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Roche provides update on Phase III MARIANNE study in people with previously untreated advanced HER2-positive breast cancer

On December 19, 2014 Roche reported top-line results of the Phase III MARIANNE study (Press release Hoffmann-La Roche, DEC 19, 2014, View Source [SID:1234501215]). The study evaluated three HER2-targeted regimens – Kadcyla (trastuzumab emtansine) plus Perjeta (pertuzumab), Kadcyla alone, and Herceptin (trastuzumab) plus taxane chemotherapy – in people with previously untreated (first line) advanced HER2-positive breast cancer. The study showed the three regimens helped people live without their disease worsening (PFS) for a similar amount of time, meeting its non-inferiority endpoint as assessed by an Independent Review Committee (IRC). However, neither Kadcyla-containing treatment arm significantly improved PFS compared to Herceptin and chemotherapy. Adverse events observed in the two experimental arms of the study were generally consistent with those seen in previous studies of Kadcyla and/or Perjeta.

In their approved uses for advanced HER2-positive breast cancer, Kadcyla and Perjeta have been shown to extend survival. Kadcyla is approved for people with previously treated disease (second and later lines). Perjeta is approved in combination with Herceptin and chemotherapy for people with previously untreated disease (first line).

“Over the past 30 years, we have made significant progress in treating one of the most aggressive forms of advanced breast cancer with medicines that extend patients’ lives across the course of their disease. In this study, we had hoped to show improvement in progression-free survival without the use of traditional chemotherapy in the first line treatment of patients with advanced HER2-positive breast cancer,” said Sandra Horning, MD, Roche’s Chief Medical Officer and Head of Global Product Development. “While MARIANNE didn’t achieve this result, we will continue to study these medicines, as well as investigational treatments for other types of breast cancer, with the goal of improving outcomes for patients.”

Data from the MARIANNE study will be presented at an upcoming medical meeting. Roche will discuss the data with health authorities.

About the MARIANNE Study

The Phase III MARIANNE study (NCT01120184; BO22589) is an international, randomized, multicenter, three-arm study involving 1,095 people with HER2-positive advanced breast cancer – either with inoperable locally advanced disease that had worsened during or returned after previous treatment, or with disease that had spread to other areas of the body.2 People with advanced breast cancer at diagnosis and people whose disease had worsened following either neoadjuvant or adjuvant treatment were eligible.

People enrolled in the study received treatment with either:

A combination of Kadcyla and Perjeta
Kadcyla alone, or
Herceptin and either docetaxel or paclitaxel chemotherapy.

The primary endpoint of the MARIANNE study is PFS as assessed by an Independent Review Committee (IRC). Secondary endpoints include overall survival, response rate, and the incidence of adverse events. Differences in these endpoints were assessed in each of the Kadcyla-containing treatment arms compared to the Herceptin plus chemotherapy arm, and also between the two Kadcyla-containing arms.

Merck Acquires OncoEthix, a Privately Held Oncology Company Developing Novel BET Inhibitors for Hematological and Solid Cancers

On December 18, 2014 Merck, known as MSD outside the United States and Canada, reported that it has acquired, through a subsidiary, OncoEthix, a Swiss-based privately held biotechnology company specializing in oncology drug development (Press release Merck & Co, DEC 18, 2014, View Source [SID:1234501212]). Through the acquisition, Merck has gained an investigational, novel oral BET (bromodomain) inhibitor, OTX015, which is currently in Phase 1b studies for the treatment of hematological malignancies and advanced solid tumors.

“Oncology is a priority area of focus for Merck and the acquisition of OncoEthix supports our strategy to prioritize the development of innovative molecules with the potential to improve the treatment of advanced cancers,” said Dr. Roy Baynes, senior vice president, global clinical development, Merck Research Laboratories. “The potential first-in-class oral BET inhibitor, OTX015, has demonstrated early promising activity in hematological cancers and strategically complements our broad immuno-oncology development program.”

“We are delighted that OTX015 will now be in the hands of Merck, a company with a successful track record of developing cutting-edge therapies,” said Bertrand Damour, chief executive officer, OncoEthix. “The acquisition underlines the promise that OTX015 has shown in the treatment of hematological malignancies, and the potential it has for the treatment of advanced solid tumors. We are confident that our transaction with Merck best positions OTX015 to be developed to its full potential in areas of high unmet medical need.”

BET proteins are considered potential therapeutic targets in cancer, as they play a pivotal role in regulating the transcription of key regulators of cancer cell growth and survival, including c-Myc. Interim data from ongoing Phase I clinical studies of OTX015 have demonstrated meaningful clinical activity in patients with hematological malignancies. Interim data were recently presented at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in April 2014. An international, open-label Phase 1 study evaluating OTX015 in five different solid tumors was initiated in November 2014.

Financial terms of the acquisition include an upfront payment of up to $110 million to OncoEthix. Additional milestone payments of up to $265 million are contingent upon certain clinical and regulatory events being achieved.

NewGen Therapeutics Targeted Anti-Cancer Drug, NT-113, Demonstrates Compelling Activity in Glioblastoma Xenograft Models

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.

CRT Pioneer Fund banks £20m investment from BACIT and expands agreement with Chroma Therapeutics to develop cancer immunotherapies

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]).

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."

U. S. Food and Drug Administration approved lanreotide

On December 16, 2014, the U. S. Food and Drug Administration approved lanreotide (Somatuline Depot Injection, Ipsen Pharma) for the treatment of patients with unresectable, well or moderately differentiated, locally advanced or metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs) to improve progression-free survival (External Source US FDA, Ipsen, DEC 16, 2014, View Source [SID:1234501196]). Lanreotide was previously approved for the long-term treatment of acromegalic patients who have had an inadequate response to surgery and/or radiotherapy, or for whom surgery and/or radiotherapy is not an option.

The approval was based on demonstration of improved progression-free survival (PFS) in a multi-center, international, randomized (1:1), double-blind, placebo-controlled study (Trial 2- 55-52030-726) that enrolled 204 patients with unresectable, well- or moderately-differentiated, locally advanced or metastatic, non-functioning GEP-NETs. Fifty-five percent of patients (113/204) had neuroendocrine tumors arising outside the pancreas. Patients were randomized to receive either lanreotide 120 mg or placebo subcutaneously every 28 days.

The primary efficacy endpoint was PFS as determined by independent radiology review. The trial demonstrated a significant prolongation of PFS for the lanreotide arm [HR 0.47 (95% CI: 0.30, 0.73); p < 0.001; log-rank test]. The median PFS in the lanreotide arm had not been reached at the time of the final analysis and will exceed 22 months. The median PFS in the placebo arm was 16.6 months. Safety data were evaluated in 101 patients who received at least one dose of lanreotide. The most commonly (greater than or equal to 10%) reported adverse reactions in lanreotide-treated patients were abdominal pain, musculoskeletal pain, vomiting, headache, injection site reaction, hyperglycemia, hypertension, and cholelithiasis. The most common serious adverse reaction of lanreotide observed in this trial was vomiting (4%). The recommended dose and schedule for lanreotide for GEP-NET is lanreotide 120 mg administered by deep subcutaneous injection every 28 days. Treatment should continue until disease progression or unacceptable toxicity. Full prescribing information is available at: View Source