneca is researching how several different compounds can be combined with DDR molecules to provide a dual threat to tumour cells. For example, treatments such as AZD5363 that selectively inhibit the PI3K / AKT signalling pathway may complement olaparib’s interference with tumour DNA repair.1

Additional Mechanisms of DDR: Cell Cycle Disruption & Double-Strand Break Repair

AstraZeneca presented data on a variety of investigational compounds acting on different aspects of the DDR pathway, both in monotherapy and in combination. Most significant were early results from a Phase Ib open-label study of AZD1775, a novel small molecule designed to inhibit the Wee1 kinase.2 Wee1 is a protein kinase that helps regulate the cell cycle.5 In many tumours, Wee1 overexpression stops the cell cycle after DNA damage occurs, allowing tumour cells time to repair any damage.5,11 By inhibiting Wee1, the cell cycle continues despite damage, which can lead to tumour cell death.5 Assessing the safety, tolerability, pharmacokinetics and anti-tumour activity of AZD1775, the Phase Ib safety run-in included patients with small-cell lung, non-small cell lung, head and neck, ovarian, breast, pancreas and unknown primary tumours.2 Early results demonstrated a partial or stable response in a third of patients (4/12), and AstraZeneca has initiated expansion cohorts in ovarian, breast and small-cell lung cancer.2 Other studies currently recruiting include a Phase I multi-centre, dose escalation study of AZD1775 combined with olaparib in refractory solid tumours.12

Several other new molecules in the clinical pipeline are entering Phase I development, including the first-in-class Ataxia telangiectasia mutated (ATM) kinase inhibitor AZD0156.3 Pre-clinical in vivo activity of AZD0156 presented at AACR (Free AACR Whitepaper) demonstrated that inhibition of ATM during the DNA damage response enhanced the efficacy of a range of DNA-damaging agents, including olaparib, and support its further study in the clinical setting.3 AstraZeneca is now recruiting for a Phase I trial of AZD0156 as monotherapy or in combination with olaparib in patients with advanced solid tumours.13

Other ongoing DDR-focused studies include additional Phase I trials of the Aurora B kinase inhibitor AZD281114 and ATR inhibitor AZD6738 in solid tumours.15

On April 17, 2016 Precision Biologics, a NantWorks affiliated clinical stage biotechnology company focused on developing therapeutic and diagnostic products for the early detection and treatment of cancer and a participant in the Cancer MoonShot 2020 program, reported it will present a poster titled, "Identification of target and cytotoxicity of novel monoclonal antibody NEO-201 in ovarian and uterine cancer subtypes" at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2016 (Press release, Precision Biologics, APR 18, 2016, View Source [SID:1234511010]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"With better identification of cancer subtypes that express the NEO201 target, we are taking a step closer to personalized medicine for women diagnosed with ovarian and uterine cancer," said Philip M. Arlen, M.D., President & Chief Executive Officer of Precision Biologics, Inc. of Rockville, MD. "Without the visionary support of NantWorks and Dr. Patrick Soon-Shiong, tumor-specific and neo-epitope cytotoxicity research would face a much slower development path, potentially impacting cancer morbidity and mortality rates."

At AACR (Free AACR Whitepaper), Precision Biologics will present preclinical data on the cytotoxic effects of NEO-201 in uterine and ovarian cancers. NEO-201 is an investigational, humanized monoclonal antibody that targets a novel neo-antigen with sequence homology to the tumor-associated antigens (TAA) CEACAM-5 and CEACAM-6, but highly sensitive to epithelial tumors with little cross reactivity to normal tissue. It is being explored as a potential therapy for epithelial malignancies. NEO-201 demonstrates antibody-dependent cellular cytotoxicity and specifically targets cancer tissues with minimal reactivity in normal tissues.

"Accelerating clinical development of neo-epitopes is a key focus of our immunotherapy initiative. Given the complexity of ovarian and uterine cancer and the great unmet need to overcome these cancers which strike women in the prime of their lives, the work that Precision Biologics is doing with NEO-201 to drive combination immunotherapy reinforces why NantWorks and Cancer MoonShot 2020 supports this program," said Patrick Soon-Shiong, M.D., founder of NantWorks and leader of the Cancer MoonShot 2020 program.

Results from in vitro cytotoxicity assays and inhibition of tumor growth in nude mice will be reported, both as single agents and in combination with a Natural Killer cell line. The preclinical data indicate that NEO-201 demonstrates tumor-specific cytotoxicity and provides promise for the development of TAA-directed therapy for ovarian and uterine malignancies.

Presentation Information: Identification of target and cytotoxicity of novel monoclonal antibody NEO-201 in ovarian and uterine cancer subtypes

Monday, April 18, 2016 at 8:00am-12:00pm in Section 25, Poster Board 27, at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) annual meeting, Ernest N. Morial Convention Center, New Orleans, LA.

Abstract Title: # 1496

Author: M. K. Neuman1, L. Hernandez1, X. P. Wang2, O. Saric2, A. Dubeykovskiy2, P. Arlen1,2 and C. M. Annunziata1,1 National Cancer Institute, Bethesda, MD, 2Precision Biologics, Rockville, MD

About Cancer MoonShot 2020
The Cancer MoonShot 2020 Program is one of the most comprehensive cancer collaborative initiative launched to date, seeking to accelerate the potential of combination immunotherapy as the next generation standard of care in cancer patients. This initiative aims to explore a new paradigm in cancer care by initiating randomized Phase II trials in patients at all stages of disease in 20 tumor types in 20,000 patients within the next 36 months. These findings will inform Phase III trials and the aspirational MoonShot to develop an effective vaccine-based immunotherapy to combat cancer by 2020.

On April 18, 2016 NanoString Technologies, Inc. (NASDAQ:NSTG), a provider of life science tools for translational research and molecular diagnostic products, reported that they presented the first proof-of-concept data from its novel multiplexed digital immunohistochemistry (IHC) technology at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) annual meeting in New Orleans, Louisiana (Press release, NanoString Technologies, APR 18, 2016, View Source [SID:1234511006]). Using a prototype device together with an nCounter Analysis System, the company and its collaborators demonstrated simultaneous counting of 30 different protein targets across a fixed, slide-mounted slice of tumor tissue. The technology demonstrated a dynamic range exceeding five logs and neared single-cell spatial resolution.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

The new approach is described on AACR (Free AACR Whitepaper) poster #1372, "Spatially resolved, multiplexed digital characterization of protein distribution and abundance in FFPE tissue sections." Gordon B. Mills, M.D., Ph.D., Professor and Chair of the Department of Systems Biology at MD Anderson Cancer Center, is co-author of the poster. Dr. Mills commented, "The expansion of NanoString technology to the spatial context of protein concentration is an exciting advance that holds much promise for biomarker discovery and implementation into patient management. We are excited by the actionable data generated by the prototype and look forward to future developments and exploring the utility of the platform in improving patient outcomes."

Based on NanoString’s proprietary barcoding technology, the multiplexed digital IHC approach measures local protein levels within heterogeneous tissue samples. The prototype includes imaging and fluidic components to capture spatial context, and existing nCounter instruments provide the quantification. Current multi-target IHC techniques involve sequential processing steps; therefore, each target addition increases the overall handling time and workload. In contrast, NanoString’s novel technology samples all analytes simultaneously to shorten experiments and simplify data analysis while preserving a higher multiplexing capacity and a wider detection range. The technology is expected to be compatible with current and upcoming nCounter Vantage products for 3D Biology analysis.

"NanoString’s new digital IHC technology combines the high multiplexing and digital quantification of single-molecule optical barcodes with the biological insights provided by protein localization," stated Joseph Beechem, Ph.D., Senior Vice President of R&D at NanoString. "Over the remainder of this year, our plan includes increasing the number of targets in our assays, enhancing the imaging resolution and exploring use with other 3D Biology applications."

Dr. Beechem will present the initial results at the AACR (Free AACR Whitepaper) meeting in Spotlight Theater B, Hall J on Tuesday, April 19th from 12:30 – 1:30 pm Central Time. His presentation is titled "New Optical Barcode Chemistries for Digital, Multiplexed Immunohistochemistry: Power of 3D Biology Enhanced by Spatially Resolved Multiplexed Protein Quantitation on FFPE."

On Innate Pharma SA (the "Company" – Euronext Paris: FR0010331421 – IPH) today presented data demonstrating enhanced anti-tumor efficacy and survival by combining anti-NKG2A with PD-1/PD-L1 pathway inhibitors in murine models at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2016 in New Orleans, Louisiana, USA (Press release, Innate Pharma, APR 18, 2016, View Source [SID:1234511005]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

The NKG2A checkpoint receptor is expressed on a subset of NK cells. Similar to the PD-1 receptors, NKG2A can also be induced on tumor-infiltrating CD8 T cells. Therefore, PD-1 and NKG2A may both inhibit anti-tumor immune responses in situations where cancers express the ligands of both these checkpoint receptors. Conversely, anti-tumor immune responses might be enhanced by combined NKG2A and PD-1 pathway blockade.

Poster #2342 reports preclinical data based on an in vivo model of PD-L1 expressing solid tumors. In this model, treatment with either an antibody blocking PD-1 or NKG2A as single agents resulted in modest anti-tumor efficacy. The frequency of tumor-infiltrating NKG2A+ CD8 T cells was increased in anti-PD-1 resistant mice, suggesting that NKG2A is a pathway involved in adaptive PD-1 resistance. Treatment with combination of NKG2A and PD-1 checkpoint inhibitors resulted in significantly enhanced anti-tumor responses. Nearly twice as many mice achieved complete tumor cell regression compared to treatment with anti PD-1 alone.

Nicolai Wagtmann, CSO of Innate Pharma, said: "We are very excited by these data showing that the NKG2A pathway acts as a major mechanism of tumor escape in this model. Considering the high frequency of patients who respond inadequately to PD-1 pathway blockade, we are intrigued by the observations that NKG2A expression on CD8 T cells was increased in PD-1 resistant mice". He added: "These data and the striking efficacy of the combination treatment in this model provide strong support for the clinical trial that was just initiated, testing the combination of monalizumab, Innate’s first-in-class NKG2A checkpoint inhibitor, and durvalumab, AstraZeneca/Medimmune’s investigational PD-L1 checkpoint inhibitor".