12TiP - A randomized, phase III study of fotemustine versus the combination of fotemustine and ipilimumab or the combination of ipilimumab and nivolumab in...

Date 20 November 2015
Event ESMO Symposium on Immuno-Oncology 2015
Session Welcome reception and general Poster viewing
Topics Anticancer Agents
Skin Cancers
Biological Therapy
Presenter Anna Maria Di Giacomo
Citation Annals of Oncology (2015) 26 (suppl_8): 5-14. 10.1093/annonc/mdv514
Authors A.M. Di Giacomo, M. Maio
  • Medical Oncology And Immunotherapy, University Hospital of Siena, Istituto Toscano Tumori, 53100 - Siena/IT



The anti-CTLA-4 monoclonal antibody (mAb) ipilimumab (Ipi) significantly improves the survival of metastatic melanoma (MM) patients. Initial studies have evaluated the therapeutic potential of Ipi also in MM patients with brain metastasis (BM), providing preliminary evidences of efficacy in this subset of subjects with a highly dismal prognosis and limited efficacy of available therapeutic options. The multicentric, phase 2, Italian Network for Tumor Biotherapy (NIBIT)-M1 trial, combining Ipi with fotemustine, showed promising signs of activity in a subset of 20 MM subjects with active BM, regardless of prior radiotherapy (Di Giacomo et al., Lancet Oncol, 2012). Noteworthy, disease control in the brain was long lasting achieving a 3-year survival rate of 28%, similar to that of patients without BM (Di Giacomo et al., Annals Oncol, 2014). Based these preliminary results and on the therapeutic efficacy of Ipi in combination with nivolumab (Nivo) in MM patients without BM, the NIBIT-M2 study has been designed to further explore the efficacy of check-point blocking mAb in MM patients with BM.

Trial design

The NIBIT-M2 is a randomized, phase 3, open-label, study that will enroll 168 MM patients with untreated, asymptomatic BM, ECOG performance status of 0 or 1, BRAF W/T or mutant disease. Patients will be randomized to receive fotemustine i.v. at 100 mg/m2 weekly for 3 weeks (wk), and q3 wk from week 9 (ARM A) or Ipi i.v. at 10 mg/kg q3 wk for 4 doses and once q12 wk from week 24 in combination with fotemustine (ARM B) or Ipi i.v. at 3 mg/kg q3 wk for 4 doses in combination with Nivo at 1 mg/kg q3 wk for 4 doses and then Nivo at 3 mg/kg q2 wk (ARM C). Primary objective is OS; secondary are safety, DCR in and outside the brain, ORR and DOR evaluated using both the modified-WHO response criteria and the immune-related response criteria; PFS, 3- and 6-months Brain-PFS rate, and Quality of Life. Phenotypic and functional cellular and humoral translational studies will correlate the immunomodulatory activity of treatment with clinical outcomes. Thirty-two patients have been enrolled to date.

Clinical trial identification



A.M. Di Giacomo: Compensated educational activities Bristol Myers Squibb, Roche, MSD. M. Maio: Consultant, Advisor or both to Bristol Myers Squibb, Roche, Medimmune-AstraZeneca, MSD.