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

Metastatic Colorectal Cancer Clinical Trial

— PASSION  

Official title:

A Phase II Study to Assess Efficacy and Safety of Capecitabine and Irinotecan Plus Bevacizumab Followed by Capecitabine and Oxaliplatin Plus Bevacizumab or the Reverse Sequence in Patients With Metastatic Colorectal Cancer

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02119026
• Other study ID #: ML25153_PASSION
• Status: Completed
• Phase: Phase 2
• Start date: February 2011
• Est. completion date: August 31, 2017

Study information

• Verified date: September 2019
• Source: Medical University of Vienna
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 120
• Est. completion date: August 31, 2017
• Est. primary completion date: August 31, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Written informed consent

2. Age >=18 years

3. Patient must be able to comply with the protocol

4. 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.

6) Life Expectancy of at least 3 months 7) At least one measurable metastatic lesion (as per RECIST criteria) 8) Prior adjuvant or neo-adjuvant chemotherapy/radiotherapy allowed if completed more than 6 months before inclusion. 9) Eastern Collaborative Oncology Group (ECOG) performance score of 0 or 1 10) Adequate haematological function: absolute neutrophil count (ANC) >= 1.5 x 109/L; platelets >= 100 x 109/L, Hb >= 9 g/dL 11) international normalized ratio (INR) <=1.5 and activated partial thromboplastin time (aPTT) <=1.5 x ULN within 7 days prior to starting study treatment 12) Adequate liver function: Serum bilirubin <=1.5 x ULN; alkaline phosphatase and transaminases <=2.5 x ULN (in case of liver metastases < 5 x ULN) 13) Serum Creatinine <=1.5 x ULN 14) Urine dipstick for proteinuria < 2+. If urine dipstick is >= 2+, 24- hour urine must demonstrate <=1 g of protein in 24 hours 15) Negative serum pregnancy test within 7 days of starting study treatment in pre- menopausal women and women < 2 years after the onset of menopause. This test has to be reconfirmed by a urine test, should the 7 days window be exceeded. Fertile women (<2 years after last menstruation) and men must use effective means of contraception (oral contraceptives, intrauterine contraceptive device, barrier method of contraception in conjunction with spermicidal jelly or surgically sterile).

Exclusion Criteria:

1. Prior chemotherapeutic treatment for metastatic CRC

2. Symptomatic central nervous system (CNS) metastases

3. 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.

4. History of haemoptysis (= a half teaspoon of bright red blood per episode) within 1 month prior start of study treatment

5. 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).

6. 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.

7. Prior history of hypertensive crisis or hypertensive encephalopathy

8. 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.

9. Known hypersensitivity to any of the study drugs

10. Current or recent (within 10 days of first dose of study treatment) chronic use of aspirin (> 325 mg/day)

11. 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.

12. Evidence of bleeding diathesis or coagulopathy.

13. Serious, non healing wound, ulcer, or bone fracture.

14. 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.

15. Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior start of study therapy

16. History of abdominal fistula, trachea-oesophageal fistula or any grade 4 non gastrointestinal fistula, gastrointestinal perforation or intra-abdominal abscess before 1st line therapy.

17. History or evidence upon physical/neurological examination of CNS disease (unrelated to cancer) (unless adequately treated with standard medical therapy) e.g. uncontrolled seizures

18. 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

19. Patients with contraindication for cross over chemotherapy (e.g. patients treated with irinotecan based first line therapy and serious polyneuropathy > grade 1, not feasible for oxaliplatin based cross over second line therapy, or patients treated with oxaliplatin based first line therapy and hereditary fructose intolerance not feasible for Irinotecan based cross over second line therapy)

20. Pregnancy or lactation

21. Fertile women (<2 years after last menstruation) and men not willing to use effective means of contraception.

Related Conditions & MeSH terms

• Colorectal Neoplasms
• Metastatic Colorectal Cancer

Intervention

Drug:
• Capecitabine
800mg/m2 bid d1-14 ± 1000 mg/m2 bid,days 1-14 q3w: maintenance
• Capecitabine
1000mg/m2 bid d1-14,
• Bevacizumab
7,5 mg/kg given on d1 q3w
• Oxaliplatin
130mg/m2 iv. d 1 q3w
• Irinotecan
200mg/m2 iv. d 1 q3w .

Locations

Country	Name	City	State
Austria	Medical University of Vienna	Vienna

Sponsors (1)

Lead Sponsor	Collaborator
Prof. Dr. Werner Scheithauer

Country where clinical trial is conducted

Austria, 

References & Publications (18)

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)

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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Gerber HP, Ferrara N. Pharmacology and pharmacodynamics of bevacizumab as monotherapy or in combination with cytotoxic therapy in preclinical studies. Cancer Res. 2005 Feb 1;65(3):671-80. — View Citation

Grothey A, Sargent D, Goldberg RM, Schmoll HJ. Survival of patients with advanced colorectal cancer improves with the availability of fluorouracil-leucovorin, irinotecan, and oxaliplatin in the course of treatment. J Clin Oncol. 2004 Apr 1;22(7):1209-14. — View Citation

Hedrick E, Kozloff M, Hainsworth J, et al. Safety of bevacizumab plus chemotherapy as firstline treatment of patients with metastatic colorectal cancer: Updated results from a large observational registry in the US (BRiTE). J Clin Oncol 2006;24:Abstract 3536.

Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, Kabbinavar F. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004 Jun 3;350(23):2335-42. — View Citation

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Mabro M, Artru P, André T, Flesch M, Maindrault-Goebel F, Landi B, Lledo G, Plantade A, Louvet C, de Gramont A. A phase II study of FOLFIRI-3 (double infusion of irinotecan combined with LV5FU) after FOLFOX in advanced colorectal cancer patients. Br J Cancer. 2006 May 8;94(9):1287-92. — View Citation

Miriam Koopman, Ninja F Antonini, Joep Douma et al. Sequential versus combination chemotherapy with capecitabine, irinotecan, and oxaliplatin in advanced colorectal cancer (CAIRO): a phase III randomised controlled trial. Lancet 2007; 370: 135-42 Kozloff M, Hainsworth J, Badarinath S, et al. Efficacy of bevacizumab plus chemotherapy as firstline treatment of patients with metastatic colorectal cancer: Updated results from a large observational registry in the US (BRiTE). J Clin Oncol 2006;24:Abstract 3537.

Saltz LB, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Lichinitser M, Yang TS, Rivera F, Couture F, Sirzén F, Cassidy J. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol. 2008 Apr 20;26(12):2013-9. doi: 10.1200/JCO.2007.14.9930. Erratum in: J Clin Oncol. 2008 Jun;26(18):3110. J Clin Oncol. 2009 Feb 1;27(4):653. — View Citation

Simmonds PC. Palliative chemotherapy for advanced colorectal cancer: systematic review and meta-analysis. Colorectal Cancer Collaborative Group. BMJ. 2000 Sep 2;321(7260):531-5. — View Citation

Souglakos J, Androulakis N, Syrigos K, Polyzos A, Ziras N, Athanasiadis A, Kakolyris S, Tsousis S, Kouroussis Ch, Vamvakas L, Kalykaki A, Samonis G, Mavroudis D, Georgoulias V. FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin and irinotecan) vs FOLFIRI (folinic acid, 5-fluorouracil and irinotecan) as first-line treatment in metastatic colorectal cancer (MCC): a multicentre randomised phase III trial from the Hellenic Oncology Research Group (HORG). Br J Cancer. 2006 Mar 27;94(6):798-805. — View Citation

Tabernero J, Aranda E, Gomez A, et al. Phase III study of first-line XELOX plus bevacizumab (BEV) for 6 cycles followed by XELOX plus BEV or single-agent (s/a) BEV as maintenance therapy in patients (pts) with metastatic colorectal cancer (mCRC): The MACRO Trial (Spanish Cooperative Group for the Treatment of Digestive Tumors [TTD]). Clin Oncol 28:7s, 2010 (suppl; abstr 3501), Abstract No: 3501

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Tournigand C, André T, Achille E, Lledo G, Flesh M, Mery-Mignard D, Quinaux E, Couteau C, Buyse M, Ganem G, Landi B, Colin P, Louvet C, de Gramont A. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol. 2004 Jan 15;22(2):229-37. Epub 2003 Dec 2. — View Citation

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Yalcin S, Uslu R, Dane F, et al. A Randomized, multicenter phase III trial of bevacizumab plus capecitabine were given as maintenance treatment after initial treatment with bevacizumab plus XELOX in previously untreated metastatic colorectal cancer. J Clin Oncol 29: 2011 (suppl 4; abstr 474)

* Note: There are 18 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	First Line Progression Free Survival (PFS)	The first line PFS was defined as the progression free survival interval during first 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). Missing onset of progression data because of refusal or because of death was replaced. If several response evaluations for a patient showed progressive disease (PD), the time to PD was assessed by using the first of these measurements.	at progression of disease (PD) in first line therapy or at 28 days safety follow-up in cases without PD
Secondary	Second Line PFS	The second line PFS was defined as the progression free survival interval 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). Missing onset of progression data because of refusal or because of death was replaced.; If several response evaluations for a patient showed progressive disease (PD), the time to PD was assessed by using the first of these measurements.	at progression of disease (PD) in second line therapy or at 28 days safety follow-up in cases without PD
Secondary	Overall Response Rate (Number of Participants With Response)	The rate of overall response was measured as the response rate from randomization until the day of documented complete response (CR) or partial response (PR) (whichever status is recorded first).	at the day of documented complete or partial response or at 28 days safety follow-up in cases without PD
Secondary	Time to Response	Time to overall response was measured from the time of randomization until the day of documented complete response (CR) or partial response (PR) (whichever status is recorded first). Patients without response were censored at the date of the last tumor assessment, the date of death or the date of refusal.	at the day of documented complete or partial response or at 28 days safety follow-up in cases without PD
Secondary	Duration of Response	Duration of overall response was measured from the time that measurement criteria are met for complete response (CR) or partial response (PR) (whichever status was recorded first) until the onset of progression. 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).; Missing onset of progression data because of refusal or because of death was replaced.; If several response evaluations for a patient showed progressive disease (PD), the time to PD was assessed by using the first of these measurements.	at the day of documented complete or partial response or at 28 days safety follow-up in cases without PD
Secondary	Overall Survival of XELIRI Plus Bevacizumab and XELOX Plus Bevacizumab	Overall survival was measured as the time from the randomization date to the date of death. Patients without death date were censored at the date of the last tumor assessment (exception: availability of validated information about a later exitus date or a prolonged survival - in such a case the date of the follow-up assessment was either defined as the exitus date or replaced the last tumor assessment date) or the date of refusal.	date of death or date of last tumor assessment (28d safety f-u) in patients without death
Secondary	Tumour Assessments (Based on RECIST Criteria) in 1st-line	Best response in first line was based on the tumor assessments (based on RECIST criteria) for target lesions and assessed by CT scans, MRI scans, X-ray, bone scan and clinical examination: Complete Response (CR), disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter (sum LD) of target lesions; Progressive Disease (PD), >= 20% increase in the sum of the LD of target lesions; Stable Disease (SD), neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started.	Baseline, every 8-9 weeks, 28d Safety follow-up
Secondary	Tumour Assessments (Based on RECIST Criteria) in 2nd-line	Best response in second line was based on the tumor assessments (based on RECIST criteria) for target lesions and assessed by CT scans, MRI scans, X-ray, bone scan and clinical examination: Complete Response (CR), disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter (sum LD) of target lesions; Progressive Disease (PD), >= 20% increase in the sum of the LD of target lesions; Stable Disease (SD), neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started.	Baseline, every 8-9 weeks, 28d Safety follow-up

External Links

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