Clinical Trials

Date: 2016-04-28

Type of information: Presentation of results at a congress

phase: 2

Announcement: update

Company: Onxeo - previously known as Bioalliance Pharma (France)

Product: Validive® (clonidine Lauriad®)

Action mechanism:

• alpha2-adrenergic receptor agonist. Validive® is a therapeutic application of clonidine based on the mucoadhesive technology Lauriad®. Onxeo’s proprietary Lauriad® technology significantly increases the mucous and salivary concentrations of the active ingredient it contains, with decreased systemic absorption. As an agonist of the alpha-2 adrenergic receptors, Validive® exhibits anti-inflammatory properties, and was developed for the prevention and treatment of chemoradioation therapy-induced severe oral mucositis in patients with head and neck cancer. Preclinical studies and a Phase II trial have confirmed Validive’s mechanism of action and demonstrated that the therapy significantly reduces incidence of severe mucositis, improves oral mucositisrelated symptoms and decreases radiotherapy-related adverse events, and exhibits a favorable safety profile and strong adherence to treatment. Validive® was granted orphan drug status in Europe in November 2011 and also received Fast-Track status from the FDA in January 2014.

Disease: chemoradiation therapy induced oral mucositis in patients with head and neck cancer

Therapeutic area: Cancer - Oncology

Country: France, Germany, Hungary, Spain, USA

Trial details:

• This phase II, multi-center, tandomised, double-blind, placebo-controlled study is comparing the efficacy and safety of Clonidine Lauriad™ 50µ g and 100 µg Mucoadhesive Buccal Tablet (MBT) applied once daily to those of placebo in the prevention and treatment of chemoradiation therapy induced oral mucositis in patients with  head and neck cancer. The clinical trial is being conducted in Europe in about thirty centers in 4 countries: France, Germany, Spain and more recently Hungary. (NCT01385748)

Latest news:

• • On April 28, 2016,  Onxeo announced its decision to proceed with the development of Validive® only with the support of an industrial partner.
• • On October 22, 2015, Onxeo announced compliance and patient acceptability results from a global Phase 2 clinical trial demonstrating daily treatment application of Validive® (Clonidine Lauriad®), a mucoadhesive buccal tablet for the prevention and treatment of chemo-radiation therapy-induced severe oral mucositis (SOM) in patients with head and neck cancer, is well-accepted and well-tolerated by patients, with high compliance, before and throughout chemoradiotherapy treatment.
• Results of the study, “Compliance and Patient Acceptability of Clonidine Mucoadhesive Buccal Tablet (Clonidine Lauriad) to Prevent Severe Radiomucositis in Head and Neck Cancer Patients” (Presentation # 1139), were presented at the 57th American Society for Radiation Oncology (ASTRO) Annual Meeting,. The compliance and acceptability portion of the study found the mean overall patient compliance, calculated as the number of tablets taken as an expression for treatment duration in days, to be 95% (95% confidence interval), with median of 98%. The median duration of tablet adherence was 9 hours. Incidence of detachment of the tablet within the 6 hours was 17.1% and replacement of detached tablets with a new tablet was 41.5%. Tablet detachment and replacement rates were higher during the first weeks of the study, suggesting a learning curve. Overall compliance according to the patient diaries was similar in all treatment groups and consistent with the compliance according to the investigator’s evaluation (mean of 89% [95%CI], with median of 98%). Overall mean values, at 95% confidence interval, of comfort, pain-burning and taste according to the daily patient scale from 0 to 10, were respectively 1.36, 1.18 and 1.16 and were not different between treatment groups. These findings follow efficacy and safety results from the global Phase 2 randomized double-blind, placebo-controlled trial, which were presented at the 2015 ASCO Annual Meeting in May, that confirmed Validive® reduced the incidence and delayed the time to chemo-radiation therapy-induced SOM, with minimal toxicity, compared to placebo in 183 patients with head and neck cancer patients undergoing chemoradiotherapy.
• • On June 30, 2015, Onxeo has presented Validive® (clonidine Lauriad®) Phase II clinical trial results at the MASCC/ISOO International Symposium and held a meeting of its Advisory Board to discuss design of the Phase III clinical trial. The annual MASCC/ISOO meeting is dedicated to supportive care in cancer and particularly to therapeutic options to minimize symptoms and complications associated with cancer as well as therapyinduced side effects. Validive® was distinguished to be part of this oncololy supportive care forum with an oral presentation of the positive final results of its Phase II clinical trial. These final data confirm the product’s favorable safety profile and efficacy in reducing severe oral mucositis in patients with head and neck cancer receiving chemoradiation therapy. These positive results provide the basis for a Phase III trial to further evaluate the efficacy of Validive®, which Onxeo plans to initiate by end 2015/early 2016.
• • On May 26, 2015, Onxeo announced the final data from its global Phase II clinical trial of Validive®  confirming the therapy’s favorable safety profile and efficacy in reducing severe oral mucositis  in patients with head and neck cancer receiving chemoradiation therapy. These positive results provide the basis for a Phase 3 trial to further evaluate the efficacy of Validive®, which Onxeo plans to initiate by end 2015. The full study results will be presented at the 2015 American Society of Clinical Oncology (ASCO) Annual Meeting,. The trial compared the efficacy and safety of Validive® 50 microgram (µg) and 100 µg mucoadhesive buccal tablets to placebo in patients with head and neck cancer receiving chemoradiation therapy. The full dataset from 183 patients (121 patients treated with Validive® and 62 patients given placebo) demonstrate that Validive® treatment reduces the incidence of severe oral mucositis grade 3 or 4, with a good safety profile. While the findings were not statistically significant, all criteria – the observed differences in the incidence, in the dose of radiation before occurrence of severe mucositis and time to occurrence – were all going in the same direction, supporting the initiation of future confirmatory studies, leading the trial’s Advisory Board to approve further investigation in a Phase 3 trial.
• The Phase 2 study found that severe oral mucositis developed in fewer patients receiving Validive® than in patients receiving placebo, 45.3% and 60.0% respectively (p = 0.064). Furthermore, patients receiving Validive® who developed severe oral mucositis did so at a higher median radiation dose (60.0 Gy) compared to patients receiving placebo (48.0 Gy) (HR = 0.754; p = 0.211), indicating that Validive® prevents the onset of severe oral mucositis over a wider radiation dose range. Safety profile of Validive® was very good, with occurrence of adverse events being similar between placebo (98.4%) and Validive® groups (90.8%). However patients treated with Validive® compared to placebo experienced less nausea (49.6% vs. 71%) and dysphagia (32.8% vs. 48.4%).
• •  On October 30, 2014, Onxeo announced preliminary top-line results from its Phase II clinical trial of Validive®  for prevention of severe oral mucositis. The trial included 183 patients with head and neck cancer. All patients received a postoperative radiochemotherapy with a mean cumulative dose of 61 Gray in combination with cisplatin-based chemotherapy in most of the cases. Endpoints were to compare the incidence, severity, time to onset and duration of severe OM as well as use of opioids and other adverse events related to cancer radiation treatment between the Validive® pooled groups and placebo. They were evaluated twice a week during the whole radiotherapy treatment.
• The key results of the Phase II study showed:
• . a significant decrease in the incidence of severe oral mucositis (grades 3 and 4) in the Validive® pooled arms versus placebo. Overall incidence of severe oral mucositis was 45% in the Validive® groups, with a maximum absolute decrease of 16% compared to placebo.
• . occurrence of severe oral mucositis has been delayed in the Validive® groups compared to placebo.
• . higher doses of radiation have been received by the Validive® treated patients before severe oral mucositis occurred.
• . improvement of critical conditions related to severe oral mucositis and radiation therapy, especially dysphagia, nausea and vomiting in both Validive® groups.
• . no significant difference in efficacy observed between Validive® 50 ?g and 100 ?g groups.
• . in terms of safety, Validive® showed a good safety profile with no major difference in the nature, incidence and severity of adverse events in the placebo and the Validive® groups.
• At last, patient’s compliance was very high, with more than 80% of patients applying Validive® or placebo tablets on the gum every day during radiation therapy as requested in the trial. The trial Advisory Board met to analyze and validate the main preliminary results. Based on these preliminary data the Board has recommended pursuing the development of Validive® with the initiation of a Phase III trial in the same patient population.
• •  On May 5, 2014, BioAlliance Pharma announced the completion of enrollment in the Phase II clinical trial with Validive® (clonidine Lauriad®) in the prevention and treatment of severe oral mucositis induced by radiotherapy and/or chemotherapy in head and neck cancer patients.
• •  On September 30, 2013, BioAlliance Pharma has held the first meeting of its international Advisory Board dedicated to oral mucositis and to the associated clinical development program with Validive® (clonidine Lauriad®). This multidisciplinary Advisory Board is composed of internationally recognized European and American experts, in the fields of oral mucositis and oral medicine, oncology and radiotherapy: Drs Stephen Sonis (Boston, Massachusetts), Paolo Bossi (Milano, Italy), Joel Epstein (LA, California), Jorge Giralt Lopez del Segredo (Barcelona, Spain) and Michael Henke (Freiburg, Germany). Its purpose is to provide advice and input on development strategy and medical positioning of Validive® in oral mucositis.
• •  On June 10, 2013, BioAlliance Pharma has announced the initiation of its Phase II clinical trial evaluating the efficacy and safety of Validive® (clonidine Lauriad®) in the United States in patients with chemoradiation therapy-induced oral mucositis with head and neck cancer, as scheduled in the advancement calendar of the project. Further to IND approval by the FDA, the first investigational sites have been initiated in May in the U.S. and are ready to start recruiting patients. About twenty sites are planned to be initiated in the U.S. in the coming weeks. So far, more than 60% of planned patients have been enrolled in Europe and the U.S. extension is planned to help accelerate the recruitment. The trial is expected to be finalized in late 2013/early 2014 with results in 2014.
• •  On February 14, 2013, BioAlliance Pharma has announced the extension of its phase II clinical trial with Validive® (clonidine Lauriad™) in the United States in radio/chemotherapy-induced oral mucositis prevention in patients with head and neck cancer. So far almost 50% of planned patients have been enrolled in about 30 European centers. With the upcoming initiation of several centers in the United States, BioAlliance Pharma expects to finalize trial recruitment in early 2014 with results expected the same year.
• •  On April 17, 2012,  BioAlliance Pharma  announced that more that 30% of planned patients are already included in the trial. To date, the participating centers have not reported any particular toxicity related to the product and they confirm their interest in this study. Thus, BioAlliance Pharma is planning to enlarge the trial, already ongoing in France, Germany and Spain, to 4 other European countries in the next weeks. This expansion to about 50 active centers will enable to accelerate the recruitment in the trial that should be finalized in 2013.
• •  On April 27, 2011, BioAlliance Pharma has announced the extension of its ongoing clonidine Lauriad® phase II clinical trial in chemoradiation therapy induced oral mucositis in patients with head and neck cancer to Germany and Spain. The expansion of the trial (currently ongoing in France) to two new countries will raise the total number of centers to over 40 and will help accelerate patient recruitment. Based on the incidence of chemoradiation therapy induced oral mucositis in this population, BioAlliance Pharma plans to submit an application dossier to the European and US agencies in Q2 2011 to obtain an Orphan Drug designation for clonidine Lauriad®.

Is general: Yes