Dual REctcal Angiogenesis or MEK Inhibition radioTHERAPY Trial (DREAMtherapy)

The Christie NHS Foundation Trust

Status and phase

Terminated

Phase 1

Conditions

Rectal Cancer

Treatments

Drug: AZD6244

Drug: Cediranib (AZD2171)

Study type

Interventional

Funder types

Other

Industry

Identifiers

NCT01160926

09_DOG03_184

2009-016524-31 (EudraCT Number)

Details and patient eligibility

About

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.

Full 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

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
Define a dose suitable for phase II evaluation
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

Enrollment

31 patients

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

Inclusion and exclusion 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