Clinical trial NCT01160926: Dual REctcal Angiogenesis or MEK Inhibition radioTHERAPY Trial
Official title: Dual Phase I Studies to Determine the Dose of Cediranib (AZD2171) or AZD6244 to Use With Conventional Rectal Chemoradiotherapy
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
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)
Lead sponsor: The Christie NHS Foundation Trust
Sponsor class: OTHER
Collaborators: name: Cancer Research UK
name: AstraZeneca
First posted: 2010-07-13
Enrollment: 31
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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

Eligibility 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

Primary outcomes:
measure: 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.
timeFrame: At point of surgery (10-12 weeks post treatment)
Secondary outcomes:
measure: Grade 3 or 4 toxicity
timeFrame: Up to point of surgery and long-term effects monitored for 3 years post treatment
measure: Radiotherapy compliance
timeFrame: for the 5 weeks of chemoradiotherapy
measure: MRI (Magnetic Resonance Imaging)Response Rate
timeFrame: 8 weeks post chemoradiation - at point of MRI scan
measure: Histologically confirmed R0 resection rate
timeFrame: 10-12 weeks post chemoradiation - at time of surgery
measure: Pathological Complete Response (pCR)
timeFrame: 10-12 weeks post chemoradiation - at point of surgery
measure: Morbidity - post operative and long term
timeFrame: 3 years post chemoradiation
measure: To explore biological and radiological markers of response or toxicity
timeFrame: Various timepoints up to point of surgery
Other outcomes:
Locations:
city: Manchester
country: United Kingdom
facility: The Christie NHS Foundation Trust
Study officials:
affiliation: The Christie NHS Foundation Trust
name: Mark P Saunders, MBBS
role: PRINCIPAL_INVESTIGATOR
References: