On December 19, 2014 Chugai Pharmaceutical reported that it filed an application with the Japanese Ministry of Health, Labour and Welfare (hereafter, MHLW) for the approval of an additional indication of "postoperative adjuvant chemotherapy for gastric cancer," for the anti-cancer agent, capecitabine (brand name: Xeloda Tablet 300) (hereafter, "Xeloda) (Press release Chugai, DEC 19, 2014, View Source [SID:1234501214]). In Japan, Xeloda is currently marketed for these indications of "inoperable or recurrent breast cancer," "postoperative adjuvant chemotherapy for colon cancer," "advanced or refractory colorectal cancer, which is not amenable to curative resection" and "advanced or recurrent gastric cancer, which is not amenable to curative resection."

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Chugai filed an application for approval with the MHLW based on the results of two studies: One is a Phase III study MO17527/L9570 (The CLASSIC study) conducted in foreign countries. Another is a Japanese Phase II study (MO28223/LOHP-PII-06) that was co-developed by Chugai and Yakult Honsha Co., Ltd. (Main Office: Minato-ku, Tokyo. President COO: Takashige Negishi).
In The CLASSIC study, patients were randomized to receive either combination therapy of Xeloda and oxaliplatin after curative gastrectomy (combination group) or surgery alone with follow-up (follow-up group). Disease-free survival (DFS) was evaluated as the primary endpoint.
As a result, the 3-year DFS rate was 74% in the combination group and 59% in the follow-up group, demonstrating statistically significant prolongation of DFS in the combination group (hazard ratio: 0.56, 95% confidence interval: 0.44 to 0.72, P<0.0001). Also, for overall survival, a secondary endpoint, 5-year survival was 78% in the combination group and 69% in the follow-up group, showing significant prolongation in the combination group (hazard ratio: 0.66, 95% confidence interval: 0.51 to 0.85, P=0.0015). The safety profile shown in the combination group was the same as those which have been reported for the two drugs.
The Japanese Phase II study investigated dose intensity (DI: cumulative dose of each drug actually administered / cumulative dose when 8 cycles were completed without treatment interruption or dose reduction) of Xeloda and oxaliplatin combination therapy as the primary endpoint. The results of the Japanese Phase II study will be presented at academic conferences and through other means.

Xeloda was developed by Nippon Roche K.K. (currently Chugai) and approved in 1998 for the first time in the US, Switzerland and Canada, in 2001 in the EU and has been approved in more than 100 countries worldwide. It has been authorized for the indication of "gastric cancer" in more than 95 countries.

Gastric cancer is prevalent in Asian countries including Japan, South Korea and China as well as in South America. In Japan, the number of patients newly diagnosed with gastric cancer continues to rise each year and is estimated to become, on annual average, approximately 133,900 during 2010-2014.

Chugai strongly believes that Xeloda will make a contribution to patients as a treatment option for "postoperative adjuvant chemotherapy for gastric cancer." In order Xeloda to be accessible for patients and healthcare professionals sooner, Chugai will continue its effort to receive an approval as soon as possible.

On December 19, 2014 AstraZeneca reported that the US Food and Drug Administration (FDA) has approved LYNPARZA (olaparib) capsules (400mg twice daily) as the first monotherapy for patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) advanced ovarian cancer, who have been treated with three or more prior lines of chemotherapy (Press release, AstraZeneca, DEC 18, 2014, View Source;lynparza-approved [SID:1234502431]). Olaparib has been approved under the FDA’s Accelerated Approval programme, based on existing objective response rate and duration of response data. Continued approval for this indication is contingent upon verification of clinical benefit in ongoing confirmatory Phase III trials.

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Olaparib is a poly ADP-ribose polymerase (PARP) inhibitor that exploits tumour DNA repair pathway deficiencies to preferentially kill cancer cells. It is the first PARP inhibitor to be approved for patients with germline BRCA-mutated advanced ovarian cancer, as detected by an FDA approved companion diagnostic test, BRACAnalysis CDx.

Dr. Briggs Morrison, Executive Vice President, Global Medicines Development and Chief Medical Officer at AstraZeneca, said "LYNPARZA is an excellent example of how advances in the understanding of cancer biology can be used to develop the next generation of targeted medicines. It is a much-needed new therapeutic option for patients with germline BRCA-mutated advanced ovarian cancer. Today’s approval also marks the first of what we hope will be a number of indications in which this medicine has the potential to improve the lives of cancer patients."

AstraZeneca filed a US regulatory submission for olaparib in February 2014, based on data from a Phase II maintenance study1 of olaparib compared to placebo in platinum-sensitive relapsed high grade serous ovarian cancer patients. Following the FDA Oncologic Drugs Advisory Committee recommendation on 25 June 2014 and in response to an FDA request for additional data, AstraZeneca submitted a major amendment to the olaparib New Drug Application on 24 July 2014. The FDA approval is therefore based on efficacy data from a single-arm, open-label, Phase II study2 of olaparib in patients with deleterious or suspected deleterious germline BRCA-mutated advanced cancers, as well as safety data from several other olaparib studies, including the placebo-controlled study.

The efficacy of olaparib is based on analysis of 137 patients with measurable, germline BRCA mutated advanced ovarian cancer treated with three or more prior lines of chemotherapy. The trial results demonstrated an overall response rate of 34% (95% Confidence Interval: 26%, 42%). The median response duration was 7.9 months (95% Confidence Interval: 5.6, 9.6 months). The most common adverse events associated with olaparib monotherapy to date have been generally mild to moderate and have included nausea, vomiting, fatigue and anaemia.

Dr. Ursula Matulonis, Associate Professor of Medicine, Harvard Medical School and Director of the Gynaecological Oncology Programme at the Dana-Farber Cancer Institute, Boston said: "Ovarian cancer is diagnosed in nearly 22,000 women per year. The long-term survival rate in patients with advanced ovarian cancer is 10% to 30%. The FDA approval of LYNPARZA is a significant milestone for our patients as currently there are only limited treatment options available to women with ovarian cancer who carry the BRCA mutation."

A full review of data from either of two ongoing studies under the SOLO Phase III clinical programme will be required for the accelerated approval of olaparib in BRCA-mutated advanced ovarian cancer to be converted to a full approval: SOLO2 is evaluating olaparib compared to placebo as a maintenance therapy and SOLO3 is evaluating olaparib compared to standard chemotherapy for relapsed disease. Data from the SOLO2 study is expected in 2015 and data from SOLO3 is expected in 2019.

The FDA’s approval follows the announcement on 18 December of the approval of olaparib in the European Union, as the first therapy for the maintenance treatment of adult patients with platinum-sensitive relapsed BRCA-mutated serous ovarian cancer.

1 Ledermann J et al. Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial. Lancet Oncology. 2014. View Source(14)70228-1

2 Kaufman B, Shapira-Frommer R, Schmultzler RK et al. Olaparib Monotherapy in Patients With Advanced Cancer and a Germline BRCA1/2 Mutation. Journal of Clinical Oncology 2014. View Source

On December 16, 2014 The Cancer Research Technology Pioneer Fund (CPF or the Fund) reported an additional £20m investor commitment from BACIT Limited (BACIT), taking the total fund to £70m (Press release, Cancer Research Technology, DEC 16, 2014, View Source [SID1234523215]).

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The news comes as the fund announces its fifth research investment, expanding its agreement with Chroma Therapeutics Ltd to develop drugs that use immune cells called macrophages – a type of white blood cell – to deliver drugs directly into tumours.

The CPF was established in 2012 by the European Investment Fund and Cancer Research Technology Ltd. It bridges the gap in cancer research between late discovery and Phase II clinical trials. Through its relationship with CRT, the Fund has access to drug discovery and development programmes funded by Cancer Research UK.

Today’s announcement takes the total capital now committed to the Fund to £70m which will allow the CPF to invest in a larger portfolio of cancer research projects and have the potential to develop existing projects further.

Today’s announcement includes an expansion of the license from Chroma to the CPF for all rights in oncology to its Esterase Sensitive Motif (ESM) technology*.

The ESM technology incorporates specific chemical motifs – such as cancer drugs – into active compounds, which are freely transported into cells. Once inside the cell, a specific enzyme found only in certain type of macrophage targeted at tumours, removes the motifs to create a compound that cannot easily exit the cell. Over time, the compound selectively accumulates in the macrophages to significant levels and it becomes active in fighting cancer cells.

Dr Robert James, managing partner of Sixth Element Capital, said: "We’re very excited to welcome BACIT as an additional investor. This enables us to create an even more diversified portfolio of novel world-class cancer therapeutics.

"The expansion of the Chroma agreement enables CPF to develop a portfolio of projects that modulate the immune system. Immunotherapy is an extremely exciting area in cancer research. Developing small molecules which activate the immune system to fight cancer could be of great importance to cancer patients."

Richard Bungay, chief executive of Chroma, said: "It is now widely accepted that modulation of a patients’ own immune system will be an important tool in the fight against cancer. Consequently, we are very pleased to have expanded our collaboration with CPF, which will facilitate further significant investment in our portfolio of novel immunotherapy treatments, and potentially expand the disease targets that the ESM macrophage-targeting technology is applied to."

Dr Piyush Unalkat, Principal – Equity Investments, commented: "I’m extremely pleased to see BACIT formalising its investment to CPF, bringing the fund to £70m. BACIT, CRT and EIF are long-term investors aligned in their mission to catalyse the development of new therapies to fight cancer, of which the ESM technology is a good example. The CPF is a cost efficient model and the additional resources shall allow for more investments than were originally foreseen."

Dr Keith Blundy, CEO of Cancer Research Technology, said: "BACIT’s investment in the CPF is warmly welcomed and will help us further accelerate drug discovery research to bring potential new treatments to patients sooner. Immunotherapy research is looking increasingly promising for the treatment of cancer, so I am delighted to see the progress that the CPF is making in attracting new investment to help bridge the UK’s innovation gap in this important area."

On December 16, 2014 NewGen Therapeutics reported the publication of preclinical research strongly supporting NT-113, the company’s novel irreversible pan-erbB inhibitor (EGFR, HER2 and HER4), as a potential new treatment for glioblastoma multiforme (GBM), the most common and most aggressive malignant primary brain tumor in adults (Press release, NewGen Therapeutics, DEC 16, 2014, View Source [SID1234633118]).

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Researchers demonstrated that NT-113 was active against a variety of patient-derived GBM xenografts in which EGFR is amplified, overexpressed and/or expresses the disease-driving EGFRvIII mutation. In studies of intracranial mouse xenografts comparing NT-113 to the approved anticancer therapeutics lapatinib and/or erlotinib, NT-113 was associated with statistically significant improvement in survival. NT-113 both reduced tumor cell proliferation and induced apoptosis (controlled cell death). In previous pharmacokinetic studies, NT-113 demonstrated a long half-life and a high propensity to cross the blood brain barrier.

Researchers concluded that the pan-erbB inhibitory activity of NT-113 and downstream inhibition of Akt provide mechanistic rationale for its heightened anti-tumor activity. Excellent bio-distribution into the brain is also believed to contribute to the anti-GBM xenograft activity of NT-113. NT-113 was active in other GBM xenograft studies including one in which the cells are PTEN deficient, a known resistance mechanism for EGFR inhibitors, and another where cells overexpress both EGFR and HER2. Data support advancing NT-113 into clinical development for the treatment of erbB positive GBM, including patients with the disease driving EGFRvIII mutation.

The findings by NewGen and the company’s collaborators at Northwestern University and The University of California, San Francisco and the Mayo Clinic were published in the December 2014 issue of Molecular Cancer Therapeutics.

Harry D. Pedersen, NewGen Therapeutics President and Chief Executive Officer commented, "EGFR, HER2 and HER4 are part of the erbB family of tyrosine kinase receptors, and 90% of solid tumors have a mutation in at least one erbB receptor family member. By irreversibly inhibiting all family members we hope to shut down the individual receptors and the cooperative signaling between family members associated with resistance."

NT-113 readily penetrates the blood brain barrier resulting in 4-8 times drug concentration in the brain relative to plasma. First-generation EGFR inhibitors like erlotinib and lapatinib are reversible and have very limited penetration of the central nervous system.

"GBM is a molecularly complex disease with significant unmet medical need: over 50% of patients have genetic alterations in EGFR or HER2," Mr. Pedersen said. "These data provide a strong rationale for the clinical investigation of NT-113 in this patient population. We anticipate beginning clinical trials in early 2016."

About NT-113

NT-113 is a potent oral irreversible pan-erbB inhibitor designed specifically to:

Target mutations in both the extracellular domain of EGFR (characteristic of GBM) and the intracellular domain of EGFR (characteristic of other tumours such as NSCLC),
Improve drug delivery into the brain to optimize drug delivery and treatment of patients with primary glioblastoma or brain metastases from an EGFR driven extracellular primary,
Overcome resistance to first generation erbB inhibitors by targeting redundancy in the pathway, and
Improve the efficacy of erbB-targeted therapies by irreversibly inhibiting multiple erbB receptors, and interfering with the cooperation that exists between receptors.

On December 15, 2014 Ignyta reported that it has entered into an amendment to its license agreement with Nerviano Medical Sciences, S.r.l. relating to its entrectinib (formerly RXDX-101) product candidate (Press release Ignyta, DEC 15, 2014, View Source [SID:1234501188]). The amendment modifies the milestones that would trigger the initial three milestone payments specified in the license agreement. Pursuant to the amendment, the initial milestone payment of $10 million will be due and payable to Nerviano by December 31, 2014, and the second and third milestone payments will be triggered by revised clinical and/or regulatory events relating to entrectinib or other licensed products. The amounts of such milestone payments have not changed.

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"The promising clinical data observed with entrectinib have spurred us to develop a more ambitious clinical development plan that enables us to accelerate development while also pursuing multiple opportunities in parallel for this exciting product candidate," said Jonathan Lim, M.D., Chairman and CEO of Ignyta. "Under the previous structure, there were future milestone payments that posed potential financial disincentives for Ignyta to accelerate the clinical development program or pursue multiple indications due to potential stacking of milestone payments. By accelerating the first payment, pushing back subsequent payments, and modifying the triggers for milestone payments under our agreement with Nerviano, we have better aligned the companies’ interests. Ignyta may now strategically accelerate the development and potential commercialization of entrectinib for the benefit of cancer patients."