Preoperative Combined Induction Chemotherapy With Capecitabine, Oxaliplatin, Bevacizumab and Radiotherapy

Phase 2

Completed

• Conditions: Rectal Cancer
• Interventions: Drug: preoperative induction chemotherapy in combination with bevacizumab followed by combined radiochemotherapy with capecitabine

• Registration Number: NCT01434147
• Lead Sponsor: Austrian Breast & Colorectal Cancer Study Group

Brief Summary

Phase II pilot study of a preoperative induction chemotherapy in combination with Bevacizumab followed by combined radiochemotherapy for patients with locally advanced rectal carcinoma

Detailed Description

Induction chemotherapy combined with Radio chemotherapy:

Therapy start: within 28 days after bioptical diagnosis capecitabine 1000 mg/m2 bid during 14 days (d1-d14) , oxaliplatin 130 mg/m2 and bevacizumab 7.5 mg/kg body weight d1; repetition day 22 and 43 (3 cycles)

Combined Radiochemotherapy after 1 week of concluded 3rd cycle of induction chemotherapy:

Radiotherapy: 5 x 5 days 1.8 Gy; cumulative dose 45 Gy Chemotherapy: capecitabine 825mg/m² bid, on each radiation day during the first 4 weeks of RCTx

Surgery according to TME-criteria (total mesorectal excision) in compliance of an interruption of min. 14 days after RCTx

Study Timeline

• Study First Submitted: 2011-09-13
• Study First Submitted QC: 2011-09-13
• Study First Posted: 2011-09-14
• Study Start: 2011-10
• Primary Completion: 2013-08
• Study Completion: 2013-08
• Status Verified: 2014-03
• Last Update Submitted: 2014-03-06
• Last Update Posted: 2014-03-07

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 25

Inclusion Criteria

• Age 18-80 years
• Histologic confirmation of rectal adenocarcinoma stage cT3 (≤ 5mm to the mesorectal fascia)/cT4( primary curative intention)NxM0
• No former chemotherapy, no former radiotherapy of the pelvic, no former tumour resection of a rectal carcinoma
• General condition WHO grade 0-2
• Adequate bone marrow reserve ( leucocytes ≥3 000/μl, thrombocytes ≥100 000/μl)
• Adequate renal function (creatinine ≤ 1,5 mg/dl, creatinine clearance > 50ml/min (Cockcroft and Gault formula))
• Adequate liver function (bilirubin ≤1,5x ULN, GOT and GPT ≤3,5xULN)
• Exclusion of pregnancy for women with childbearing potential (negative pregnancy test urine or serum)
• Female patients with childbearing potential and male patients that are not surgically sterile must be practicing a medically acceptable contraceptive regimen while on study treatment until 3 months after the end of the study (e.g. oral contraceptives, condom, intrauterine device)
• Life expectancy of at least 3 months
• INR and aPTT ≤ 1,5 x LLN
• Provision of signed informed consents before registration

Exclusion Criteria

• Rectal carcinoma stage cT3 (> 5mm from the mesorectal fascia) all stages <cT3, M1
• Other malignant tumours within the last 5 years except cervical carcinoma in situ and basal cell carcinoma of the skin
• General contraindication or known hypersensitivity against Bevacizumab, Capecitabine and Oxaliplatin
• Not malignant diseases for which treatment with radiotherapy, resection of the rectum and treatment with chemotherapy (Bevacizumab, Capecitabine) is contraindicated: uncontrolled hypertension (systolic > 150 mmHG and/or diastolic > 100 mmHG) or clinically significant (e.g. active) cardiovascular diseases: CVA (cardiovascular accident)/ apoplectic insult (≤ 6 months prior to registration), myocardial infarction (≤ 6 months prior to registration), unstable angina pectoris, CHF(congestive heart failure) with NYHA (New York heart Association) Grade II or higher, cardiac arrhythmia requiring therapy, hepatic diseases, significant neurologic or psychiatric disorders
• Florid, serious infection at registration
• Peripheral neuropathy (NCI CTCAE v 4.0 ≥ grade 1)
• Juridically limited contractual capability, indication of neurological or psychiatric disease which constrains upon investigators opinion the patients capability to adhere to the study routines
• Major surgical procedure within 28 days prior start of the study, open wounds
• Significant traumatic injury, bone fracture, unhealed wounds
• Patients with spinal cord compression or metastases in the central nervous system
• Indication of bleeding diathesis or coagulopathy
• Intake of anticoagulant or thrombolytic agents and/or Aspirin > 325 mg/d within 10 days prior to registration
• Current or recent (within 10 days prior to treatment start) therapy with full dosed anticoagulants. Preventive therapy is allowed.
• Previous thromboembolic or haemorrhagic events within 6 months prior to registration
• Previous abdominal fistulas, gastro-intestinal perforation or intrabdominal abscesses within 6 months prior to registration
• Treatment with another investigational drug within 28 days prior to registration
• Patients with malabsorption syndrome or difficulties in swallowing
• Indication of poor compliance of the patient
• Pregnant or breast-feeding women
• Proteinuria: Dipstick <2+. If the Dipstick is ≥2+ protein has to be estimated in the 24 hours urine. The value should not be higher then 1g/24 hours.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
induction chemotherapy + radiochemotherapy	preoperative induction chemotherapy in combination with bevacizumab followed by combined radiochemotherapy with capecitabine	preoperative induction chemotherapy in combination with bevacizumab followed by combined radiochemotherapy with capecitabine induction chemotherapy: starts within 28 days after bioptical diagnosis. All patients are administered with capecitabine (Xeloda®) 1000 mg/m2 bid during 14 days (d1-d14), oxaliplatin 130 mg/m2 and bevacizumab (Avastin®) 7.5 mg/kg body weight on day 1; repetition days 22 and 43 (3 cycles) Combined radiochemotherapy: starts at the earliest one week after concluded third cycle of induction chemotherapy. Radiotherapy takes place on 5 x 5 days (dose: 1.8 Gy; cumulative dose: 45 Gy). For chemotherapy patients are administered with capecitabine (Xeloda®) 825mg/m² bid, on each radiation day during the first 4 weeks of radiochemotherapy.

Primary Outcome Measures

Name	Time	Method
termination of therapy	up to 17 weeks	before surgery (after conclusion of therapy phase)
occurence of toxicity	up to 18-19 weeks	until timepoint of discharge of patient

Secondary Outcome Measures

Name	Time	Method
collection of response rate	up to week 18	T- and N-downstaging, pathological complete remission: measurement at the timepoint of surgery
post-surgery morbidity	after 18-19 weeks	according to Accordion; measurement at the timepoint of discharge of patient

Trial Locations

Locations (7)

Paracelsus Medical University Salzburg - Oncology; 🇦🇹 Salzburg, Austria

Medical University of Vienna, General Hospital; 🇦🇹 Vienna, Austria

Medical University Graz, Oncology; 🇦🇹 Graz, Styria, Austria

State Hospital Feldkirch, Radiotherapy; 🇦🇹 Feldkirch, Vorarlberg, Austria

Medical University Innsbruck, Internal Medicine; 🇦🇹 Innsbruck, Tyrol, Austria

Hospital BHB St. Veit/Glan, Surgery; 🇦🇹 St. Veit a. d. Glan, Carinthia, Austria

Klinikum Wels-Grieskirchen; 🇦🇹 Wels, Upper Austria, Austria