DREAMtherapy: Dual REctcal Angiogenesis or MEK Inhibition radioTHERAPY Trial

Sponsor

The Christie NHS Foundation Trust (Other)

Overall Status

Terminated

CT.gov ID

NCT01160926

Collaborator

Cancer Research UK (Other), AstraZeneca (Industry)

Enrollment

Location

Arms

76.2

Duration (Months)

0.4

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Rectal Cancer	Drug: AZD6244 Drug: Cediranib (AZD2171)	Phase 1

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

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

Study Design

Study Type:

Interventional

Actual Enrollment :

31 participants

Allocation:

Non-Randomized

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Dual Phase I Studies to Determine the Dose of Cediranib (AZD2171) or AZD6244 to Use With Conventional Rectal Chemoradiotherapy

Study Start Date :

Jul 1, 2010

Actual Primary Completion Date :

Oct 1, 2013

Actual Study Completion Date :

Nov 4, 2016

Arms and Interventions

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

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

Outcome Measures

Primary Outcome Measures

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

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 [Various timepoints up to point of surgery]
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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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