On March 26, 2014 GlaxoSmithKline reported that it has withdrawn its Marketing Authorisation Application (MAA) to the European Medicines Agency (EMA) for the use of Mekinist (trametinib) in combination with the previously approved BRAF inhibitor Tafinlar (dabrafenib) for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation (Press release GlaxoSmithKline, MAR 26, 2014, View Source;combined-use-of-mekinist–trametinib–and-taf.html [SID:1234500335]). The application for the use of Mekinist as a single agent in the same patient population, submitted simultaneously with the MAA for the combination, is still undergoing review by the EMA.
The Committee for Medicinal Products for Human Use (CHMP) of the EMA has indicated that the data provided to date by GSK did not allow the Committee to conclude on a positive benefit-risk balance of the combination. GSK intends to re-submit the MAA for the combined use of Tafinlar and Mekinist when additional data from the ongoing Phase III programme become available.
The regulatory submission for the combination was based on the results from an open-label randomised three-arm phase II study, provided to EMA in 2012. The study aimed to assess the safety and efficacy of dabrafenib in combination with two different doses of trametinib compared to dabrafenib monotherapy in patients with unresectable or metastatic BRAF V600 E or K mutation-positive melanoma.
Additional data from the randomised, double-blind Phase III study (COMBI-d) comparing the combination of dabrafenib and trametinib to dabrafenib and placebo as first-line therapy in the same patient population were also provided to EMA earlier this year.

On March 25, 2014 Exelixis reported that the European Commission has approved COMETRIQ (cabozantinib) for the treatment of adult patients with progressive, unresectable locally advanced or metastatic medullary thyroid carcinoma (MTC) (Press release Exelixis, MAR 25, 2014, View Source [SID:1234500329]). The European Commission granted conditional marketing authorization following a positive opinion from the European Committee for Medicinal Products for Human Use (CHMP) issued in December 2013. Similar to another drug approved in this setting, the approved indication states that for patients in whom Rearranged during Transfection (RET) mutation status is not known or is negative, a possible lower benefit should be taken into account before individual treatment decisions.
Additionally, the Committee for Orphan Medicinal Products (COMP) during its January 2014 meeting reviewed the designation for COMETRIQ (cabozantinib) as an orphan medicinal product for the treatment of medullary thyroid carcinoma and recommended maintenance of orphan drug designation at the time of marketing authorization.
The U.S. Food and Drug Administration approved COMETRIQ for the treatment of progressive, metastatic MTC in the United States on November 29, 2012. The approvals of COMETRIQ in both the United States and the European Union were based on data from EXAM, the international, multi-center, randomized double-blinded controlled phase 3 clinical trial conducted in 330 patients with progressive, unresectable locally advanced or metastatic MTC, in which cabozantinib met its primary efficacy endpoint of improving progression-free survival (PFS) as compared to placebo. Please see Important Safety Information for COMETRIQ, including Boxed Warnings, below.
Pursuant to the terms of a commercialization and distribution agreement between Exelixis and Swedish Orphan Biovitrum (Sobi) signed in February 2013, Sobi will support the commercialization of COMETRIQ in the European Union for the approved indication through the end of 2015.

On March 24, 2014 CytRx reported that it has initiated a pivotal global Phase 3 clinical trial (NCT02049905) to evaluate the efficacy and safety of aldoxorubicin as a second-line treatment for patients with soft tissue sarcoma (STS) under a Special Protocol Assessment with the FDA (Press release CytRx, MAR 24, 2014, View Source [SID:1234500318]). Aldoxorubicin combines the chemotherapeutic agent doxorubicin with a novel linker-molecule that binds specifically to albumin in the blood to allow for delivery of higher amounts of doxorubicin (3.5 to 4 times) without several of the major treatment-limiting toxicities seen with administration of doxorubicin alone.
This multicenter, randomized, open-label Phase 3 clinical trial is designed to enroll approximately 400 patients with metastatic, locally advanced or unresectable soft tissue sarcomas who have either not responded to, or have progressed following treatment with, one or more systemic regimens of non-adjuvant chemotherapies. Trial patients will be randomized 1:1 to be treated with aldoxorubicin or the investigator’s choice of an approved chemotherapeutic regimen, including doxorubicin, ifosfamide dacarbazine, pazopanib (Votrient), or gemcitabine plus docetaxel, with up to three comparator regimens to be selected by the investigator at each clinical site. The primary endpoint of the study is progression-free survival (PFS), and secondary endpoints include overall survival, response rates and safety. In January 2014, the Company announced it has received approval from the FDA to amend the Phase 3 protocol to continue dosing patients with aldoxorubicin until disease progression (defined as an increase in the size of measurable tumors by 20% or the development of a new tumor lesion), which creates the potential for substantially improved Phase 3 efficacy results. The Company expects to complete trial enrollment in 2015.
Following discussions with the FDA, the Phase 3 protocol has been agreed upon under a Special Protocol Assessment (SPA). As part of that assessment, the FDA agreed that the design and planned analysis of the study adequately addresses the objectives necessary to support a regulatory submission for approval.
The clinical trial will be conducted at approximately 100 clinical sites in the U.S., Europe, Canada, Latin America, Asia Pacific and Australia.