On November 24, 2014 Genmab reported that its collaboration partner, Janssen Biotech, Inc. (Janssen) plans to start a Phase II study of daratumumab in smoldering multiple myeloma (Press release Genmab, NOV 24, 2014, View Source [SID:1234501009]). The study (SMM2001) will evaluate three different dose schedules of daratumumab for the treatment of smoldering multiple myeloma. The study is expected to start enrolling patients in 2015.

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"We are pleased to announce this study, which illustrates that the development plan for daratumumab encompasses all stages of multiple myeloma. Smoldering multiple myeloma is a challenging indication, as physicians will evaluate treating patients at an early stage of the disease, with the intent to extend the period before the disease transitions to symptomatic multiple myeloma," said Jan van de Winkel, Ph.D., Chief Executive Officer of Genmab.

On November 21, 2014 The Cancer Research Technology Pioneer Fund (CPF) reported a collaboration with the Cancer Research UK Manchester Institute Drug Discovery Unit*, at The University of Manchester, to develop a promising class of drugs called RET inhibitors to treat cancer (Press release, Cancer Research Technology, NOV 21, 2014, View Source [SID1234523219]).

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Cancer Research Technology (CRT), Cancer Research UK’s commercial arm, and the European Investment Fund (EIF) launched the £50M CPF in 2012 to bridge the UK funding gap between cancer drug discovery and early drug development. Sixth Element Capital was appointed to manage the fund.

Today’s investment is the fourth made by the CPF. It will build on research by scientists at Cancer Research UK’s Manchester Institute, enabling them to accelerate the development of RET inhibitors and fund early clinical trials of potential drugs developed through the collaboration.

The RET gene plays a critical role in the development of medullary thyroid cancer. And up to two percent of non-small cell lung adenocarcinomas – originating in the mucus-secreting cells lining the airways – have RET mutations. The goal of the project is to discover novel compounds that will specifically focus on the RET gene in a targeted population of patients.

Ian Miscampbell, managing partner of Sixth Element Capital, said: "We’re delighted to announce the fourth project to be funded by the CRT Pioneer Fund at the Cancer Research UK Manchester Institute and to be collaborating with their world class team. Their expertise in cancer drug discovery and in the genetics of non-small cell lung cancer makes this a very exciting investment for CPF.

"This investment will pave the way for potential new cancer drugs to be taken into Phase I clinical trials. If the first studies are successful we will seek industry partners to further develop and commercialise these drugs."

Dr Donald Ogilvie, head of drug discovery at the Cancer Research UK Manchester Institute at The University of Manchester, said: "We’re extremely pleased to work with the CRT Pioneer Fund to help accelerate progress on the exciting RET inhibitors discovered by Cancer Research UK scientists at our Institute. Lung cancer remains a significant clinical challenge. As part of the Cancer Research UK Centre of Excellence on Lung Cancer, we are determined to deliver new treatments into the clinic for this disease and this programme offers the potential to improve the outlook for cancer patients."

Dr Keith Blundy, chief executive of Cancer Research Technology, said: "It’s fantastic news that CRT’s Pioneer Fund will help accelerate this important research from the lab to a stage where it could potentially benefit patients. It’s absolutely essential that we take steps to bridge the innovation gap in UK drug discovery, so that patients can quickly access the promising new drugs being developed in Cancer Research UK labs and elsewhere around the world."

On November 20, 2014 Blueprint Medicines disclosed a new drug discovery program targeting cancers with RET fusions and predicted resistance mutations (Press release, Blueprint Medicines, NOV 20, 2014, View Source [SID:1234508104]). The announcement was made during an oral presentation at the 26th EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Symposium on Molecular Targets and Cancer Therapeutics in Barcelona, Spain, on Blueprint Medicines’ discovery of several novel kinase fusions implicated in cancer and identification of several new cancer indications for known kinase fusions.
"One of the greatest challenges in treating cancer is addressing cancer cells’ ability to become resistant to therapy. Our new drug discovery program uniquely addresses both the activated wild-type form of RET and its predicted resistance mutations, enabling us to potentially develop a transformative therapy for cancer patients with RET fusions," said Christoph Lengauer, PhD, MBA, Chief Scientific Officer of Blueprint Medicines. "With the unveiling of this program, we add another proof point for the productivity of Blueprint Medicines’ team and the differentiation of its kinase-focused drug discovery platform, which combines an innovative target discovery engine with a first-of-its-kind fully-annotated chemical library."
Using proprietary computational tools and techniques, Blueprint Medicines’ scientists identified RET fusions in four of 20 cancer types analyzed, including thyroid, lung, breast and colon cancers, providing a strong rationale for the development of a novel RET inhibitor across multiple patient populations. The identification of RET fusions in colon and breast cancers was one of the novel findings in the research. Combining genomics with structural and cell biology, Blueprint Medicines’ scientists were able to predict future resistance mutations of RET inhibitors currently in clinical studies. Blueprint Medicines’ drug discovery is ongoing.
Blueprint Medicines’ new RET inhibitor program adds to the Company’s existing pipeline, consisting of BLU-285, the first known selective inhibitor of KIT Exon 17 for patients with systemic mastocytosis and gastrointestinal stromal tumors (GIST), and BLU-554, the first known selective FGFR4 inhibitor for patients with hepatocellular carcinoma (HCC). Blueprint Medicines expects to initiate clinical trials for its KIT and FGFR4 programs in 2015.
Fusion genes (or fusions) are known to contribute to the development of cancers. A fusion gene is formed from the abnormal association of two normally separated genes, as a result of a translocation or other chromosomal rearrangements. Fusion genes are proven cancer drug targets, and a number of approved and exploratory drugs target kinase fusions.

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On November 20, 2014 Nektar Therapeutics reported results of a study investigating the preclinical anti-tumor activity and tolerability of etirinotecan pegol (NKTR-102) in combination with the PARP inhibitor rucaparib in a BRCA1-deficient MX-1 breast tumor model (Press release Nektar Therapeutics, NOV 20, 2014, View Source [SID:1234500995]). The preclinical study results demonstrated that all dose combinations of NKTR-102 and rucaparib were well-tolerated, synergistic, and led to 100% prolonged survival in this tumor model. These data were presented during the Symposium on Molecular Targets and Cancer Therapeutics in Barcelona, Spain, sponsored by the European Organisation for Research and Treatment of Cancer (EORTC), the National Cancer Institute (NCI) and the American Association for Cancer Research (AACR) (Free AACR Whitepaper).

"We are encouraged by these results which demonstrate that NKTR-102 in combination with the PARP inhibitor rucaparib has a synergistic effect resulting in 100% prolonged survival in a BRCA 1-deficient tumor model," said Stephen K. Doberstein, Ph.D., senior vice president and chief scientific officer of Nektar Therapeutics. "As a next-generation topo-I inhibitor with broad anti-tumor activity, NKTR-102 has the potential to be combined with a number of targeted agents in multiple tumor settings."

NKTR-102 is the first long-acting topoisomerase I inhibitor with an extended half-life and a unique structure that is also designed to concentrate the drug in tumors. In patients, NKTR-102 leads to greatly prolonged plasma SN38 exposure compared to irinotecan (elimination half-life of 50 days compared to 2 days) yet peak SN38 concentrations are at least 5- to 10-times less, which may also result in a favorable tolerability profile.

Preclinical Study Design and Results
Study investigators initiated tumor xenografts with MX-1 human breast carcinomas maintained by serial subcutaneous transplantation in female athymic nude (Crl:NU(Ncr)-Foxn1nu), 8-week-old mice. On the day of tumor implant, each test mouse received a 1-mm3 MX-1 fragment implanted subcutaneously in the right flank. Animals were randomized into treatment groups (n=10/grp) when their tumors reached 63-196 mm3 and subsequently received either vehicle, NKTR-102, rucaparab, or combinations of NKTR-102 + rucaparib. Doses selected were known to provide clinically relevant exposure levels. Twice weekly, animals were weighed, and tumor volumes were measured until the endpoint (2000 mm3 or Day 88) was met. Efficacy was measured by tumor growth delay and regression response rate.

NKTR-102 and rucaparib in combination exhibited marked synergy, demonstrated by durable complete responses, even at the lowest doses of both agents dosed in combination. The combination of NKTR-102 and rucaparib was tolerated at all dose levels. Doses used in this study provide exposures of NKTR-102 (SN38 trough) and rucaparib that are achievable clinically, underscoring the translational relevance of these results.

Combination studies of NKTR-102 and rucaparib are ongoing in patient-derived xenograft models in collaboration with Professor Paul Haluska at Mayo Clinic and Clovis Oncology.

On November 20, 2014 Deciphera Pharmaceuticals reported the presentation of preclinical data which demonstrated that altiratinib (DCC-2701) provided balanced inhibition of MET, TRK, TIE2 and VEGFR2 kinases (Press release Deciphera Pharmaceuticals, NOV 20, 2014, View Source [SID:1234500992]). Altiratinib exhibited potency against both wild-type and mutant forms of MET and TRK kinases. In in vivo studies, altiratinib was shown to inhibit tumor growth, evasive vascularization, invasion and/or metastasis. In one model an increased overall survival was observed. Altiratinib exhibited anti-tumor activity in a variety of xenograft or allograft tumor models, including melanoma, gastric, lung, colorectal, breast, ovarian and glioblastoma. These data were presented today at the 26th EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Symposium on Molecular Targets and Cancer Therapeutics in Barcelona, Spain. Altiratinib is currently in a Phase 1 clinical study in cancer patients with solid tumors.

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"In this preclinical data set, the profile observed with altiratinib demonstrated robust and durable inhibition of kinases related to multiple hallmarks of cancer., Our data demonstrate blocking of tumor progression and growth and tumor microenvironment related mechanisms, including evasive vascularization and metastasis in a variety of cancer models," said Michael D. Taylor, PhD, Deciphera’s President and Chief Executive Officer. "We look forward to further evaluation of altiratinib’s anti-cancer activity, including top-line data from our ongoing Phase 1 clinical study in patients with advanced solid tumors which is expected in mid-2015."

In a poster presentation titled "Altiratinib: a balanced inhibitor of MET, TRK, TIE2, and VEGFR2 kinases that exhibits broad anti-tumor and anti-angiogenic activities," Deciphera researchers described data which demonstrated that altiratinib inhibited tumors driven by MET amplification, overexpression, or mutation and also provided the potential for blocking tumor microenvironment angiogenic resistance mechanisms and pro-tumoral effects. Findings from the data include:

Altiratinib potently inhibited MET, TIE2, VEGFR2, and TRK kinases in functional cellular assays, including activity against proliferation, migration, and capillary tube formation, and with sufficient single-digit nanomolar potency such that all of these targets could be effectively inhibited simultaneously in vivo.
Altiratinib exhibited efficacy at preventing tumor growth, as well as inhibiting evasive vascularization, pro-tumoral macrophages, epithelial-to-mesenchymal transition (EMT) and metastasis in a variety of cancer models.
Altiratinib inhibited MET kinase for more than 24 hours after a single 10 mg/kg dose in a gastric cancer xenograft model leading to significant inhibition of tumor growth.
Altiratinib blocked bevacizumab-induced evasive vascularization and EMT in an aggressive, invasive glioblastoma model.
Altiratinib inhibited primary tumor growth and showed additive activity with paclitaxel; in addition, it reduced TIE2-expressing macrophages in the tumor stroma and significantly reduced lung metastases in a metastatic breast cancer model.
Altiratinib exhibited a long off-rate from kinases (greater than 24 hours from TIE2 and TRKA) in a variety of cell-based assays, based on its binding mode.
Altiratinib inhibited microvessel density and tumor growth in a xenograft model where both TIE2 and VEGFR2 kinases contribute to vessel growth.
Altiratinib compared favorably with other multi-targeted MET inhibitors, and had additional activity in inhibiting oncogenic MET mutants found in papillary renal cell carcinoma (PRCC), while other MET inhibitors have not been shown to inhibit activated MET mutants.