Company: BioAlliance Pharma, now Onxeo (France)
Product: Livatag® (doxorubicin Transdrug®)
- antineoplastic antibiotic. Livatag® (Doxorubicin Transdrug™) is a doxorubicin formulation in the form of lyophilized nanoparticles of polyisohexylcyanoacrylate (PIHCA).This new therapeutic approach allows drug resistance to be avoided by shortcircuiting the mechanisms of multi-drug resistance developed by tumor cells through the masking of the anticancer agent. Acting as a ‘Trojan horse,’ the nanoparticle formulation avoids rejection of doxorubicin outside the cell so that it can exert its cytotoxic action.
Disease: hepatocellular carcinoma, primary liver cancer
area: Cancer - Oncology
Country: France, Germany, USA, Lebanon, Egypt, Saudi Arabia
- The international, multicenter, randomized phase III trial ReLive aims at evaluating the efficacy of Livatag® on overall survival in nearly 400 patients suffering from hepatocellular carcinoma, resistant or intolerant to sorafenib. The trial started in France in June 2012 and is running in almost 20 French investigational sites and this Phase III trial is ongoing in 11 countries (Europe, USA, Middle-East & North Africa). (NCT01655693)
- • On September 11, 2017, Onxeo announced top line results from the phase III ReLive trial of Livatag® (doxorubicine Transdrug™) in adult patients with unresectable hepatocellular carcinoma, intolerant to sorafenib or having progressed after a systemic therapy including sorafenib, when compared to best standard of care. The study did not meet its primary endpoint of improving survival over the comparative group. The major reason is an unexpected high survival in the comparative group. Indeed, the study was not placebo controlled and patients in the comparative group could receive other anticancer agents (including oxaliplatin, gemcitabine or tyrosine kinase inhibitors) which might explain the high survival rate of the control arm. Livatag®, as single agent, showed a similar effect as the one observed in that comparative group with active treatments. There was no difference in efficacy between the two arms (Livatag 20mg/m² and 30mg/m²). The overall safety and tolerability profile of Livatag® in ReLive was favorable with a fully manageable toxicity profile in both groups of Livatag (20mg/m² and 30mg/m²) including in those patients who
underwent the longest treatment periods, over one year. The overall tolerability was comparable to the one observed in the comparative group. The monitoring of the patients still enrolled in the study will continue to completion expected in H1 2019. The analysis of predefined subgroups is ongoing and the main results from the ReLive study will be presented on at the upcoming 11th Annual Conference of the International Liver Cancer Association in Seoul. “Once the Relive data are fully analyzed, we will reinitiate licensing discussion with potential partners based on key study outcomes to define the best path forward”,said Judith Greciet, Chief Executive Officer of Onxeo. “As already announced, Onxeo will continue to advance its diversified pipeline of innovative
assets in oncology. Refocusing our R&D activities on AsiDNA™ and Beleodaq® should extend our financial visibility until early 2020."
- • On January 24, 2017, Onxeo announced the completion of enrollment in ReLive. To date, 390 patients have been randomized, with about 260 patients in the Livatag® treatment group and 130 in the the comparative group (best standard of care). The completion of patient randomization confirms the expected timeline of issuing the preliminary efficacy outcomes of the study mid-2017. From a safety standpoint, nine DSMB reviews of the ReLive study have already been conducted over the course of the study. During these reviews, the experts did not identify unexpected adverse effects or signals and unanimously recommended each time the continuation of the trial without modification. These repeated positive recommendations – based on data from the administration of almost 1,000 Livatag® infusions – seem to indicate an adequate safety profile of the drug to date.
- • On November 21, 2016, Onxeo announced that the company has received the 9th unanimous recommendation from the Data Safety Monitoring Board (DSMB), an independent European board of experts that monitors the safety of the Livatag® Phase III trial, “ReLive”, to continue the study without modification. The study plans to enroll a total of 400 patients across approximately 90 sites. To date, more than 90% of the patients have been randomized in the study. The DSMB reviews the safety data of the treated patients in the study, totaling more than 900 infusions of Livatag®.
- • On April 4, 2016, Onxeo announced that it has received a unanimous recommendation from the Data Safety Monitoring Board (DSMB) that monitors the safety of the Livatag® Phase III trial, “ReLive”, to continue the study without modification. The positive DSMB recommendation granted for the eighth time further confirms the acceptable safety profile of Livatag®.
- • On October 5, 2015, Onxeo announced that it has received a unanimous recommendation from the Data Safety Monitoring Board (DSMB), the independent European board of experts that monitors the safety of the Livatag® Phase III trial, “ReLive”, to continue the study without modification. To date, more than 50% of the patients have been randomized in the study. The DSMB has reviewed the safety data from these patients, totaling more than 500 infusions of Livatag® in the trial and for the seventh time since study initiation, has unanimously recommended to continue the study without modification, based on its positive assessment of the safety data of Livatag®.
• On July 21, 2015, Onxeo updates on the clinical development status of ReLive. As of July 2015, ReLive clinical phase III trial authorized in 11 countries. To date, 50% of patients (i.e. about 200 patients) have been randomized, around 65 patients per arm and more than 100 patients have been treated with Livatag® for a total of about 450 infusions. This recruitment rate is in line with expected timelines of issuing preliminary outcomes of the phase III by H1 2017.
- • On March 26, 2015, Onxeo announced that Livatag® phase III clinical trial “ReLive” is expanded to 3 new countries in the Middle-East and North Africa region (MENA). The study is designed to assess Livatag®’s (Doxorubicin Transdrug™) efficacy on survival in 400 patients with refractory hepatocellular carcinoma in progression following treatment with Sorafenib. The study is already implemented in about 65 clinical centers in 8 countries, in Europe and North America, with more than 40% of the patients having already been randomized.
- In line with Onxeo’s strategic expansion plan for the Livatag® “ReLive” phase III trial, the company is opening up trial centers in three new countries: Lebanon, Egypt, and the Kingdom of Saudi Arabia (KSA). These new countries are in addition to the 8 countries where patients are currently being recruited. The decision to expand the number of countries in the study is based on the reassuring feedback that has been received from the data safety monitoring board (DSMB) and the additional funds that Onxeo has available post the recent successful capital raising. The addition of these 3 new countries is designed to optimize recruitment rate in the study. Onxeo has engaged MCT, a contract research organization (CRO) specialized in running clinical trials in the Middle East and North Africa (MENA region), to implement the trial in the Lebanon, Egypt, and KSA. MCT, which will be driven by Onxeo´s internal clinical development team, will be in charge of all administrative procedures as well as the opening and follow-up of new trial centers. Approximately 10 additional trial centers should be open and the first patient expected to be enrolled as soon as mid- 2015.
- • On November 24, 2014, Onxeo announced that the European Independent Board of Experts (Data Safety and Monitoring Board, DSMB) in charge of the safety monitoring of the Livatag® Phase III trial has unanimously recommended continuing the study without modification.
- • On April 14, 2014, BioAlliance Pharma has announced that the European Independent Board of Experts (Data Safety and Monitoring Board, DSMB) in charge of the safety profile of the ReLive Phase III trial, held its fourth meeting and unanimously recommended continuing the study without modification. As of today, about 40 centers are opened in Europe and more than 25% of patients are enrolled, on track with the plan. The trial is still expanding in Europe and implementation of investigator centers is ongoing in the United States further to the green light obtained from the FDA last December. The recruitment should be completed end of 2015 for expected data end of 2016.
- • On December 4, 2013, BioAlliance Pharma has announced that it has received authorization to start its Phase III ReLive clinical trial in primary liver cancer in the US, following the review of the Livatag® development program by the FDA, as well as in Germany after the German health agency green light. “The deployment strategy planned was to implement the clinical trial first in France, then to expand it to Europe and then to the United States in 2014. The schedule is currently fully respected as the study is already implemented in Europe since last summer, and clinical operations will now be able to start in the U.S in order to open investigating centers “, stated Pierre Attali, COO in charge of Strategy and Medical affairs of BioAlliance Pharma. To date, twenty centers have been opened and more than 80 patients have been enrolled, in line with the recruitment objectives set by the Company. The international extension of Livatag® trial is necessary to meet the recruitment timelines objectives which anticipate an end of recruitment in 2015 and preliminary results in 2016.
- • On October 22, 2013, BioAlliance Pharma has announced that the International Independent Board of Experts’ Data and Safety Monitoring Board (DSMB), in charge of the safety profile of the ReLive Phase III trial, unanimously recommended continuing the study without modification for the third time since the trial’s initiation. As of the end of September, about 20 centers are opened in France. The European extension of the trial is ongoing as planned with authorizations already obtained in 6 countries (Spain, Italy, Russia, Hungary, Austria and Belgium). The Company plans to expand the trial to the United States in 2014, enabling completion of recruitment in 2015 and data in 2016.
- • On May 13, 2013, BioAlliance Pharma has announced that the International Independent Board of Experts’ Data and Safety Monitoring Board (DSMB) recommended continuing the ReLive Phase III trial without modification. The DSMB meets every 6 months and/or after the recruitment of 75 patients to evaluate the tolerance of Livatag®, and to ensure patient safety.
- • On December 6, 2012, BioAlliance Pharma has announced that the European Independent Board of Experts (Data Safety and Monitoring Board, DSMB) held its first meeting on the ReLive Phase III trial and recommended continuing it without modification to evaluate the efficacy of Livatag® (doxorubicin Transdrug™) in primary liver cancer. In order to ensure a regular safety monitoring of patients enrolled in ReLive, the organization of a Board of international experts was to meet every 6 months, and/or after inclusion of the first 25 patients, to review the safety data of patients included in the trial, and to recommend possible modifications of the protocol.
- • On May 14, 2012, BioAlliance Pharma has announced the initiation of ReLive, its phase III clinical trial with Livatag® (doxorubicin Transdrug™). The clinical trial batches of Livatag® have been performed by qualified companies for injectable cytoxic products in nanoparticle form, in collaboration with the BioAlliance Pharma’s team specialized in industrial development that ensured the transmission of its know-how specific to nanoparticle Transdrug™ technology, and followed throughout theprocess. The clinical batches will be sent to the investigating sites in the next days. At last, the European independent Board of experts of the ReLive trial has met, with Pr. Michel Beaugrand (Jean Verdier University Hospital, Paris) as President and Pr. Jordi Bruix (Hospital Clinic i Provincial, Barcelona), as Vice-President. It will perform a regular monitoring of the study.
- • On July 13, 2011, BioAlliance Pharma has announced the validation of its application for a Phase III clinical trial for Livatag® (doxorubicin Transdrug™) in the treatment of primary liver cancer submitted to the French Drug Agency (Afssaps). This will enable the review of the preclinical and clinical dossiers by the experts of the Agency. Submitted on June 27, 2011, the Phase III clinical trial application is based on striking survival data observed in the Phase II trial (17-month increase in the median overall survival as compared to that of chemoembolization) together with a new administration scheme, validated on an animal model, enabling to significantly prevent acute pulmonary adverse events. This trial aims at demonstrating efficacy of Livatag® on survival in patients with hepatocellular carcinoma after failure of or intolerance to sorafenib. A regular monitoring will be performed by an independent expert board. The validation of the application allows BioAlliance to confirm its schedule with the initiation in 2012 of the Phase III clinical trial.
- • On June 27, 2011, BioAlliance Pharma has announced that it has submitted a phase III clinical trial application for Livatag® in the treatment of primary liver cancer to the French Drug Agency (Afssaps).