Dual REctcal Angiogenesis or MEK Inhibition radioTHERAPY Trial

NCT01160926 | Terminated Phase 1

• 2 other identifiers: 09_DOG03_1842009-016524-31
• Study Type: interventional
• Target: 31
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Rectal Cancer

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)

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (7)

• 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

Study Arms (2)

AZD6244 + capecitabine + radiotherapy

EXPERIMENTAL

10 days single-agent dosing AZD6244 Then 35 days dosing of AZD6244 in combination with standard chemoradiotherapy

Drug: AZD6244

Cediranib + capecitabine + radiotherapy

EXPERIMENTAL

10 days single agent dosing with Cediranib (AZD2171) then 35 days dosing of AZD2171 in combination with standard chemoradiotherapy

Drug: Cediranib (AZD2171)

Interventions

AZD6244 DRUG

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

AZD6244 + capecitabine + radiotherapy

Cediranib (AZD2171) DRUG

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

Also known as: AZD2171

Cediranib + capecitabine + radiotherapy

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

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

Contact the study team to discuss eligibility requirements. They can help determine if this study is right for you.

Sponsors & Collaborators

• The Christie NHS Foundation Trust: lead
• Cancer Research UK: collaborator
• AstraZeneca: collaborator

Study Sites (1)

The Christie NHS Foundation Trust

Manchester, M20 4BX, United Kingdom

Location

MeSH Terms

Conditions

Rectal Neoplasms

Interventions

AZD 6244; cediranib

Condition Hierarchy (Ancestors)

Colorectal Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Diseases; Rectal Diseases

Study Officials

• Mark P Saunders, MBBS

  The Christie NHS Foundation Trust

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 7, 2010
• First Posted: July 13, 2010
• Study Start: July 1, 2010
• Primary Completion: October 1, 2013
• Study Completion: November 4, 2016
• Last Updated: April 24, 2023

Record last verified: 2023-04

Locations

GB (1)