Dual REctcal Angiogenesis or MEK Inhibition radioTHERAPY Trial
- Registration Number
- NCT01160926
- Lead Sponsor
- The Christie NHS Foundation Trust
- Brief Summary
To determine the maximum tolerated dose (MTD) of AZD6244 or AZD2171 when combined with pre-operative capecitabine and radiotherapy in patients with locally advanced rectal cancer.
- Detailed Description
The best curative resection rates reported for patients with operable rectal cancer treated with standard chemoradiotherapy are approximately 50-60%.The pathological complete response rates are only 10-20%. Therefore, there is a need for more effective treatment. In this trial we will evaluate the combination of chemoradiotherapy with either a VEGFR (vascular endothelial growth factor receptor) or MEK (MAP Kinase)inhibitor.
Aims
1. Define the tolerability, MTD (maximum tolerated dose) and DLT (dose limiting toxicities) of chemoradiotherapy in combination with
* cediranib, a VEGF receptor tyrosine kinase inhibitor that inhibits angiogenesis or
* AZD6244, a potent MEK inhibitor that inhibits cell proliferation
2. Define a dose suitable for phase II evaluation
3. Test the impact of the combination on soluble and imaging (FLT-PET and DCEMRI/DWI) biomarkers to guide their use in phase II testing Summary Patients will receive standard chemoradiotherapy plus ascending doses of AZD6244 or cediranib from day -10 (relative to start of chemoradiotherapy) to day 35. If feasible, patients' tumours will be resected 10-12 weeks after treatment. Translational studies on available tissue and blood will be performed and DCE-MRI/DWI and FLT-PET will be carried out on 5 patients in the expanded cohort for AZD6244 (FLT-PET and DCE-MRI) and 5 patients in the expanded cohort for cediranib (DCE-MRI).
Cohorts Cediranib - 15mg od, 20mg od and 30mg od AZD6244 - 50mg bd and 75mg bd
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 31
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description AZD6244 + capecitabine + radiotherapy AZD6244 10 days single-agent dosing AZD6244 Then 35 days dosing of AZD6244 in combination with standard chemoradiotherapy Cediranib + capecitabine + radiotherapy Cediranib (AZD2171) 10 days single agent dosing with Cediranib (AZD2171) then 35 days dosing of AZD2171 in combination with standard chemoradiotherapy
- Primary Outcome Measures
Name Time Method To determine the MTD (maximum tolerated dose) of AZD6244 or AZD2171 when combined with pre-operative capecitabine and radiotherapy in patients with locally advanced rectal cancer. At point of surgery (10-12 weeks post treatment)
- Secondary Outcome Measures
Name Time Method Grade 3 or 4 toxicity Up to point of surgery and long-term effects monitored for 3 years post treatment Radiotherapy compliance for the 5 weeks of chemoradiotherapy MRI (Magnetic Resonance Imaging)Response Rate 8 weeks post chemoradiation - at point of MRI scan Histologically confirmed R0 resection rate 10-12 weeks post chemoradiation - at time of surgery Pathological Complete Response (pCR) 10-12 weeks post chemoradiation - at point of surgery Morbidity - post operative and long term 3 years post chemoradiation To explore biological and radiological markers of response or toxicity Various timepoints up to point of surgery Tissue samples - from diagnostic sample, biopsy 6-8 days after single agent AZD6244/Cediranib and resection sample from surgery.
Blood samples - screening, weeks 1, 3 and 5 during chemoradiotherapy and 8 weeks post chemoradiotherapy.
FLT-PET scans - patients in AZD6244 cohorts only - at screening, after 10 days of dosing with single agent AZD6244 and 2 weeks post chemoradiation DCE-MRI scans - patients in both groups - at screening, after 10 days of dosing with single agent AZD6244/Cediranib and 2 weeks post chemoradiation
Trial Locations
- Locations (1)
The Christie NHS Foundation Trust
🇬🇧Manchester, United Kingdom