Dual REctcal Angiogenesis or MEK Inhibition radioTHERAPY Trial

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

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

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