Dual REctcal Angiogenesis or MEK Inhibition radioTHERAPY Trial (DREAMtherapy)

• Grade 3 or 4 toxicity [ Time Frame: Up to point of surgery and long-term effects monitored for 3 years post treatment ] [ Designated as safety issue: Yes ]
• Radiotherapy compliance [ Time Frame: for the 5 weeks of chemoradiotherapy ] [ Designated as safety issue: No ]
• MRI (Magnetic Resonance Imaging)Response Rate [ Time Frame: 8 weeks post chemoradiation - at point of MRI scan ] [ Designated as safety issue: No ]
• Histologically confirmed R0 resection rate [ Time Frame: 10-12 weeks post chemoradiation - at time of surgery ] [ Designated as safety issue: No ]
• Pathological Complete Response (pCR) [ Time Frame: 10-12 weeks post chemoradiation - at point of surgery ] [ Designated as safety issue: No ]
• Morbidity - post operative and long term [ Time Frame: 3 years post chemoradiation ] [ Designated as safety issue: No ]
• To explore biological and radiological markers of response or toxicity [ Time Frame: Various timepoints up to point of surgery ] [ Designated as safety issue: No ]

  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

• Grade 3 or 4 toxicity [ Time Frame: Up to point of surgery and long-term effects monitored for 3 years post treatment ] [ Designated as safety issue: Yes ]
• Radiotherapy compliance [ Time Frame: for the 5 weeks of chemoradiotherapy ] [ Designated as safety issue: No ]
• MRI (Magnetic Resonance Imaging)Response Rate [ Time Frame: 8 weeks post chemoradiation - at point of MRI scan ] [ Designated as safety issue: No ]
• Histologically confirmed R0 resection rate [ Time Frame: 10-12 weeks post chemoradiation - at time of surgery ] [ Designated as safety issue: No ]
• Pathological Complete Response (pCR) [ Time Frame: 10-12 weeks post chemoradiation - at point of surgery ] [ Designated as safety issue: No ]
• Morbidity - post operative and long term [ Time Frame: 3 years post chemoradiation ] [ Designated as safety issue: No ]
• To explore biological and radiological markers of response or toxicity [ Time Frame: Various timepoints up to point of surgery ] [ Designated as safety issue: No ]

  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 bothe groups - at screening, after 10 days of dosing with single agent AZD6244/Cediranib and 2 weeks post chemoradiation

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

• Drug: AZD6244

  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

  Other Name: AZD6244
• Drug: Cediranib (AZD2171)

  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

  Other Name: AZD2171

• Experimental: AZD6244 + capecitabine + radiotherapy
  10 days single-agent dosing AZD6244 Then 35 days dosing of AZD6244 in combination with standard chemoradiotherapy
  Intervention: Drug: AZD6244
• Experimental: Cediranib + capecitabine + radiotherapy
  10 days single agent dosing with Cediranib (AZD2171) then 35 days dosing of AZD2171 in combination with standard chemoradiotherapy
  Intervention: Drug: Cediranib (AZD2171)

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

• Cancer Research UK
• AstraZeneca