ACO-ASSO Studien:
mCRC/Leber/Gallenwege

Synopsis

TITLE	Pre- and postoperative chemotherapy including Bevacizumab in potentially curable metastatic colorectal Cancer (mCRC). A multicenter, single arm Phase I/II academic trial.
SPONSOR	ACO-ASSO
COORDINATING INVESTIGATOR	Univ. Prof. Dr. Thomas Gruenberger Medical University of Vienna, Department of Surgery Waehringer Guertel 18-20 , 1090 Vienna Tel. : +431/40400- 5621 Fax : +431/40400- 5641 email: thomas.gruenberger@meduniwien.ac.at
PROTOCOL VERSION	1.0
INDICATION	metastatic CRC
OBJECTIVES	primary objective: Resectability (R0) rate after neoadjuvant Avastin in potentially resectable mCRC secondary objectives: Feasibility with regards to GI bleeding and wound healing complications after surgery of liver metastases, general safety, ORR, RFS, OS
TRIAL DESIGN	single arm, multicenter Phase I/II
NUMBER OF SUBJECTS / SITES	43 / 6 sites
TARGET POPULATION	patients with potentially resectable metastatic colorectal cancer previously untreated for metastatic disease
INCLUSION / EXCLUSION CRITERIA	Inclusion Criteria: Patients with histologically confirmed diagnosis of metastatic CRC including potentially resectable liver metastases, which are untreated yet with chemotherapy At least one measurable metastatic lesion (as per RECIST criteria) Prior adjuvant, neo-adjuvant chemotherapy/radiotherapy or chemotherapy for prior metastatic disease allowed ECOG performance status 0 or 1 Signed written informed consent life expectancy greater than 3 months patients ³ 18 years of age Adequate haematological function: White blood count ≥ 3 x 109/L with neutrophils ≥ 1.5 x 109/L, platelet count ≥ 100 x 109/L, and hemoglobin ≥ 5.6 mmol/L (9g/dL) Adequate liver function: Total bilirubin ≤ 1.5 x upper limit of normal (ULN) range, alkaline phosphatase, Aspartate aminotransferase (ASAT) and Alanin aminotransferase (ALAT) ≤ 5 x ULN Serum creatinine ≤ 1.25 ULN and/or creatinine clearance ≥ 60 ml/min Urine dipstick of proteinuria <2+. Patients discovered to have ³2+ proteinuria on dipstick urinalysis at baseline, should undergo a 24-hour urine collection and must demonstrate £  1 g of protein/24 hr INR ≤ 1.5 and PTT ≤ 1.5 x ULN within 7 days prior to enrolment Women of childbearing potential must have a negative serum pregnancy test done 1 week prior to the administration of the study drug. She and her partner should prevent pregnancy (oral contraceptives, intrauterine contraceptive device, barrier method of contraception in conjunction with spermicidal jelly or surgically sterile) up to at least 6 months after last treatment completion or the last drug dose, whatever happens first. Patient must be able to comply with the protocol Exclusion criteria: Extrahepatic disease, except concurrent diagnosis of primary CRC or also potentially resectable lesions of other organs Prior chemotherapeutic treatment of current liver lesion(s). Serious, non healing wound, ulcer, or bone fracture. Major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to treatment, Evidence of any other disease, metabolic dysfunction, physical examination finding or laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or puts the patient at high risk for treatment-related complications Lack of physical integrity of the upper gastro-intestinal tract, malabsorption syndrome, or inability to take oral medication Pregnancy (absence to be confirmed by ß-HCG test) or lactation Men of childbearing potential not willing to use effective means of contraception Previous exposure to anti-VEGF antibodies Treatment with any investigational agent(s) within 4 weeks prior to study entry Known allergic/hypersensitivity reaction to any of the components of study treatments Clinically significant cardiovascular disease, for example CVA (£ 6 months before treatment start), myocardial infarction (£ 6 months before treatment start), unstable angina, NYHA  ³ grade 2 CHF, or uncontrolled hypertension. History of significant neurologic or psychiatric disorders including dementia, seizures, bipolar disorder Medical or psychological condition that would not permit the patient to complete the study or sign informed consent Known alcohol or drug abuse Clinical or radiological evidence of CNS metastases. Past or current history (within the last 2 years prior to treatment start) of other malignancies except metastatic colorectal cancer (Patients with curatively treated basal and squamous cell carcinoma of the skin or in situ carcinoma of the cervix are eligible). History of thromboembolic or haemorrhagic events within 6 months prior to treatment. Evidence of bleeding diathesis or coagulopathy Current or recent (within 10 days prior to study treatment start) ongoing treatment with anticoagulants for therapeutic purposes i.e. except for anticoagulation for maintenance of patency of permanent indwelling IV catheters. Chronic daily treatment with aspirin (> 325 mg/day) or clopidogrel (>75 mg/day). Chronic daily treatment with corticosteroids (dose of  ³ 10 mg/day methylprednisolone equivalent) (excluding inhaled steroids). Any other serious or uncontrolled illness which, in the opinion of the investigator, makes it undesirable for the patient to enter the trial gastrointestinal ulceration Known peripheral neuropathy ³ NCI CTC Grade 1. Absence of deep tendon reflexes (DTRs) as the sole neurological abnormality does not render the patient ineligible
LENGTH OF STUDY	Recruitment period: 2 year Treatment duration: approx. 33 weeks Follow up: 2 years
INVESTIGATIONAL PRODUCT(S) DOSE/ ROUTE/ REGIMEN	Bevacizumab 5 mg/m2 q2w for 5 cycles pre-surgery Bevacizumab 5 mg/m2 q2w for 6 cycles post-surgeryXELOX Regimen: Liquid Oxaliplatin  85 mg/m² q2w for 6 cycles pre- & post-surgery Capecitabine 3000mg/m² days 1-7 every 2 weeks for 6 cycles pre- & post-surgery
COMPARATOR “DRUG” DOSE/ ROUTE/ REGIMEN	n.a.
ASSESSMENTS OF:
- EFFICACY	tumour assessments (based on RECIST criteria) using CT scans (chest, abdomen and 3 phase liver), MRI scans (if required), clinical examination
- SAFETY	Physical exam and vital signs ECG (at baseline), ECOG Performance score, concomitant disease and medication Haematology Haemoglobin, Platelet count, RBC, WBC including differential (Neutrophiles, Lymphocytes, Monocytes, Eosinophiles, Basophiles), INR, aPTT Serum Chemistry Na+, K+, Ca++, Cl–, Urea (BUN), Uric Acid, total Protein, Albumin, Alkaline Phosphatase, ALT, AST, GGT, LDH, direct and total Bilirubin, Serum creatinine, Glucose Urinalysis Dip stick test and 24 hours urine collection in the event of  ³ +2 protein Adverse Events to be reported according to NCI CTC AE v3.0 Surgical adverse Events: according to NCI CTC AE v3.0 1. Hemorrhage with surgery (Hemorrhage/bleeding associated with surgery, intra-operative or postoperative) Grad 1: - Grad 2: - Grad 3: requiring transfusion of 2 units non-autologous pRBCs beyond protocol specification; postoperative interventional radiology, endoscopic, or operative intervention indicated Grad 4: life-threatening consequencesREMARK: postoperative period is defined as < 72 hours after surgery. Verify protocol-specific acceptable guidelines regarding pRBC transfusion.ALSO CONSIDER: Fibrinogen; INR; Platelets; PTT 2. Hemorrhage GI Grad 1: mild, intervention (other than iron supplements) not indicated Grad 2: symptomatic and medical intervention or minor cauterization indicated Grad 3: transfusion, interventional radiology, endoscopic, or operative intervention indicated; radiation therapy (i.e., hemostasis of bleeding site) Grad 4: life-threatening consequences; major urgent intervention indicatedRequirement of blood transfusions, relaparotomy due to bleeding events, wound dehiscence, bowel perforation during treatment
ANGIOGENETIC BALANCE	Only performed at the centre of coordinating investigator Prof. Gruenberger, Department of general surgery, MUW, Währinger Gürtel 18-20, 1090 Vienna  Blood samples will be collected and analyzed by immunological methods to get information about the impact of bevaciczumab on angiogentic balance and therefore get more detailed information about the systemic effectiveness of this substance.

PROCEDURES (summary): mCRC patients will be treated for 6 neoadjuvant cycles (5 for Bevacizumab) and potentially curative resection is planned 5 weeks after last Bevacizumab, 3 weeks after last Oxaliplatin and 2 weeks after last Xeloda dose.
Treatment with the same regimen will be restarted for additional 6 cycles 4-5 weeks after surgery at the discretion of the investigator.