An international expanded-access programme of Everolimus : Addressing safety and efficacy in patients with metastatic renal cell carcinoma who progress after initial vascular endothelial growth factor receptor-tyrosine kinase inhibitor therapy

BACKGROUND AND OBJECTIVES: The RECORD-1 trial established the clinical benefit of everolimus in patients with metastatic renal cell carcinoma (mRCC) after failure of initial vascular endothelial growth factor receptor-tyrosine kinase inhibitor (VEGFr-TKI) therapy. The REACT (RAD001 Expanded Access Clinical Trial in RCC) study was initiated to address an unmet medical need by providing everolimus prior to commercial availability, and also to further assess the safety and efficacy of everolimus in patients with VEGFr-TKI-refractory mRCC. PATIENTS AND METHODS: REACT (Clinicaltrials.gov: NCT00655252) was a global, open-label, expanded-access programme in patients with mRCC who were intolerant of, or who had progressed on or after stopping treatment with, any available VEGFr-TKI therapy. Patients received everolimus 10mg once daily, with dose and schedule modifications allowed for toxicity. Patients were closely monitored for the development of serious and grades 3/4 adverse events (AEs). Response was assessed by RECIST every 3months for the first year and every 6months thereafter. RESULTS: A total of 1367 patients were enroled. Safety findings and tumour responses were consistent with those observed in RECORD-1, with no new safety issues identified. The most commonly reported serious AEs were dyspnoea (5.0%), pneumonia (4.7%) and anaemia (4.1%), and the most commonly reported grades 3/4 AEs were anaemia (13.4%), fatigue (6.7%) and dyspnoea (6.5%). Best overall response was stable disease in 51.6% and partial response in 1.7% of patients. Median everolimus treatment duration was 14weeks. CONCLUSION: Everolimus is well tolerated in patients with mRCC and demonstrates a favourable risk-benefit ratio

Hydride alkenylcarbyne osmium complexes versus cyclopentadienyl type half-sandwich ruthenium derivatives

The dihydride complex OsH2Cl2(PiPr 3)2 (1) reacts with 2-methyl-1-hexen-3-yne and 2,4-dimethyl-1,3-pentadiene to give the hydride alkenylcarbyne derivatives OsHCl2{≡CC(Me)=CHR}(PiPr3)2 (R = nPr (2), iPr (3)), which have been characterized by X-ray diffraction analysis. DFT calculations (B3PW91) suggest that the enyne is initially hydrogenated to afford a conjugated diene. The latter evolves into the hydride alkenylcarbyne derivative by means of two hydrogen migrations. The first migration is a 1,4-hydrogen shift within the diene (from the terminal CH2 group to the internal double bond) which takes place through the metal center. The second migration is a 1,2-hydrogen shift from the terminal CH2 group to the osmium atom. In contrast to the case for 1, the ruthenium counterpart RuH2Cl2(PiPr 3)2 (16) reacts with 2-methyl-1-hexen-3-yne to give a complex mixture of compounds, from which the derivatives Ru(η5- C5HR1R2R3R4)Cl(P iPr3) (17; R1 = C(CH3)=CH 2, R2 = Et, R3 = nPr, R4 = Me) and RuCl2{=C(Et)CH=CMe2}(PiPr 3)2 (18, traces) are isolated. Both 17 and 18 have been also characterized by X-ray diffraction analysis. DFT calculations (B3PW91) on the formation of 17 suggest that in the ruthenium case the hydrogenation of the enyne leads to an alkenylcarbene intermediate, which reacts with a second enyne molecule to afford the tetrasubstituted cyclopentadienyl group. © 2011 American Chemical Society.Financial support from the Spanish MICINN (Project numbers CTQ2008-00810 and Consolider Ingenio 2010 CSD2007-00006), the DGA (E35), and the European Social Fund is acknowledged. A.C. thanks the CSIC for her JAE grant.Peer Reviewe