Phase I Results Support Volasertib Plus Nintedanib Investigation

Preliminary research has determined a maximum tolerated dose for volasertib plus nintedanib and shown some indication of efficacy against solid tumours

medwireNews: Phase I trial findings suggest that the anti-mitotic agent volasertib may be a promising therapy for patients with heavily pretreated, advanced solid tumours when given in combination with the angiokinase inhibitor nintedanib.

The open-label study, published in the Annals of Oncology, included 30 patients with metastatic solid tumours refractory to conventional therapy who were given 2-hour infusion doses of the selective Polo-like kinase (Plk)-inhibitor ranging from 100 mg to 400 mg.

For the first 28-day cycle, volasertib was given on day 8, with a fixed 200 mg twice daily dose of nintedanib given on days 1 to 7 and 9 to 28. Thereafter, volasertib was given on day 1 of a 21-day cycle and nintedanib on days 2 to 21.

Both patients given volasertib 400 mg experienced dose limiting toxicity (DLT) in the form of grade 4 thrombocytopenia alone or alongside grade 4 febrile neutropenia. And of the three assessable patients given a 350 mg dose, two patients each experienced two DLTs – grade 4 neutropenia and thrombocytopenia in one case and grade 4 neutropenia and grade 3 alanine aminotransferase in the other.

None of the six patients given volasertib 300 mg experienced DLT and the maximum tolerated dose (MTD) was set at 300 mg once every 3 weeks, “the same dose recommended for single-agent treatment of solid tumors”, say Filippo de Braud, from Fondazione IRCCS Istituto Nazionale dei Tumori in Milan, Italy, and co-investigators.

Although two of seven patients in an extension cohort given the MTD developed DLT – grade 3 elevations in alanine aminotransferase or aspartate aminotransferase – the overall incidence of DLT (2/12 patients) was considered acceptable.

The majority (90%) of patients experienced drug-related adverse events during treatment and 27% had serious adverse events; 47% of patients reduced their volasertib or nintedanib dose and 17% discontinued treatment.

Neutropenia (69%), diarrhoea (62%) and thrombocytopenia (62%) were the most common adverse events affecting patients given the MTD, followed by elevations of the two liver enzymes (54% each). Two patients died during the study but both deaths were attributed to disease progression.

“At this dose [MTD], the safety profile of combination treatment is manageable and in line with the known safety profiles of the individual drugs and the combination may be feasible in patients with solid tumors based on the very good compliance and the long-lasting disease stabilization observed in this study”, the authors comment.

They highlight that RECIST tumour assessment showed a complete response in one patient with moderately differentiated ductal infiltrating carcinoma of the breast and a partial response in one with non-small-cell lung cancer with a KRAS mutation. These patients had received the MTD of volasertib plus nintedanib and had progression-free survival of 447 and 267 days, respectively.

And 16 patients had stable disease, giving an overall disease control rate of 60% and a median response duration of 161.5 days.

“Given the phase I design, this study is of limited value in defining the patient population that would benefit from this combination in future clinical studies”, the researchers comment.

“However, given the wide antitumor activity (response or significant disease stabilization) observed in this heavily pretreated patient population, further clinical investigation of combination volasertib and nintedanib is warranted.”

But, they add: “The identification of biomarkers predictive of response will be critical for the further development of this therapy in patients with advanced solid tumors.”


de Braud F, Cascinu S, Spitaleri G,et al. A phase I, dose-escalation study of volasertib combined with nintedanib in advanced solid tumors. Ann Oncol 2015; Advance online publication 22 September. doi: 10.1093/annonc/mdv354

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