A NOVEL TRIAL DESIGN FOR RECTAL CANCER: THE DREAMtherapy TRIAL (Dual REctal Angiogenesis MEK inhibition radioTherapy)

BackgroundRectal cancer affects 10,000 new patients in the UK and around 39,000 new patients in the US every year. Historically, the risk of local recurrence for patients presenting with a locally advanced rectal tumour and treated with surgery alone is of around 20%. Improvements in surgical techniques and the use of perioperative radiotherapy have resulted in improved outcomes. A long course of preoperative radiotherapy used concurrently with fluoropyrimidine-based chemotherapy constitutes the current standard of care. However, despite the recent optimisation of the treatment schedules, the best curative resection rates with this chemoradiotherapy (CRT) treatment are only about 50-60% and the generally accepted pathological complete response rates are only about 15-20%. In recent years, the addition of targeted agents to CRT has been explored aiming to improve the current response rates with encouraging results. Assessment of novel agents in combination with CRT is also difficult due to the need to wait many weeks for toxicity assessment before dose escalation. Here, we present the DREAMtherapy trial, a phase I study of long course CRT plus a targeted agent (either ZD6244 or ZD2171). Methods The DREAMtherapy trial is a single-centre, dual single arm, open label, phase I trial of escalating doses of a MEK inhibitor (ZD6244) at 50mg or 75mg twice daily, or cediranib (ZD2171), a VEGFR TKI at 15mg, 20mg or 30mg once daily, administered orally as a single agent for 10 days and then in combination with standard CRT (45Gy in 25 fractions over 5 weeks with capecitabine 825mg/m2 bd d1-d35). The primary end point is to determine MTD of ZD6244 or ZD2171 when combined with CRT in patients with locally advanced rectal cancer. This innovative design allows the parallel evaluation of the two experimental drugs optimising use of the natural toxicity follow-up periods encountered in traditional phase I trials. Whilst patients are recovering from CRT with ZD2171, a cohort of patients are treated with ZD6244.Then, during the ZD6244 toxicity assessment period, the next ZD2171cohort is started at a higher dose. This means two drugs will be assessed efficiently in an inter-twining “dual” phase one study. A comprehensive translational research program complements this protocol. The tests performed and candidate biomarkers have been tailored to each one of the drugs which will provide information to support the optimal biological dose. Serial blood samples, translational biopsies, DCE-MRIs and FLT-PET scans are being performed. Results The first ZD2171 cohort (15 mg) has been recruited and no dose limiting toxicities (DLTs) have been encountered so far. Two out of three patients have been entered into the first ZD6244 cohort with no DLT recorded. Translational sampling consisting of blood samples for the analysis of serological biomarkers, tissue biopsies and DCE-MRIs have been performed for all patients. FLT-PETs are also performed in the ZD6244 cohorts. Conclusion Current data supports this trial design as an efficient way of evaluating new combinations of targeted therapy with standard CRT in the phase I setting helping to fast-track candidate drugs to phase II and III trial designs.