Dual REctcal Angiogenesis or MEK Inhibition radioTHERAPY Trial

• Status: Terminated
• Trial end date: 2016-11-04
• Target enrollment: 0
• Participant gender: All

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.

• Phase: Phase 1
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: The Christie NHS Foundation Trust
• Collaborators: AstraZeneca; Cancer Research UK
• Treatments: Capecitabine; Cediranib

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