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Novartis drug Afinitor® extended progression-free survival in Phase III trial in advanced gastrointestinal or lung neuroendocrine tumors

On May 21, 2015 Novartis reported that the Phase III study of Afinitor (everolimus) tablets plus best supportive care in patients with advanced nonfunctional neuroendocrine tumors (NET) of gastrointestinal (GI) or lung origin met its primary endpoint: significant extension of progression-free survival (PFS) compared to placebo plus best supportive care[1] (Press release, Novartis, MAY 21, 2015, View Source [SID:1234504609]). The RADIANT-4 study is part of one of the largest clinical trial programs in NET[1].

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NET are a rare type of cancer that originate in neuroendocrine cells found throughout the body, and are most often found in the GI tract, lungs or pancreas[4]. NET can be functional or nonfunctional: functional NET produce symptoms caused by the secretion of hormones and other substances; nonfunctional NET do not secrete hormones, and may only produce symptoms caused by the tumor’s growth, such as intestinal blockage, pain and bleeding[5],[6],[7]. At time of diagnosis, up to 44% of patients with GI NET and 28% of patients with lung NET have advanced disease, meaning the cancer has spread to other parts of the body and is more difficult to treat[2],[3],[4]. There are limited treatment options for patients with advanced GI or lung NET[4].

"We look forward to presenting the findings from the RADIANT-4 trial of everolimus, which has the potential to become an important treatment option for patients with advanced nonfunctional GI or lung NET," said Alessandro Riva, MD, Global Head, Novartis Oncology Development and Medical Affairs. "The results will serve as the basis of planned worldwide regulatory filings for everolimus in these two types of NET, bringing us closer to our goal of offering Afinitor for these patients."

Full results from the RADIANT-4 study will be submitted to a major medical meeting. Worldwide regulatory filings are planned for 2015.

About RADIANT-4

RADIANT-4 is a Phase III prospective, double-blind, randomized, parallel group, placebo-controlled, multicenter study. The trial examined the efficacy and safety of everolimus plus best supportive care versus placebo plus best supportive care in 302 patients with well differentiated advanced NET of GI or lung origin, and no history or active symptoms of carcinoid syndrome, who had documented disease progression within the previous 6 months. Patients were randomized 2:1 to receive either daily everolimus 10 mg or daily placebo orally.

The primary endpoint of RADIANT-4 was PFS. Secondary endpoints included safety, objective response rate and overall survival.

About Afinitor (everolimus) tablets

Afinitor (everolimus) is approved in more than 95 countries, including the United States and throughout the European Union, for locally advanced, metastatic or unresectable progressive neuroendocrine tumors of pancreatic origin. It is also approved in 119 countries including the United States and European Union for advanced renal cell carcinoma following progression on or after vascular endothelial growth factor (VEGF)-targeted therapy.

Afinitor is approved in the European Union for the treatment of hormone receptor-positive, human epidermal growth factor receptor-2 negative (HR+/HER2-) advanced breast cancer, in combination with exemestane, in postmenopausal women without symptomatic visceral disease after recurrence or progression following a non-steroidal aromatase inhibitor (NSAI). In the United States, Afinitor is approved for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2 negative (advanced HR+/HER2-) breast cancer in combination with exemestane after failure of treatment with letrozole or anastrozole.

Everolimus is also available from Novartis for use in certain non-oncology patient populations under the brand names Afinitor or Votubia, Certican and Zortress and is exclusively licensed to Abbott and sublicensed to Boston Scientific for use in drug-eluting stents.

Indications vary by country and not all indications are available in every country. The safety and efficacy profile of everolimus has not yet been established outside the approved indications. Because of the uncertainty of clinical trials, there is no guarantee that everolimus will become commercially available for additional indications anywhere else in the world.

Important Safety Information about Afinitor (everolimus) tablets

Afinitor/Votubia can cause serious side effects including lung or breathing problems, infections (including sepsis), and kidney failure, which can lead to death. Patients taking concomitant angiotensin-converting enzyme (ACE) inhibitors may be at an increased risk for angioedema. Mouth ulcers and mouth sores are common side effects. Afinitor/Votubia can affect blood cell counts, kidney and liver function, and blood sugar, cholesterol, and triglyceride levels. Afinitor/Votubia may cause fetal harm in pregnant women. Highly effective contraception is recommended for women of child-bearing potential while receiving Afinitor/Votubia and for up to eight weeks after ending treatment. Women taking Afinitor/Votubia should not breast feed. Fertility in women and men may be affected by treatment with Afinitor/Votubia.

The most common adverse drug reactions (incidence >=10 percent) are mouth ulcers, skin rash, feeling tired or weak, diarrhea, absence of menstrual periods, infections (including upper respiratory tract infection, sore throat and runny nose, sinusitis, and pneumonia), nausea, decreased appetite, low level of red blood cells, high levels of cholesterol, abnormal taste, acne, irregular menstrual periods, inflammation of lung tissue, high level of blood sugar, weight loss, itching, swelling of extremities or other parts of the body, nose bleeds, and headache. The most common Grade 3-4 adverse drug reactions (incidence >=2 percent) are mouth ulcers, absence of menstrual periods, low level of red blood cells, infections (including pneumonia), high level of blood sugar, feeling tired or weak, low white blood cells, inflammation of lung tissue, diarrhea, and spontaneous bleeding or bruising. Cases of hepatitis B reactivation, blood clots in the lung or legs, and pneumocystis jirovecii pneumonia (PJP) have been reported. Abnormalities were observed in hematology and clinical chemistry laboratory tests.

10-Q – Quarterly report [Sections 13 or 15(d)]

Cellectar Biosciences has filed a 10-Q – Quarterly report [Sections 13 or 15(d)] with the U.S. Securities and Exchange Commission (Filing, 10-Q, Cellectar Biosciences, MAY 20, 2015, View Source [SID1234504606]).

EISAI LAUNCHES IN-HOUSE DEVELOPED NOVEL ANTICANCER AGENT LENVIMA(R) (LENVATINIB MESYLATE) AS TREATMENT FOR UNRESECTABLE THYROID CANCER IN JAPAN

On May 20, 2015 Eisai reported that it has launched its in-house developed novel anticancer agent Lenvima Capsule 4 mg and 10 mg (lenvatinib mesylate, "Lenvima") as a treatment for unresectable thyroid cancer in Japan on May 20, 2015 (Press release, Eisai, MAY 20, 2015, View Source [SID:1234504597]).

Lenvima is the first molecular targeted treatment in Japan approved with an indication for unresectable thyroid cancer which covers differentiated thyroid cancer as well as medullary thyroid carcinoma and anaplastic thyroid carcinoma. In a global Phase III study (the SELECT study) of Lenvima in differentiated thyroid cancer, Lenvima demonstrated a statistically significant extension in progression free survival and improved response rates compared to placebo(1). In the SELECT study, the five most common Lenvima treatment-related adverse events of any grade were hypertension, diarrhea, fatigue or asthenia, decreased appetite, and weight loss. Furthermore, a Phase II study (Study 208) conducted in Japan suggested tolerability and efficacy of Lenvima in medullary thyroid carcinoma and anaplastic thyroid carcinoma as well.

The number of patients with thyroid cancer in Japan is estimated to be between 13,000 and 29,000. Although treatment is possible for most types of thyroid cancer, there are few treatment options available for unresectable thyroid cancer and so there is a pressing need for the development of new treatment options. With a high degree of clinical malignancy and a prognosis among the worst of all types of cancer, anaplastic thyroid carcinoma in particular is a disease with significant unmet medical needs. Eisai hopes that Lenvima will make a contribution to patients as a new standard treatment for unresectable thyroid cancer, which has no established standard treatment in Japan at present.

Discovered at Eisai’s Tsukuba Research Laboratories and developed in-house, Lenvima is an orally administered molecular targeted agent that selectively inhibits the activities of several different molecules including VEGFR, FGFR, RET, KIT and PDGFR. In particular, the agent simultaneously inhibits VEGFR, FGFR and also RET which are especially involved in tumor angiogenesis and proliferation of thyroid cancer. Furthermore, Lenvima has been confirmed through X-ray co-crystal structural analysis to demonstrate a new binding mode (Type V) to VEGFR2, and exhibits rapid binding to the target molecule and potent inhibition of kinase activity, according to kinetic analysis(2).

Lenvima was launched in the United States in February 2015, and received a positive opinion from the European Medicines Agency’s Committee for Medicinal Products for Human Use in March 2015. In addition, the agent is currently undergoing regulatory review in Switzerland, South Korea, Canada, Singapore, Russia, Australia and Brazil. Furthermore, Eisai is conducting a global Phase III study of Lenvima in hepatocellular carcinoma as well as Phase II studies of Lenvima in several other tumor types such as renal cell carcinoma and non-small cell lung cancer.

In addition to providing Lenvima as a new treatment option for thyroid cancer, in accordance with the conditions of approval, Eisai will work after launch to carry out a special use investigation (all-case study) and promote the appropriate use of Lenvima. Eisai is committed to exploring the potential clinical benefits of Lenvima in order to further contribute to, and address the diverse needs of, patients with cancer, and their families.

SignalRx Pharmaceuticals Inc. Awarded STTR Grant from the National Institutes of Health for Development of Dual PI3 Kinase/Bromodomain Inhibitors as Anticancer Agents

On May 19, 2015 SignalRx Pharmaceuticals Inc., focused on developing more effective oncology drugs though molecular design imparting selective multiple target inhibition, reported that it has received non-dilutive funding to advance the preclinical development of unique small molecule inhibitors designed to inhibit multiple critical cancer targets (Press release, SignalRx, MAY 19, 2015, http://www.ireachcontent.com/news-releases/signalrx-pharmaceuticals-inc-awarded-sttr-grant-from-the-national-institutes-of-health-for-development-of-dual-pi3-kinasebromodomain-inhibitors-as-anticancer-agents-504347611.html [SID1234527329]).

SignalRx was awarded a Phase 1 Small Business Technology Transfer Research (STTR) grant from the National Cancer Institute (NCI), a division of the National Institutes of Health (NIH), in support of the preclinical development of novel small molecules that simultaneously inhibit two key cancer targets: PI3kinase (PI3K) and the bromodomain protein BRD4. The principal investigator on the STTR grant is SignalRx’s scientific advisor Dr. Donald Durden, MD, PhD who also serves as the academic collaborator for the grant while in his capacity as the Associate Director for Pediatric Oncology at the Moores UCSD Cancer Center at the University of California, San Diego.

Inhibiting the key cancer promoting transcription factor MYC (both cMYC and MYCN) is vigorously pursued since this inactivates many genes that drive cancer cell growth and proliferation. To date, small molecule inhibitors of MYC have been elusive. SignalRx’s innovative approach is to indirectly orthogonally diminish the activity of MYC by enhancing its degradation using PI3K inhibition combined with simultaneous blocking the transcription of the gene producing MYC via inhibition of the bromodomain protein BRD4—all resulting from a single molecule. Combination treatments are necessary in cancer, and there is an ever increasing need for more complex combinations to inhibit multiple targets to maximize efficacy. However, combining single-action drugs becomes unfeasible due to prohibitive costs when combining expensive targeted therapies in addition to being a barrier to early clinical evaluation of such complex combinations of drugs. SignalRx provides proprietary single molecules designed to inhibit multiple specific key cancer targets and thus strive for more cost-effective efficacy-improved therapeutics.

SignalRx has discovered and patented a novel molecular scaffold whose members are potent PI3K inhibitors designed to simultaneously inhibit the bromodomain protein BRD4. These dual PI3K/BRD4 inhibitors are the subject of the awarded grant along with the development of molecular modeling tools to help facilitate the structure activity relationships now under study. Preliminary results of these dual PI3K/BRD4 inhibitors have demonstrated in vivo efficacy without toxicity in several mouse cancer models, confirming the advantage of circumventing potential safety concerns arising from the use of multiple drugs. Moreover, successful proof of concept by showing knockdown of both the PI3K pathway and MYC levels was confirmed from the examination of excised mouse tumors 4 hours after administration of a dual PI3K/BRD4 inhibitor.

"The STTR grant award by the NCI to develop a single molecule that inhibits both PI3K and BRD4 represents a major step forward in translating new findings in cancer biology to maximize the activity and durability of effect in new anticancer agents" said Donald L. Durden, MD, PhD. "This approach, in addition to challenging the current dogma of single-targeted oncology drugs, has promise to maximally block the tumor suppressor gene MYC which drives many cancers including CLL, medulloblastoma, multiple myeloma, and high-grade epithelial ovarian cancers exhibiting elevated MYCN expression."

Ipsen strengthens its presence in the oncology field with the acquisition of OctreoPharm Sciences, a company developing innovative radiopharmaceuticals for the diagnosis and treatment of neuroendocrine tumours

On May 19, 2015 Ipsen reported the signature of an agreement to acquire OctreoPharm Sciences (referred to as OctreoPharm), a private German life sciences company focusing on the development of innovative radioactive labeled compounds for molecular imaging diagnostics and therapeutic applications (Press release, Ipsen, MAY 19, 2015, View Source [SID:1234504593]). Ipsen plans to maintain the company location and staff to ensure successful transition of know-how and expertise. Ipsen expects to complete its acquisition once closing conditions have been cleared.

Under the terms of the agreement, which is subject to closing conditions, OctreoPharm’s shareholders are eligible to receive up to a total of approximately €50 million for the purchase of 100% of the company’s shares in the form of an upfront payment and downstream payments contingent upon clinical and regulatory milestones.

The transaction fits into Ipsen’s strategy to extend the scope of its portfolio and its leadership in neuroendocrine tumors (NET). OctreoPharm is developing an innovative theranostic approach for the management of NET based on a somatostatin receptor antagonist peptide. The therapeutic compound is a tumor cell-selective somatostatin antagonist peptide labeled with 177Lutetium ( 177Lu) for use as ‘peptide receptor radionuclide therapy’ (PRRT) for the treatment of neuroendocrine tumors, and is currently in preclinical development. The diagnostic compound is an NET imaging tool utilizing positron emission tomography (PET, PET/CT), and is currently in clinical development.

The acquisition includes an agreement with Eckert and Ziegler, one of OctreoPharm’s shareholders, to provide contract manufacturing services for the radio-labeling of the therapeutic compound.

Marc de Garidel, Chairman and CEO of Ipsen stated: "The acquisition of OctreoPharm will enlarge our footprint in the NET field, and gives Ipsen access to a new scientific field where OctreoPharm has a unique expertise in antagonist peptides for the diagnosis and treatment of neuroendocrine tumors. This is an important step in our ambition to become a global leader in the management of NET, and illustrates the pertinence of our business development strategy."