Efficacy And Safety Of Xeliri + Avastin Followed By Xelox + Avastin Or Reverse Sequence In Metastatic Colorectal Cancer

NCT02119026 | Completed Phase 2 Results

• 1 other identifier: ML25153_PASSION
• Study Type: interventional
• Target: 120
• Locations: 1 country
• Sites: 1

Brief Summary

Since its introduction, 5-fluorouracil (5-FU) has been the cornerstone of treatment for metastatic colorectal cancer (mCRC). Meanwhile the oral 5FU pro-drug Capecitabine (Xeloda®) proved equivalence to 5-FU and is a well tolerated alternative combination partner for Irinotecan (XELIRI) or Oxaliplatin (XELOX) which are widely used for first line treatment of mCRC. Recent advances in molecular biology have resulted in the development of an inhibitor of the vascular endothelial growth factor (VEGF) by the monoclonal humanized antibody bevacizumab (Avastin®). XELOX or XELIRI +bevacizumab have been investigated in several trials, but not in an approach with clearly defined cross-wise XELIRI-XELOX change criteria. This trial investigates two different sequential treatment options with XELIRI/ XELOX in first and second line with the addition of bevacizumab and tries to give answer to the question if there is an optimal sequence for the benefit of the patient. This is a prospective, randomized, open-label, 2-arm pilot trial in patients with mCRC who did not receive systemic treatment for their metastatic disease. The study is designed to evaluate the efficacy of XELIRI followed by XELOX and XELOX followed by XELIRI + bevacizumab in terms of Duration of Disease Control (DDC). Patients will be treated with an established first line therapy consisting of either XELOX or XELIRI + bevacizumab. The chemotherapy treatment will be given for 6 months except prior disease progression, unacceptable toxicity or patient refusal. Bevacizumab will be given until disease progression, unacceptable toxicity or patient refusal. Capecitabine can be given in addition at the investigators' discretion until disease progression, unacceptable toxicity or patient refusal. If serious side effects occur despite adequate dose reduction, Oxaliplatin or Irinotecan should be discontinued. In case of Oxaliplatin or Irinotecan-related discontinuation Capecitabine and Bevacizumab should be continued. If Capecitabine also has to be discontinued in first line treatment bevacizumab should be continued. In case of permanent discontinuation of bevacizumab for toxicities, chemotherapy should be continued. Upon completion of first line chemotherapy patients with disease control will receive bevacizumab maintenance treatment. On investigators decision patients can receive Capecitabine as additional maintenance treatment. The primary endpoint is to determine the efficacy of a modified XELIRI + bevacizumab followed by XELOX + bevacizumab scheme at progression in comparison with the reverse sequence based on DDC. Secondary endpoints are first line progression-free survival (PFS), second line PFS, overall response rate, time to response, duration of response, overall survival, tumor assessments (based on RECIST criteria) using CT scans, MRI scans, X-ray, bone scan, clinical examination.

Conditions

Metastatic Colorectal Cancer

Keywords

metastatic colorectal cancer; Patients with metastatic colorectal cancer who did not receive; systemic treatment for their metastatic disease

Outcome Measures

Primary Outcomes (1)

• Efficacy Duration of Disease Control by Tumor Assessment (CT/MRI/Clinical Examination)

  The primary variable was duration of disease control (DDC) and was defined as the sum of progression free survival intervals during first line and second line treatment (= time from the beginning of first line treatment until onset of progression during second line treatment). Patients without progression at the last tumor assessment date during their study participation were censored at this last tumor assessment date (exception: availability of validated information about a later onset of progression or a longer progression free interval - in such a case the date of the follow-up assessment was either defined as the onset of progression or replaced the last tumor assessment date).

  screening, every 8 to 9 weeks until progression, at end of treatment (other than progression), every 3 months until progression, death or up to 24 months (whatever comes first)

Secondary Outcomes (8)

• First Line Progression Free Survival (PFS)

  at progression of disease (PD) in first line therapy or at 28 days safety follow-up in cases without PD

• Second Line PFS

  at progression of disease (PD) in second line therapy or at 28 days safety follow-up in cases without PD

• Overall Response Rate (Number of Participants With Response)

  at the day of documented complete or partial response or at 28 days safety follow-up in cases without PD

• Time to Response

  at the day of documented complete or partial response or at 28 days safety follow-up in cases without PD

• Duration of Response

  at the day of documented complete or partial response or at 28 days safety follow-up in cases without PD

Study Arms (2)

A: XELIRI + BEV Followed by XELOX + BEV

ACTIVE COMPARATOR

capecitabine and irinotecan (XELIRI) plus bevacizumab (AVASTIN; BEV) Capecitabine : 800mg/m2 bid d1-14, bevacizumab 7,5 mg/kg given on day 1 q3w combined with irinotecan 200mg/m2 iv. d 1 q3w . Bevacizumab (7.5 mg/kg q3w) ± Capecitabine (1000 mg/m2 bid, days 1-14 q3w) maintenance At disease progression irinotecan will be replaced by oxaliplatin (arm A). Bevacizumab will be continued.

Drug: Capecitabine; Drug: Bevacizumab; Drug: Irinotecan

B: XELOX + BEV followed by XELIRI + BEV

ACTIVE COMPARATOR

capecitabine and oxaliplatin (XELOX) plus bevacizumab (Avastin; BEV) Arm B: Capecitabine: 1000mg/m2 bid d1-14, bevacizumab 7,5 mg/kg given on d1 q3w combined with oxaliplatin 130mg/m2 iv. d 1 q3w Bevacizumab (7.5 mg/kg q3w) ± Capecitabine (1000 mg/m2 bid, days 1-14 q3w) maintenance At disease progression oxaliplatin will be replaced by irinotecan (arm B). Bevacizumab will be continued.

Drug: Capecitabine; Drug: Bevacizumab; Drug: Oxaliplatin

Interventions

Capecitabine DRUG

800mg/m2 bid d1-14 ± 1000 mg/m2 bid,days 1-14 q3w: maintenance

Also known as: Brand Name: Xeloda

A: XELIRI + BEV Followed by XELOX + BEV

Bevacizumab DRUG

7,5 mg/kg given on d1 q3w

Also known as: Brand name: Avastin

A: XELIRI + BEV Followed by XELOX + BEV; B: XELOX + BEV followed by XELIRI + BEV

Oxaliplatin DRUG

130mg/m2 iv. d 1 q3w

B: XELOX + BEV followed by XELIRI + BEV

Irinotecan DRUG

200mg/m2 iv. d 1 q3w .

A: XELIRI + BEV Followed by XELOX + BEV

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Written informed consent
• Age \>=18 years
• Patient must be able to comply with the protocol
• Histologically or cytologically confirmed carcinoma of the colon and/or rectum with evidence of metastases. 5 )Diagnosis of metastatic disease according to Response Evaluation Criteria in Solid Tumours (RECIST) not more than 3 months prior to enrolment.

You may not qualify if:

• Prior chemotherapeutic treatment for metastatic CRC
• Symptomatic central nervous system (CNS) metastases
• Significant vascular disease (e.g. aortic aneurysm potentially requiring surgical intervention, pulmonary embolism or recent peripheral arterial thrombosis) within 6 months prior start of study treatment.
• History of haemoptysis (= a half teaspoon of bright red blood per episode) within 1 month prior start of study treatment
• Past or current history (within the last 2 years prior to treatment start) of other malignancies (Patients with curatively treated basal and squamous cell carcinoma of the skin or in situ carcinoma of the cervix are eligible).
• Clinically significant cardiovascular disease, for example central venous access (CVA) (\<=6 months before treatment start), myocardial infarction (\<=6 months before treatment start), unstable angina, New York Heart Association (NYHA) \>= grade 2, congestive heart failure (CHF), arrhythmia requiring medication, or uncontrolled hypertension.
• Prior history of hypertensive crisis or hypertensive encephalopathy
• Treatment with any other investigational agent or any other biological agent (e.g.cetuximab), or participation in another clinical trial within 30 days prior to entering this study.
• Known hypersensitivity to any of the study drugs
• Current or recent (within 10 days of first dose of study treatment) chronic use of aspirin (\> 325 mg/day)
• Current or recent (within 10 days prior to study treatment start) use of full-dose oral or parenteral anticoagulants or thrombolytic agent for therapeutic (as opposed to prophylactic) purposes.
• Evidence of bleeding diathesis or coagulopathy.
• Serious, non healing wound, ulcer, or bone fracture.
• Major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to treatment, or anticipation of the need for major surgery during the course of the study. If central venous access device (CVAD) is required for chemotherapy administration, it should be inserted within 2 days prior to study treatment cycle.
• Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior start of study therapy

Sponsors & Collaborators

• Prof. Dr. Werner Scheithauer: lead

Study Sites (1)

Medical University of Vienna

Vienna, 1090, Austria

Location

Related Publications (18)

• Arnold D, Petersen , Kindler M, et al. Patterns of maintenance treatment (Tx) following firstline bevacizumab (bev) plus chemotherapy (CT) for metastatic colorectal cancer (mCRC): Results from a large German community-based cohort study. J Clin Oncol 29: 2011 (suppl 4; abstr 502)

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• A. C. Reinacher-Schick, S. Kubicka, W. Freier, et al. Activity of the combination of bevacizumab (Bev) with capecitabine/irinotecan (CapIri/Bev) or capecitabine/oxaliplatin (CapOx/Bev) in advanced colorectal cancer (ACRC): A randomized phase II study of the AIO Colorectal Study Group (AIO trial 0604). J Clin Oncol 26: 2008 (May 20 suppl; abstr 4030)

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Related Links

• ethical review committee
• Regulatory authority Austria
• Medical University Vienna/Clin. Division of Oncology

MeSH Terms

Conditions

Colorectal Neoplasms

Interventions

Capecitabine; Bevacizumab; Oxaliplatin; Irinotecan

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Fluorouracil; Uracil; Pyrimidinones; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Coordination Complexes; Organic Chemicals; Camptothecin; Alkaloids

Results Point of Contact

• Title: Werner Scheithauer, MD
• Organization: Medical University Vienna, Internal Med. I, Dep. of Oncology

werner.scheithauer@meduniwien.ac.at

+43 1 40400

Study Officials

• Werner Scheithauer, Prof. Dr.

  Medical University of Vienna

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Prof. Dr.

Study Record Dates

• First Submitted: April 1, 2014
• First Posted: April 21, 2014
• Study Start: February 1, 2011
• Primary Completion: August 31, 2017
• Study Completion: August 31, 2017
• Last Updated: September 25, 2019
• Results First Posted: September 25, 2019

Record last verified: 2019-09

Locations

AU (1)