Dual REctcal Angiogenesis or MEK Inhibition radioTHERAPY Trial (DREAMtherapy)

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.

Study Overview

• Status: Terminated
• Conditions: Rectal Cancer
• Intervention / Treatment: Drug: AZD6244; Drug: Cediranib (AZD2171)

Detailed Description

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

• Study Type: Interventional
• Enrollment (Actual): 31
• Phase: Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • Manchester, United Kingdom, M20 4BX
    • The Christie NHS Foundation Trust

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: AZD6244 + capecitabine + radiotherapy; 10 days single-agent dosing AZD6244 Then 35 days dosing of AZD6244 in combination with standard chemoradiotherapy	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
Experimental: Cediranib + capecitabine + radiotherapy; 10 days single agent dosing with Cediranib (AZD2171) then 35 days dosing of AZD2171 in combination with standard chemoradiotherapy	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 Names: AZD2171

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: The Christie NHS Foundation Trust
• Collaborators: AstraZeneca; Cancer Research UK
• Investigators: Principal Investigator: Mark P Saunders, MBBS, The Christie NHS Foundation Trust

Publications and helpful links

Helpful Links

• CRUK Results Summary

Study record dates

Study Major Dates

• Study Start: July 1, 2010
• Primary Completion (Actual): October 1, 2013
• Study Completion (Actual): November 4, 2016

Study Registration Dates

• First Submitted: July 7, 2010
• First Submitted That Met QC Criteria: July 12, 2010
• First Posted (Estimate): July 13, 2010

Study Record Updates

• Last Update Posted (Actual): April 24, 2023
• Last Update Submitted That Met QC Criteria: April 20, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Keywords: capecitabine; radiotherapy; rectal cancer; MEK inhibitor; Cediranib; AZD6244; AZD2171; VEGFR inhibitor; FLT-PET (fluoro-l-pyrimidine positron emission tomography); DCE-MRI (dynamic contrast enhanced magnetic resonance imaging)
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Rectal Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Cediranib
• Other Study ID Numbers: 09_DOG03_184; 2009-016524-31 (EudraCT Number)