Dual REctcal Angiogenesis or MEK Inhibition radioTHERAPY Trial

Study Overview
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Brief Summary
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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
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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 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 Define a dose suitable for phase II evaluation 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

Official Title
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Dual Phase I Studies to Determine the Dose of Cediranib (AZD2171) or AZD6244 to Use With Conventional Rectal Chemoradiotherapy

Conditions
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Rectal Cancer

Intervention / Treatment
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* Drug: AZD6244
* Drug: Cediranib (AZD2171)


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AZD6244 + capecitabine + radiotherapy<br>10 days single-agent dosing AZD6244 Then 35 days dosing of AZD6244 in combination with standard chemoradiotherapy | Drug: AZD6244<br>* Dose finding trial AZD6244 cohort 1 - 50mg bd AZD6244 cohort 2 - 75mg bd Capsule form, given for 10 days as single agent then for 35 days in combination with standard chemoradiotherapy<br>|
| Experimental: Cediranib + capecitabine + radiotherapy<br>10 days single agent dosing with Cediranib (AZD2171) then 35 days dosing of AZD2171 in combination with standard chemoradiotherapy | Drug: Cediranib (AZD2171)<br>* 10 days single agent dosing with Cediranib then 35 days in combination with standard chemoradiotherapy AZD2171 cohort 1 - 15mg od AZD2171 cohort 2 - 20mg od AZD2171 cohort 3 - 30mg od Oral tablets<br>* Other names: AZD2171;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 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 | Various timepoints up to point of surgery | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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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)