On February 29, 2016 Provectus Biopharmaceuticals, Inc. (NYSE MKT: PVCT, www.pvct.com), a clinical-stage oncology and dermatology biopharmaceutical company ("Provectus" or "The Company"), reported that it is initiating a protocol titled, "A Phase 1 Study to Assess the Safety, Tolerability and Effectiveness of PV-10 Chemoablation of Neuroendocrine Tumours (NET) Metastatic to the Liver in the Reduction of Biochemical Markers and Symptoms Caused by Secretory Products (Filing, 8-K, Provectus Pharmaceuticals, FEB 29, 2016, View Source [SID:1234509272])."

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The 12-patient phase 1 study will run up to 48 months with interim data anticipated at the half-way point of the two-cohort study. Patients in the first of the two successive cohorts will receive PV-10 to a single NET tumor in their liver, while patients in the second cohort may receive PV-10 to multiple NET tumors.

Timothy Price, M.D. will serve as principal investigator for the study at The Queen Elizabeth Hospital in Woodville, South Australia.
Dr. Price explained, "The primary endpoint of our study will be assessment of safety and tolerability of PV-10 in the treatment of these metastatic NETs. Our secondary endpoints address preliminary efficacy, disease symptoms and biomarkers, and include assessments of Objective Response Rate (ORR) of injected and uninjected tumors; change in tumor biomarkers (somatostatin receptor expression, chromogranin A and 5-hydroxyindole acetic acid); change in NET symptoms assessed by standard quality of life instruments; and possible change in peripheral blood mononuclear cells (PBMCs)."

Dr. Eric Wachter, CTO of Provectus, noted, "This protocol is a natural complement to work ongoing in our initial study of hepatic cancers under protocol PV-10-LC-01, which has allowed us to assess PV-10 in a number of tumor types using the method of administration that will be used in this new study. In addition to providing further data on the overall safety of this approach, this study is tailored to NET patients and will allow us to assess potential clinical benefit in terms of objective response and changes in biomarkers and symptoms of these tumors. Patients with metastatic NET tumors are often plagued by persistent diarrhea, flushing, breathing difficulties, abdominal cramping and swelling of the arms and legs. It will be very useful to determine whether PV-10 ablates NET tumors and if ablation has a positive impact on quality of life for patients."

For further information, please visit View Source The study is expected to open for enrollment in March 2016.

About the Queen Elizabeth Hospital

The Queen Elizabeth Hospital (TQEH) is a 311 bed, acute care teaching hospital that provides inpatient, outpatient, emergency and mental health services to a population of more than 250,000 people living primarily in Adelaide’s western suburbs.

On February 29, 2016 Oncothyreon Inc. (Nasdaq:ONTY), a clinical-stage biopharmaceutical company dedicated to the development of therapeutic products that can improve the lives and outcomes of patients with cancer, reported the dosing of the first patient in a randomized, placebo-controlled Phase 2 trial of ONT-380 in combination with Herceptin (trastuzumab) and Xeloda (capecitabine) (Press release, Oncothyreon, FEB 29, 2016, View Source [SID:1234509270]).

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ONT-380 is an oral, HER2-selective, central nervous system (CNS)-active tyrosine kinase inhibitor. The trial is enrolling heavily pretreated patients with advanced HER2-positive breast cancer with or without brain metastases.

"There is a great need for effective, well-tolerated treatments for women with progressing metastatic HER2-positive breast cancer, especially those with metastases to the brain, which develops in up to half of these patients and who are frequently excluded from clinical trials. With no approved therapy for the treatment of brain metastases, options for this patient population are currently limited," said Erika Hamilton, M.D., director, Breast and Gynecologic Cancer Research Program, Sarah Cannon Research Institute. "This trial includes specifically designed endpoints around HER2-positive CNS disease to further explore the activity of ONT-380 in combination with Herceptin and Xeloda on brain metastases and the potential to address this unmet medical need."

"Based on data from our Phase 1b studies, which show that the combination of ONT-380 with other active treatments was well tolerated and resulted in objective responses and prolonged, stable disease, we believe that ONT-380 has the potential to be an important new treatment for HER2-positive breast cancer patients, especially for women with brain metastases," said Christopher S. Henney, chairman and interim CEO of Oncothyreon. "We are excited to advance the development of ONT-380 in the third-line metastatic setting with the initiation of this Phase 2 trial. Additionally, we continue to evaluate opportunities for ONT-380 and to establish the most efficient regulatory path forward."

About the Study

The clinical trial is a Phase 2 randomized, double-blind, placebo-controlled study of ONT-380 in combination with Herceptin and Xeloda in patients with pretreated, unresectable locally advanced or metastatic HER2-positive breast cancer. (ClinicalTrials.gov Identifier: NCT02614794) The trial is expected to enroll approximately 180 patients in multiple centers located in the United States, Canada and Western Europe. Patients must have been previously treated with a taxane, Herceptin, Perjeta (pertuzumab) and Kadcyla (ado-trastuzumab emtansine or T-DM1). Patients with or without brain metastases are eligible, including patients with asymptomatic untreated brain metastases not needing immediate local therapy and patients with previously treated brain metastases.

The trial’s objectives are to assess the efficacy, safety and pharmacokinetics of ONT-380 in combination with Herceptin and Xeloda. The primary endpoint is progression free survival (PFS) based on assessment of both CNS and non-CNS disease. Additional endpoints include time to CNS progression, objective response rate and overall survival.

About ONT-380

ONT-380 is an oral, CNS-active, reversible and selective small molecule HER2 inhibitor being developed for the treatment of metastatic breast cancer. Unlike other approved and investigational treatments, ONT-380 selectively inhibits HER2 without significant inhibition of EGFR (also called HER1), resulting in highly potent inhibition of HER2 while potentially avoiding the side effects associated with dual inhibitors, including skin rash and gastrointestinal toxicities. In addition, ONT-380 has been shown to have durable, objective responses in HER2-positive patients with brain metastases. Brian metastases impact up to 50 percent of women with HER2-positive metastatic breast cancer and represent a major unmet medical need.

On February 29, 2016 BioInvent International (BINV) reported that it will receive a €2 million milestone payment under the collaboration with Daiichi Sankyo pertaining to the progression of an anti-FGFR4 antibody into a Phase I clinical trial in the EU (Press release, BioInvent, FEB 29, 2016, http://www.bioinvent.com/media-centre/press-releases/release/?ReleaseID=0343D46385679286 [SID:1234509259]).

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The anti-FGFR4 antibody, known as U3-1784, was discovered by Daiichi Sankyo utilizing BioInvent’s n-CoDeR phage display library. Its target indication is for solid cancer tumors.

Under the terms of BioInvent’s licensing agreement with Daiichi Sankyo, payments are due to BioInvent when certain clinical milestones are achieved and royalty payments are due when a product is sold on the market. Beginning a Phase I clinical trial is a milestone that triggers a payment to BioInvent.

"We are very pleased that our partner Daiichi Sankyo has progressed U3-1784 into a Phase I clinical trial", said Michael Oredsson, CEO of BioInvent. "It is yet another example of an n-CoDeR library derived antibody that is being successfully developed through to the clinic by a leading global pharmaceutical company. We wish Daiichi Sankyo continued success with this antibody in their clinical program."

On February 29, 2016 Eisai Co., Ltd. (Headquarters: Tokyo, CEO: Haruo Naito, "Eisai") reported that it has received approval in Japan for its in-house developed anticancer agent Halaven (eribulin mesylate) as a treatment of patients with soft tissue sarcoma (Press release, Eisai, FEB 29, 2016, View Source [SID:1234509258]).

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Halaven is the first and only single agent to demonstrate an overall survival (OS) benefit in a Phase III trial in patients with advanced, recurrent or metastatic soft tissue sarcoma (liposarcoma or leiomyosarcoma). Following approval for use in the treatment of inoperable or recurrent breast cancer in Japan, this marks the second indication for which Halaven has been approved based on a statistically significant extension of OS.

In a Phase III clinical study (Study 309) in patients with locally advanced, locally recurrent or metastatic soft tissue sarcoma (liposarcoma or leiomyosarcoma) who had disease progression following standard therapies which must have included an anthracycline and at least one other additional regimen, Halaven demonstrated a statistically significant extension in the study’s primary endpoint of OS over the comparator treatment dacarbazine. 1 The most common adverse reactions (incidence greater than or equal to 25%) in patients treated with Halaven in the study were neutropenia, fatigue, alopecia, nausea, and peripheral neuropathy, which was consistent with the known side-effect profile of Halaven. Furthermore, in a Phase II clinical study (Study 217) of Halaven in patients with advanced or recurrent soft tissue sarcoma who had received chemotherapy conducted within Japan, the results also suggested clinical efficacy for Halaven.2

Soft tissue sarcoma is a collective term for a diverse group of malignant tumors that occur throughout the soft tissues (including fat, muscle, nerves, fibrous tissues and blood vessels) in the body. According to a patient survey conducted by Japan’s Ministry of Health, Labour and Welfare, there are approximately 4,000 patients with soft tissue sarcoma in Japan.
In January 2016, Halaven was approved in the United States as a treatment of patients with unresectable or metastatic liposarcoma who have received a prior anthracycline-containing regimen, and applications seeking approval for use in the treatment of soft tissue sarcoma are currently under review in the EU, Switzerland, Russia, Australia, and Brazil. Halaven has been designated as an orphan drug for the treatment of soft tissue sarcoma in the United States and Japan.

Halaven is a halichondrin class microtubule dynamics inhibitor with a distinct binding profile. Recent non-clinical studies showed that Halaven is associated with increased vascular perfusion and permeability in tumor cores.3 Halaven promotes the epithelial state and decreases the capacity of breast cancer cells to migrate. 4 Halaven is currently approved for use in the treatment of breast cancer in approximately 60 countries including Japan and countries in Europe, the Americas and Asia.
Through obtaining this additional approval, Eisai aims to enhance the clinical value of Halaven to contribute further toward addressing the diverse needs of, and increasing the benefits provided to, patients with cancer, their families, and healthcare providers.

[Notes to editors]
1. Product Outline (New Information Related to Additional Indication Underlined) 1) Product name Halaven Injection 1 mg 2) Generic name Eribulin mesylate 3) Indication for use Inoperable or recurrent breast cancer, soft tissue sarcoma 4) Dosage and administration The usual adult dose of eribulin mesylate is 1.4 mg/m2 body surface area, administered intravenously as a single dose over 2 to 5 minutes, once a week. Treatment should be continued for 2 consecutive weeks, followed by a third week of drug cessation. With each cycle lasting 3 weeks, the treatment should be repeated. The dose may be reduced, depending on the condition of the individual patient.

2. About Halaven
Halaven is the first in the halichondrin class of microtubule dynamics inhibitors with a novel mechanism of action. Structurally Halaven is a simplified and synthetically produced version of halichondrin B, a natural product isolated from the marine sponge Halichondria okadai. Halaven is believed to work by inhibiting the growth phase of microtubule dynamics which prevents cell division. In addition, recent non-clinical studies showed that Halaven is associated with increased vascular perfusion and permeability in tumor cores.3 Halaven promotes the epithelial state and decreases the capacity of breast cancer cells to migrate.4

Halaven was first approved in November 2010 in the United States as a treatment for patients with metastatic breast cancer who have received at least two chemotherapeutic regimens for the treatment of metastatic disease. Prior therapy should have included an anthracycline and a taxane in either the adjuvant or metastatic setting. Halaven is currently approved for use in the treatment of breast cancer in approximately 60 countries worldwide, including Japan and countries in the Europe, Americas and Asia. In Japan, Halaven has been approved to treat inoperable or recurrent breast cancer and was launched in the country in July 2011. Halaven has also been approved in countries in Europe and Asia indicated as a treatment for patients with locally advanced or metastatic breast cancer who have progressed after at least one chemotherapeutic regimen for advanced disease. Prior therapy should have included an anthracycline and a taxane in either the adjuvant or metastatic setting, unless patients were not suitable for these treatments.

Regarding soft tissue sarcoma, Halaven was approved in the United States for the treatment of patients with unresectable or metastatic liposarcoma who have received a prior anthracycline-containing regimen in January 2016, and was approved in Japan for the treatment of soft tissue sarcoma in February 2016. Applications seeking approval for use in the treatment of soft tissue sarcoma are currently under review in the EU, Switzerland, Russia, Australia, and Brazil. Furthermore, Halaven has been designated as an orphan drug for soft-tissue sarcoma in the United States and Japan.

3. About Soft Tissue Sarcoma
Soft tissue sarcoma is a collective term for a diverse group of malignant tumors that occur throughout the soft tissue (including fat, muscle, nerves, fibrous tissues and blood vessels) in the body. Approximately 12,000 patients in the United States and 29,000 patients in Europe are diagnosed with soft tissue sarcoma each year. According to a patient survey conducted by Japan’s Ministry of Health, Labour and Welfare, there are approximately 4,000 patients with soft tissue sarcoma in Japan. As the structures where the tumors originate are diverse, there are various types of soft tissue sarcoma, and the most common types include leiomyosarcoma, liposarcoma and malignant fibrous histiocytoma. While treatment of soft tissue sarcoma is focused on curative surgery, if the degree of malignancy is high, treatment then becomes a combination of chemotherapy and radiation therapy. As outcomes are poor for patients with advanced disease, it remains a disease with significant unmet medical need.

4. About Study 3091
Conducted primarily in Europe and the United States, Study 309 was a multicenter, open-label, randomized Phase III study comparing the efficacy and safety of Halaven ("eribulin") versus dacarbazine in 452 patients (aged 18 or over) with locally advanced, locally recurrent or metastatic soft tissue sarcoma (liposarcoma or leiomyosarcoma) who had disease progression following standard therapies which must have included an anthracycline and at least one other additional regimen. Patients received either eribulin (1.4 mg/m2 administered intravenously on Day 1 and Day 8) or dacarbazine (850–1200 mg/m2 administered intravenously on Day 1) every 21 days until disease progression. From the results for the study, eribulin demonstrated a statistically significant extension in the study’s primary endpoint of overall survival (OS) over the comparator treatment dacarbazine (eribulin median OS: 13.5 months vs dacarbazine median OS: 11.5 months; Hazard Ratio 0.77 [95% CI=0.62-0.95], p=0.0169). Furthermore, in the study’s secondary endpoints, there was no statistically significant difference found between eribulin and dacarbazine in either progression-free survival (PFS) (median PFS: 2.6 months in both arms) or progression-free rate at 12 weeks (PFR12wks) (eribulin PFR12wks: 33% vs dacarbazine PFR12wks: 29%). The most common adverse reactions (incidence greater than or equal to 25%) in study patients with liposarcoma or leiomyosarcoma treated with eribulin were neutropenia, fatigue, alopecia, nausea, and peripheral neuropathy, which was consistent with the known side-effect profile of eribulin.

5. About Study 217 (Results Presented at 50th Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper)) 2
Conducted in Japan, Study 217 was an open label, multicenter, Phase II study to evaluate the efficacy and safety of eribulin in 51 previously treated subjects with advanced or recurrent soft tissue sarcoma. Patients in the study received eribulin (1.4 mg/m2 administered intravenously on Day 1 and Day 8) every 21 days until disease progression, and the primary endpoint was PFR12wks. The results of the study demonstrated efficacy for eribulin in previously treated patients with advanced soft tissue sarcoma. PFR12wks in all evaluated groups of soft tissue sarcoma was 51.0%. Furthermore, the PFR12wks in patients with liposarcoma or leiomyosarcoma (35 patients) and in patients with other types of soft tissue sarcoma (16 patients) were 60.0% and 31.3%, respectively. The most common treatment emergent adverse events of Grade 3 or higher (Common Terminology Criteria for Adverse Events) were neutropenia (86.3%), white blood cell decrease (74.5%), lymphocyte decrease (31.4%), anemia (11.8%) and febrile neutropenia (7.8%).

On February 29, 2016 Boehringer Ingelheim reported that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) issued a positive opinion for the approval of Giotrif (afatinib) for the treatment of patients with advanced squamous cell carcinoma (SqCC) of the lung whose disease has progressed on or after treatment with platinum-based chemotherapy (Press release, Boehringer Ingelheim, FEB 29, 2016, View Source [SID:1234509257]).

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Afatinib is already approved for the treatment of patients with EGFR mutated non-small cell lung cancer (NSCLC).*

The CHMP positive opinion is based on the results of the head-to-head LUX-Lung 8 trial in patients with SqCC of the lung whose tumours progressed on or after first-line chemotherapy. Afatinib, compared to erlotinib, demonstrated:1

Significant delay in progression of lung cancer (PFS, progression-free survival, primary endpoint), reducing the risk of cancer progression by 19%
Significant improvement in overall survival (OS, key secondary endpoint), reducing the risk of death by 19%
An improvement in quality of life and control of cancer symptoms
The rate of severe adverse events was similar between the two treatment arms with differences observed in the incidence of certain side effects: a higher incidence of severe diarrhoea and stomatitis (mouth sores) was observed with afatinib compared to erlotinib (grade 3 diarrhoea: 10% vs 2%; grade 3 stomatitis: 4% vs 0%), while a higher incidence of severe rash/acne was reported with erlotinib compared to afatinib (grade 3 rash/acne: 10% vs 6%).1
SqCC of the lung develops in the cells lining the airways and represents approximately 20-30% of NSCLC cases.2,3 It is associated with a poor prognosis, limited survival and symptoms like cough and dyspnoea; the median OS after diagnosis of advanced SqCC is around one year.4,5

Dr. Mehdi Shahidi, Medical Head, Solid Tumour Oncology, Boehringer Ingelheim commented: "Despite recent advances in the treatment of squamous cell lung cancer, this disease remains challenging to treat. We are pleased to receive this positive opinion from the CHMP for afatinib; not only does it represent the potential availability of the first oral treatment option specifically approved for patients with squamous cell lung cancer, it also confirms the positive profile of afatinib, a second-generation EGFR targeting agent, when compared to a first-generation agent."

LUX-Lung 8 is part of the afatinib LUX-Lung programme – the largest collection of clinical trials of any EGFR tyrosine kinase inhibitor (TKI), with over 3760 patients across eight studies conducted across the world. The comprehensive programme includes two pivotal studies in the first-line setting, LUX-Lung 3 and 6, as well as two head-to-head studies (LUX-Lung 7 and 8) of afatinib versus first-generation EGFR TKIs. The LUX-Lung programme has involved lung cancer specialists across over 680 sites in 40 countries around the world, reflecting the strong partnership between Boehringer Ingelheim and the lung cancer specialist community.

Afatinib is already approved in over 60 countries for the first-line treatment of EGFR mutation-positive NSCLC*, and recent results from the LUX-Lung 7 trial positively underscored benefits of afatinib versus another first-generation EGFR targeting agent in this indication.6 Results of this global Phase IIb head-to-head trial demonstrated afatinib was superior in reducing the risk of lung cancer progression and the risk of treatment failure both by 27% compared to gefitinib.6

For more information about the LUX-Lung 8 Trial, please see Professor Jean-Charles Soria’s publication in The Lancet Oncology