609P - First results from the phase I dual rectal angiogenesis MEK inhibition radiotherapy (DREAMTHERAPY) trial in locally advanced rectal cancer
|Date||01 October 2012|
|Event||ESMO Congress 2012|
|Session||Poster presentation III|
|Topics|| Drug Development
Surgery and/or Radiotherapy of Cancer
|Presenter||Francisca Marti Marti|
F.E. Marti Marti1, A. Backen2, A.G. Renehan3, P. Manoharan4, A. Jackson5, V. Misra6, O. Ataman7, G.C. Jayson8, C. Dive2, M. Saunders6
Less than 15% of patients (pts) receiving pre-operative chemoradiation (CRT) for rectal cancer have a complete pathological response (pCR). We tested the hypothesis that the addition of cediranib (a VEGFR TKI) or selumetinib (a MEK inhibitor), in combination with CRT, increases the proportion of complete responders. A translational protocol was also developed to study potential predictive biomarkers.Methods
This hypothesis was evaluated in a dual phase I design. The drugs are evaluated in parallel in an intertwined design: once a cohort of pts on cediranib completed treatment and during the toxicity assessment period, another cohort of pts was commenced on selumetinib at the next dose level. Alternating cohorts maximised the efficacy of their evaluation. The analysis here is for cediranib only. Pts received CRT (45Gy in 25#, capecitabine 825 mg/m2 twice daily for 35 days) in three cohorts with cediranib: 15 mg, 20 mg and 30 mg/once daily (OD). Dose escalation was done upon fulfilment of the safety criteria outlined in the protocol. Cediranib was commenced 10 days prior to the start of CRT and continued throughout. Pts were followed up until and then after surgery. Safety, RECIST and pathological data were collected. In addition, blood, tissue and DCE-MRIs were obtained at baseline, post-monotherapy, throughout and post CRT for the study of candidate biomarkers.Results
15 mg cohort: 3 pts were recruited. 2 pts had a pCR and the 3rd pt had a clinical complete response (cCR) not requiring surgery. 20 mg cohort: 3 pts were treated. 1 had a cCR and ypT3N0 on resection. The other 2 had partial responses on MRI with ypT3N0 and ypT3N2 pathologically. 30 mg cohort: 3 pts were recruited at this dose level. Two pts had a cCR and the other one is waiting restaging. There was one DLT in this cohort (Grade III lethargy). This cohort will be expanded to a maximum n = 6. As yet, all pts have had R0 resections and completed all planned treatment (except pt with DLT who did not complete capecitabine). cCR pts remain disease free and have not had surgery.Conclusions
The addition of cediranib to pre-operative CRT is a well tolerated regimen. All pts have responded with 5 out of 8 evaluable pts (62.5%) having either a pCR (n = 2) or cCR (n = 3). Updated clinical data, proposed optimal dose and translational data will be available for presentation at the meeting.Disclosure
F.E. Marti Marti: Dr Marti's research fellowship is funded in equal parts by Cancer Research UK and Astra Zeneca.
O. Ataman: Dr Ataman is an Astra Zeneca employee.
G.C. Jayson: AZ advisory boards and research funding.
M.P. Saunders: I have previously been a paid advisor on an AZ trial with AZD2171 (Horizon II). However, I have no conflicts on the use of this agent in the DREAMtherapy trial.
All other authors have declared no conflicts of interest.