Clinical trial NCT01433614: Epirubicin and Paclitaxel, Alone or Together With Capecitabine as First Line Treatment in Metastatic Breast Cancer
Official title: Treatment With the Combination of Epirubicin and Paclitaxel Alone or Together With Capecitabine as First Line Treatment in Metastatic Breast Cancer. A Multicenter, Randomized Phase III Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Metastatic Breast Cancer
Lead sponsor: Karolinska University Hospital
Sponsor class: OTHER
First posted: 2011-09-14
Enrollment: 304
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Anthracycline-taxane regimens are effective means of postponing progression in metastatic breast cancer. It is yet unclear whether addition of capecitabine to this combination improves the treatment outcome.

Patients with advanced breast cancer are randomized to first-line chemotherapy with a combination of epirubicin (Farmorubicin®) and paclitaxel (Taxol®) alone (ET) or in combination with capecitabine (Xeloda®, TEX). Starting doses for ET are epirubicin 75 mg/m2 plus paclitaxel 175 mg/m2, and for TEX epirubicin 75mg/m2, paclitaxel 155 mg/m2, and capecitabine 825 mg/m2 BID for 14 days. Subsequently, doses are tailored related to side effects.

Primary endpoint is progression-free survival (PFS); secondary endpoints are overall survival (OS), time to treatment failure (TTF), objective response (OR), safety and quality of life (QoL).


Eligibility criteria: Inclusion Criteria:

* Morphologically proven breast carcinoma
* Written patient consent must be obtained
* Measurable disease (i.e. at least one lesion that can be accurately measured in at least one dimension as ≥20 mm by conventional techniques, or as ≥10 mm by spiral CT scan) as defined in section 8.
* Lytic and blastic bone metastases as only site of recurrence are allowed
* Age 18 years or older
* ECOG performance status 0-2
* Life expectancy of at least three months
* Adequate cardiac functions
* Adequate hematological, renal and hepatic functions
* Patient must be accessible for treatment and follow-up.

Exclusion Criteria:

* Treatment-free interval less than one year, if previous adjuvant, neoadjuvant or after radically treated locoregional recurrence given regimen contained anthracycline, taxane or capecitabine. This limitation does not apply for regimens containing other than the drugs mentioned
* During adjuvant treatment obtained cumulative doses exceeding 375 mg/m2 for doxorubicin, or 550 mg/m2 for epirubicin, abnormal ECG or reduced cardiac function measured by left ventricular ejection fraction (LVEF).
* Indication for the use of trastuzumab (Herceptin) as first-line treatment in patients with tumor overexpressing c-erbB2.
* Any previous chemotherapy for metastatic disease, except for radically treated locoregional relapse
* Neoplasm other than breast carcinoma, except for non-melanoma skin cancer or curatively treated carcinoma in situ of the cervix, diagnosed during the past five years
* Pregnancy or lactation
* Known brain metastases
* History of atrial or ventricular arrhythmias and/or congestive heart failure, even if medically controlled. History of clinical and electrocardiographically documented myocardial infarction
* Preexisting motor or sensory neuropathy ≥ grade 2 according to NCI CTC 2.0 criteria (severe paresthesia and/or mild weakness, or worse)
* Severe hepatic or renal impairment (for capecitabine: calculated creatinine clearance below 30 ml/min; for calculation, see p. 5.1.4) not allowing for adequate use of the proposed regimens
* History of known dihydropyrimidine dehydrogenase (DPD) deficiency (severe reaction on previous treatment with fluorouracil, e.g experience of mucositis, hand-foot syndrome, or diarrhea)
* Active infection or other serious underlying medical condition which would impair the ability of the patient to receive protocol treatment, including prior allergic reactions to drugs containing cremophor, such as teniposide, cyclosporin or vitamin K
* Dementia or significantly altered mental status that would prohibit the understanding and giving of informed consent.

Primary outcomes:
measure: Time to progression
timeFrame: From date of randomisation until date of first radiolocically documented progression or death from any cause, whichever comes first up to 78 months
Secondary outcomes:
measure: Time to treatment failure
timeFrame: From date of randomization until date of treatment disruption for any reason up to 78 months
measure: Response rate
timeFrame: Every 9 weeks during treatment
measure: Overall survival
timeFrame: Time from randomisation until date of death up to 78 months
measure: Number of participants with adverse events
timeFrame: Continuously during treatment and until 2 months after termination
measure: Quality of life
timeFrame: Baseline, 2, 4, 6 and 9 months
measure: Tumor biological data related to treatment
timeFrame: Within two weeks before start of treatment
Other outcomes:
Locations:
city: Göteborg
country: Sweden
facility: Sahlgrenska University Hospital
city: Helsingborg
country: Sweden
facility: Helsingborg Gen. Hospital
city: Kalmar
country: Sweden
facility: Kalmar Central Hospital
city: Karlstad
country: Sweden
facility: Karlstad Gen. Hospital
city: Linköping
country: Sweden
facility: Linköping University Hospital
city: Lund
country: Sweden
facility: Lund University Hospital
city: Malmö
country: Sweden
facility: Malmö General University Hospital
city: Sundsvall
country: Sweden
facility: Sundsvall Gen. Hospital
city: Umeå
country: Sweden
facility: Norrland University Hospital
Study officials:
affiliation: Karolinska University Hospital
name: Thomas Hatschek, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Svensson H, Brandberg Y, Einbeigi Z, Hatschek T, Ahlberg K. Psychological reactions to progression of metastatic breast cancer--an interview study. Cancer Nurs. 2009 Jan-Feb;32(1):55-63. doi: 10.1097/01.NCC.0000343374.09270.ff.
citation: Svensson H, Einbeigi Z, Johansson H, Hatschek T, Brandberg Y. Quality of life in women with metastatic breast cancer during 9 months after randomization in the TEX trial (epirubicin and paclitaxel w/o capecitabine). Breast Cancer Res Treat. 2010 Oct;123(3):785-93. doi: 10.1007/s10549-010-1084-8. Epub 2010 Aug 3.
citation: Svensson H, Hatschek T, Johansson H, Einbeigi Z, Brandberg Y. Health-related quality of life as prognostic factor for response, progression-free survival, and survival in women with metastatic breast cancer. Med Oncol. 2012 Jun;29(2):432-8. doi: 10.1007/s12032-011-9844-9. Epub 2011 Feb 6.
citation: Hatschek T, Carlsson L, Einbeigi Z, Lidbrink E, Linderholm B, Lindh B, Loman N, Malmberg M, Rotstein S, Soderberg M, Sundquist M, Walz TM, Hellstrom M, Svensson H, Astrom G, Brandberg Y, Carstensen J, Ferno M, Bergh J. Individually tailored treatment with epirubicin and paclitaxel with or without capecitabine as first-line chemotherapy in metastatic breast cancer: a randomized multicenter trial. Breast Cancer Res Treat. 2012 Feb;131(3):939-47. doi: 10.1007/s10549-011-1880-9. Epub 2011 Nov 18.
citation: Suzuki C, Blomqvist L, Hatschek T, Carlsson L, Einbeigi Z, Linderholm B, Lindh B, Loman N, Malmberg M, Rotstein S, Soderberg M, Sundqvist M, Walz TM, Astrom G, Fujii H, Jacobsson H, Glimelius B. Impact of the first tumor response at eight weeks on overall survival in metastatic breast cancer patients treated with first-line combination chemotherapy. Med Oncol. 2013 Mar;30(1):415. doi: 10.1007/s12032-012-0415-5. Epub 2013 Jan 16.
citation: Bjohle J, Bergqvist J, Gronowitz JS, Johansson H, Carlsson L, Einbeigi Z, Linderholm B, Loman N, Malmberg M, Soderberg M, Sundquist M, Walz TM, Ferno M, Bergh J, Hatschek T. Serum thymidine kinase activity compared with CA 15-3 in locally advanced and metastatic breast cancer within a randomized trial. Breast Cancer Res Treat. 2013 Jun;139(3):751-8. doi: 10.1007/s10549-013-2579-x. Epub 2013 Jun 5.
citation: Tobin NP, Harrell JC, Lovrot J, Egyhazi Brage S, Frostvik Stolt M, Carlsson L, Einbeigi Z, Linderholm B, Loman N, Malmberg M, Walz T, Ferno M, Perou CM, Bergh J, Hatschek T, Lindstrom LS; TEX Trialists Group. Molecular subtype and tumor characteristics of breast cancer metastases as assessed by gene expression significantly influence patient post-relapse survival. Ann Oncol. 2015 Jan;26(1):81-88. doi: 10.1093/annonc/mdu498. Epub 2014 Oct 31.
citation: Kimbung S, Kovacs A, Bendahl PO, Malmstrom P, Ferno M, Hatschek T, Hedenfalk I. Claudin-2 is an independent negative prognostic factor in breast cancer and specifically predicts early liver recurrences. Mol Oncol. 2014 Feb;8(1):119-28. doi: 10.1016/j.molonc.2013.10.002. Epub 2013 Oct 14.
citation: Kimbung S, Johansson I, Danielsson A, Veerla S, Egyhazi Brage S, Frostvik Stolt M, Skoog L, Carlsson L, Einbeigi Z, Lidbrink E, Linderholm B, Loman N, Malmstrom PO, Soderberg M, Walz TM, Ferno M, Hatschek T, Hedenfalk I; TEX study group. Transcriptional Profiling of Breast Cancer Metastases Identifies Liver Metastasis-Selective Genes Associated with Adverse Outcome in Luminal A Primary Breast Cancer. Clin Cancer Res. 2016 Jan 1;22(1):146-57. doi: 10.1158/1078-0432.CCR-15-0487. Epub 2015 Aug 14.
citation: Hoon SN, Lau PK, White AM, Bulsara MK, Banks PD, Redfern AD. Capecitabine for hormone receptor-positive versus hormone receptor-negative breast cancer. Cochrane Database Syst Rev. 2021 May 26;5(5):CD011220. doi: 10.1002/14651858.CD011220.pub2.