dual rectcal angiogenesis or mek inhibition radiotherapy trial

Conditions: Rectal Cancer

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.

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

Eligibility criteria:
inc criteria: * histologically confirmed rectal adenocarcinoma * mri (magnetic resonance imaging) and triphasic ct (computerised tomography) defined locally advanced rectal cancer: * mesorectal fascia involved or * mesorectal fascia threatened or * any t3 tumours \< 5cm from the anal verge * primary resection unlikely to achieve clear margins * no previous chemotherapy or radiotherapy for rectal cancer * bone marrow function: absolute neutrophil count ≥1.5 x109/l and platelet count \>100 x109/l * hepatobiliary function: serum bilirubin \<1.5 x upper limit of normal (uln); serum alp \<5 x uln; serum transaminase (ast or alt) \<2.5 x uln * renal function: serum creatinine clearance \>50ml/min by either cockcroft-gault formula or edta (ethylenediaminetetraacetic acid) clearance * ecog ps(eastern cooperative oncology group performance status) 0-1 * disease can be encompassed within a radical radiotherapy treatment volume * no pre-existing condition which would deter radiotherapy, e.g. fistulas, severe ulcerative colitis, crohn's disease, prior adhesions * for women of child-bearing potential a negative pregnancy test is required and adequate contraceptive precautions such as a condom for their partner must be used. for men - adequate contraception must be used. * fit to receive all study treatments * able to comply with oral medication and protocol * signed, written and dated informed consent. * life expectancy ≥ 3 months. exc criteria: * concurrent uncontrolled medical illness, or other previous/current malignant disease likely to interfere with protocol treatments * age\<18 * any pregnant, lactating women or potentially childbearing patients not using adequate contraception * previous chemotherapy or radiotherapy for rectal cancer * metastatic disease * ecog ps\>1 * patients who have very significant small bowel delineated within the radiation fields. * current or impending rectal obstruction (unless defunctioning stoma present), metallic colonic rectal stent in situ * pelvic sepsis. * uncontrolled cardiac, respiratory or other disease, or any serious medical or psychiatric disorder that would preclude trial therapy or informed consent. * cardiac conditions as follows: * uncontrolled hypertension (resting bp ≥150/95mmhg despite optimal therapy) * heart failure nyha class ii or above * prior or current cardiomyopathy * atrial fibrillation with heart rate \>100 bpm * unstable ischaemic heart disease * refractory nausea and vomiting, chronic gastrointestinal diseases, or significant bowel resection that would preclude adequate absorption of trial drug * patients who are deemed unsuitable for surgery because of co-morbidity or coagulation problems. * recent (\<14 days) major thoracic or abdominal surgery prior to entry into the study or a surgical incision that is not fully healed which would prevent administration of study treatment * known dpd (dihydropyrimidine dehydrogenase)deficiency * patients suffering from any condition that may affect the absorption of capecitabine or imp (investigational medical product) * any evidence of severe or uncontrolled systemic disease, active infection, active bleeding diatheses or renal transplant, including any patient known to have hep b, hep c or hiv * mean qtc with bazetts correction \>470msec in screening ecg or history of familial long qt syndrome exc criteria (azd6244 cohorts) * kras (kirsten ras sarcoma viral oncogene) wild-type * prior treatment with a mek inhibitor * baseline lvef (left ventricular ejection fraction) ≤50% exc criteria (cediranib cohorts) * known hypersensitivity to cediranib or any of its excipients * greater than +1 proteinuria on two consecutive dipsticks taken no less than 1 week apart unless urinary protein \< 1.5g in a 24 hr period or protein/creatinine ratio \< 1.5. * significant haemorrhage (\>30ml bleeding/episode in previous 3 months) or haemoptysis (\>5ml fresh blood in previous 4 weeks) * aptt ratio \> 1.5 x uln * arterial thromboembolic event (including ischemic attack) in the previous 12 months

Keywords: rectal cancer capecitabine radiotherapy azd6244 mek inhibitor azd2171 cediranib vegfr inhibitor flt-pet (fluoro-l-pyrimidine positron emission tomography) dce-mri (dynamic contrast enhanced magnetic resonance imaging)