On December 12, 2014 Oncothyreon reported that the positive preliminary data from two ongoing Phase 1b trials of ONT-380 (ARRY-380), an orally active, reversible and selective small molecule HER2 inhibitor, will be presented at the San Antonio Breast Cancer Symposium (Press release Oncothyreon, DEC 12, 2014, View Source [SID:1234501172]).

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The first trial (ClinicalTrials.gov Identifier NCT02025192) is a parallel dose-escalation study of ONT-380 in combination with Xeloda (capecitabine) and/or Herceptin (trastuzumab) in patients previously treated with Herceptin and Kadcyla (ado-trastuzumab emtansine or TDM-1) for metastatic breast cancer. Interim data will be presented for 21 patients, including seven in the ONT-380 plus Xeloda cohort, eight in the ONT-380 plus Herceptin cohort, four in the ONT-380 plus Xeloda and Herceptin cohort, and two in an ongoing expansion cohort in patients with untreated or progressive central nervous system (CNS) metastases, both treated with ONT-380 plus Herceptin.

Seventeen of the patients were evaluable for best overall response using RECIST 1.1 criteria. In the ONT-380 plus Xeloda cohort, four patients had a partial response (PR) and three patients had stable disease (SD), for an overall clinical benefit rate of 100 percent (defined as either PR/CR or stable disease for > 6 months). In the ONT-380 plus Herceptin cohort, best response has been a complete response (CR) in one patient, PR in two patients, SD in four patients, and progressive disease (PD) in one patient. Two patients in the ONT-380 plus Xeloda and Herceptin cohort are currently evaluable, one of whom had a PR and one PD. One patient in the CNS expansion cohort had a PR and the other SD.

Fourteen of the 21 patients in this trial had a history of CNS metastases, of whom six had evaluable target lesions per modified RECIST 1.1 at the time of entry into the trial. Of these, best initial response has been SD, with decreases in CNS target lesions in four patients. Five of these six patients remain active on study.

The second trial (ClinicalTrials.gov Identifier NCT01983501) is a dose-escalation study of ONT-380 in combination with Kadcyla in patients who have been previously treated with Herceptin and a taxane for metastatic breast cancer. Data will be presented for 17 patients, of whom 16 were evaluable for response. Patients in this trial were heavily pre-treated, having received a median of two prior systemic treatments for metastatic disease, including prior pertuzumab in six, and prior lapatinib in five. Best overall response has been PR in five patients, SD in seven patients, and PD in four patients. Nine patients in this trial had a history of CNS metastases, of whom four had measurable disease per modified RECIST 1.1 at the time of entry into the trial. Three of these four patients have SD in the CNS and remain active on the study, including two with decreases in measurable target lesions.

ONT-380 was well-tolerated in both studies and in all combinations tested. The most common adverse events included nausea and vomiting, diarrhea, fatigue and elevated liver function tests. Most adverse events were grade 1 or 2 in severity. Elevated liver function tests were more common in patients also receiving Kadcyla. No grade 3 diarrhea was seen in either trial; anti-diarrheal prophylaxis was not a study requirement.

A maximally tolerated dose (MTD) for ONT-380 has not been identified to date in any of the combinations tested in either trial. An improved tablet formulation of ONT-380 with increased absorption was used in these trials compared to the powder in capsule formulation used in the previously reported Phase 1 trial. All patients in both current trials received an initial dose of 300 mg twice per day. At that dose, measured drug levels were similar to those seen with 600 mg twice per day (the single agent MTD) of the prior formulation. Drug exposure in the current trials was well above the level needed for 90 percent inhibition of HER2.

"The preliminary signs of efficacy in both of these trials are encouraging for the further development of ONT-380," said Stacy Moulder, M.D., Associate Professor, Breast Medical Oncology, University of Texas MD Anderson Cancer Center. "These patients were heavily pre-treated, with the majority already having a history of CNS metastases. Nevertheless, meaningful responses and prolonged stable disease have been observed and many patients currently remain on study. Importantly, ONT-380 has been well-tolerated, with a toxicity profile that facilitates its combination with other agents."

"We are continuing to enroll patients in both of these Phase 1b trials," said Diana Hausman, M.D., Chief Medical Officer of Oncothyreon. "We are currently testing an increased dose level of ONT-380 of 350 mg twice daily in both trials. We are also enrolling cohorts of patients in both trials with CNS metastases from HER2+ breast cancer that are either asymptomatic and untreated or progressive following treatment to better define the potential role of ONT-380 in treating patients with this serious unmet medical need."

About ONT-380

ONT-380 is an orally active, reversible and selective HER2 inhibitor invented at Array BioPharma Inc. In multiple preclinical tumor models, ONT-380 was well tolerated and demonstrated significant dose-related tumor growth inhibition that was superior to Herceptin (trastuzumab) and Tykerb (lapatinib). Additionally, in these models, ONT-380 demonstrated synergistic or additive tumor growth inhibition when dosed in combination with the standard-of-care therapeutics Herceptin or Taxotere (docetaxel). ONT-380 has also demonstrated superior activity, based on overall survival, compared to Tykerb and to the investigational drug, neratinib, in an intracranial HER2 positive breast cancer xenograft model.

A Phase 1 trial of ONT-380, with both dose-escalation and expansion components, has been completed in 50 patients, 43 of whom had HER2 positive metastatic breast cancer. All HER2 positive breast cancer patients had progressed on a Herceptin-containing regimen. In addition, over 80 percent had been treated with Tykerb, with many having progressed on therapy. In this study, ONT-380 demonstrated an acceptable safety profile; treatment-related adverse events were primarily Grade 1. Because ONT-380 is selective for HER2 and does not inhibit EGFR, there was a low incidence and severity of treatment-related diarrhea, rash and fatigue. Additionally, there were no treatment-related cardiac events or Grade 4 treatment-related adverse events reported. Twenty-two HER2 positive breast cancer patients with measurable disease were treated with ONT-380 at doses greater than or equal to 600 mg BID. In this heavily pretreated patient population, there was a clinical benefit rate (partial response [n = 3] plus stable disease for at least 6 months [n = 3]) of 27 percent.

On 10 December, 2014 the USA Food and Drug Administration (FDA) approved Gardasil 9 (Human papillomavirus 9-valent Vaccine, Recombinant) for the prevention of certain diseases caused by nine types of Human Papillomavirus (HPV). Covering nine HPV types, five more HPV types than Gardasil (previously approved by the FDA), Gardasil 9 has the potential to prevent approximately 90% of cervical, vulvar, vaginal and anal cancers (Press release, US FDA, DEC 10, 2014, View Source [SID1234607427]).

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Gardasil 9 is a vaccine approved for use in females ages 9 through 26 and males ages 9 through 15. It is approved for the prevention of cervical, vulvar, vaginal and anal cancers caused by HPV types 16, 18, 31, 33, 45, 52 and 58, and for the prevention of genital warts caused by HPV types 6 or 11. Gardasil 9 adds protection against five additional HPV types—31, 33, 45, 52 and 58— which cause approximately 20% of cervical cancers and are not covered by previously FDA-approved HPV vaccines.

"Vaccination is a critical public health measure for lowering the risk of most cervical, genital and anal cancers caused by HPV," said Dr Karen Midthun, director of the FDA’s Center for Biologics Evaluation and Research. "The approval of Gardasil 9 provides broader protection against HPV-related cancers."

A randomised, controlled clinical study was conducted in the USA and internationally in approximately 14,000 females ages 16 through 26 who tested negative for vaccine HPV types at the start of the study. Study participants received either Gardasil or Gardasil 9. Gardasil 9 was determined to be 97% effective in preventing cervical, vulvar and vaginal cancers caused by the five additional HPV types (31, 33, 45, 52, and 58). In addition, Gardasil 9 is as effective as Gardasil for the prevention of diseases caused by the four shared HPV types (6, 11, 16, and 18) based on similar antibody responses in participants in clinical studies.

Due to the low incidence of anal cancer caused by the five additional HPV types, the prevention of anal cancer is based on Gardasil’s demonstrated effectiveness of 78% and additional data on antibodies in males and females who received Gardasil 9.

The effectiveness of Gardasil 9 in females and males ages 9 through 15 was determined in studies that measured antibody responses to the vaccine in approximately 1,200 males and 2,800 females in this age group. Their antibody responses were similar to those in females 16 through 26 years of age. Based on these results, the vaccine is expected to have similar effectiveness when used in this younger age group.

Gardasil 9 is administered as three separate shots, with the initial dose followed by additional shots given two and six months later. For all of the indications for use approved by the FDA, Gardasil 9’s full potential for benefit is obtained by those who are vaccinated prior to becoming infected with the HPV strains covered by the vaccine.

The safety of Gardasil 9 was evaluated in approximately 13,000 males and females. The most commonly reported adverse reactions were injection site pain, swelling, redness, and headaches.

Gardasil 9 is manufactured by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., based in Whitehouse Station, New Jersey.

Avanir has filed a 10-K – Annual report [Section 13 and 15(d), not S-K Item 405] with the U.S. Securities and Exchange Commission .

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On December 10, 2014 marker companies have been reported to work with the Early Diagnosis Consortium, a collaboration between Cancer Research UK, its commercial arm, Cancer Research Technology, and Abcodia, a specialist company engaged in the validation of biomarkers for the early detection and screening of cancer (Press release, Cancer Research Technology, DEC 10, 2014, View Source [SID1234523216]).

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The decision follows completion of a pilot phase to evaluate leading technologies for their ability to discover biomarkers that can detect cancer in its earliest stages, long before symptoms appear, when treatment is most likely to be effective. The technologies were tested against serum samples selected from a biobank of more than five million serum samples, collected from women as part of the UKCTOCS trial*, to which Abcodia has exclusive commercial access.

Based on these findings, the three companies involved will be Caprion which specialises in proteomics, Asuragen which uses next-generation sequencing to find circulating microRNAs, and the AIT Austrian Institute of Technology using its tumour auto-antibodies platform.

This next stage of the programme will focus on identifying biomarkers for colorectal, lung, oesophageal and pancreatic cancers, chosen because of the limited availability of screening tests for these cancers and patients’ poor survival when diagnosed at a late stage.

Dr Julie Barnes, chief executive of Abcodia, said: "We are excited to work with these world leading companies to bring their cutting edge technology to this endeavour. The application of such technologies to biomarker discovery in longitudinal samples donated before the clinical presentation of cancer is a real innovation and has the potential to make a real difference to the field of early cancer detection."

Professor Ian Jacobs, vice president at the University of Manchester, principal investigator of UKCTOCS and one of the founders of Abcodia, said: "Cancers that are diagnosed at a later stage are much more difficult to manage, so I am delighted to see the progress that this consortium is making. The experiments aimed at identifying biomarkers that could form simple, non-invasive tests for early cancer detection represent an ideal use of the biobank developed through UKCTOCS."

Dr Keith Blundy, chief executive of Cancer Research Technology, said: "After a successful pilot, we are delighted to be able to bring additional technological capability into this collaborative effort, to add to the clinical, scientific and commercial expertise of existing partners. The biobank derived from UKCTOCS is providing us with the opportunity, through this initiative, to potentially unlock a future in which thousands of cancer cases could be detected and treated before symptoms emerge."