Clinical trial NCT00798070: Panther: A Study Comparing Biweekly and Tailored EC-T Versus Three Weekly FEC-T in Breast Cancer Patients
Official title: A Randomised Phase 3 Study Comparing Biweekly and Tailored Epirubicin + Cyclophosphamide Followed by Biweekly Tailored Docetaxel Versus Three Weekly Epirubicin + Cyclophosphamide + 5-fluorouracil Followed by Docetaxel in Lymph Node Positive or High Risk Lymph Node Negative Breast Cancer Patients
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Breast Cancer
Keywords: Lymph node positive or high risk lymph node negative breast
cancer
Lead sponsor: Karolinska University Hospital
Sponsor class: OTHER
Collaborators: name: Swedish Breast Cancer Group
name: Austrian Breast & Colorectal Cancer Study Group
name: GBG Forschungs GmbH
First posted: 2008-11-25
Enrollment: 2017
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is an adjuvant, open, prospective, randomized study to compare:

A. Individually tailored and two weekly dosed epirubicin + cyclophosphamide followed by a three weeks break followed by biweekly and tailored docetaxel (dtEC→dtT) given every second week, to

B. Fixed dosed and three weekly epirubicin, cyclophosphamide and 5-fluorouracil, followed by fixed dosed and three weekly docetaxel (FEC→T).

Patients with primary node-positive or high risk lymph node negative breast cancer will be eligible for the study.

The primary objective of the phase 3 study is to compare breast cancer relapse-free survival (BCRFS) between the dtEC→dtT and FE100C→T. To detect a five-year BCRFS difference of 0.710 to 0.790 about 1000 patients per arm will be needed. They will be recruited during four years and followed another two years for breast cancer events.

Secondary objectives are to compare

1. Distant disease-free survival (DDFS)
2. Event-free survival and
3. Overall survival
4. Health-related quality of life and toxicity analyses according to CTC
5. Outcome in relation to tumour biological factors and polymorphism patterns

   1. RFS in relation to the Sorlie classes using immunohistochemical markers and/or gene expression profiling comparing A vs B arm
   2. RFS with receptor positive disease (analyzed in the local laboratories as described in the CRFs and also analyzed as continuous variables) in the comparison between the A- and B- arms.
   3. RFS with high and low proliferation, respectively, (analyzed in the local laboratories as described in the CRFs and also analyzed as a continuous variable, or centrally analyzed), in the comparison between the A- and B-arms.
   4. RFS in relation to HER-2/neu status (analyzed in the local laboratories as described in the CRFs) in the primary cancers in the comparison between the A- and B-arms and analyzed whether trastuzumab was given in sequence or concurrently.
   5. RFS analyzed in relation to other molecular markers (e.g. gene expression profiling/ sequencing) in the primary cancers and SNPs signatures in normal DNA (related to toxicities for EC/FEC and docetaxel components, respectively, and given dose levels and outcome in relation to these factors and in relation QoL) to outcome per arm.
   6. RFS analyzed in relation to tumour associated lymphocytes and Y-box binding protein in the comparison between the A- and B-arms.

Tumour tissue will be obtained and stored for studies of prognostication and therapy prediction.

Last patient randomized was September 2011.

Detailed description: Are described under the heading "Outcome measures"

Eligibility criteria: Inclusion Criteria:

* Histological proven invasive primary breast cancer, with at least 5 (recommended 10) removed axillary lymph nodes OR negative sentinel node biopsy performed for the node negative cohort. Interval between definitive surgery that includes axillary lymph node dissection and registration must be less than 60 days. Paraffin block from the primary tumour must be retained (not mandatory for Austrian sites). Frozen tumour tissue is strongly recommended to be stored.
* Receptor negative or positive tumours with 1 or more positive axillary lymph nodes (more than 0.2 mm) OR axillary node negative breast cancers if the primary tumour is larger than 20 mm and receptor negative (Er and Pgr with no receptor content) and being Elston grade III. In Germany high risk node negative breast cancer patients are not eligible until labelling for docetaxel includes node-negative disease.
* A primary breast cancer patient being 35 years or younger considered suitable for adjuvant chemotherapy (may be receptor negative or positive, HER-2/neu negative or positive, with or without axillary lymph node metastases).
* Macroscopically and microscopically free margins after radical surgery (no cancer cells at borders of resection).
* No proven distant metastases (negative chest/pulmonary X-ray, bone scintigram (when clinical signs of skeletal metastases or elevated ALP) supplemented with normal conventional X-ray of hot spots, normal liver function test and haematological function tests; when abnormal values, CT or ultrasound of the liver, patient can be included if no metastases are demonstrated.
* Female age 18-65.
* Ambulant patients (ECOG 1 or less).
* No major cardiovascular morbidity NYHA I or II. (Appendix 3).
* Written informed consent according to the local ethics committee requirements.
* Patients of childbearing potential should have a negative pregnancy test within seven days of registration. (In Austria, pregnancy tests have to be repeated monthly during the treatment phase).

Exclusion Criteria:

* Previous neo-adjuvant treatment.
* Non-radical surgery (histopathological positive margins).
* Proven distant metastases.
* Pregnancy or lactation.
* Other serious medical condition.
* Previous or concurrent malignancies at other sites, except basal cell carcinoma and/or squamous cell carcinoma in situ of the skin or cervix. Patients with previous breast cancer (invasive and/or ductal carcinoma in situ) in the other breast without loco-regional (large lung volumes) radiotherapy, without objective findings for relapse, with \> 5 years since diagnosis can be included.
* Abnormal laboratory values precluding the possibility to safely deliver the used cytotoxic agents in the study.
* Hypersensitivity to drugs formulated in polysorbate 80.
* Peripheral neuropathy grade ≥2.

Primary outcomes:
measure: Breast cancer relapse-free survival
timeFrame: 2 years
Secondary outcomes:
measure: Distant disease-free survival
timeFrame: 2 years
measure: Event-free survival
timeFrame: 2 years
measure: Overall survival
timeFrame: 2 years
measure: Health-related quality of life and toxicity analyses according to CTC
timeFrame: 2 years
measure: Outcome in relation to tumour biological factors and polymorphism patterns
timeFrame: 2 years
measure: BCRFS in arm A in relation to given dose levels
timeFrame: 2 years
Other outcomes:
Locations:
city: Graz
country: Austria
facility: MUG - Med. Univ.-Klinik Graz
city: Innsbruck
country: Austria
facility: MUI - Univ. Klinik f. Frauenheilkunde, Innsbruck
city: Leoben
country: Austria
facility: LKH Leoben
city: Linz
country: Austria
facility: AKH Linz
city: Linz
country: Austria
facility: KH BHS Linz
city: Rankweil
country: Austria
facility: LKH Rankweil
city: Salzburg
country: Austria
facility: LKH Salzburg / PMU
city: St. Veit/Glan
country: Austria
facility: KH BHB St. Veit/Glan
city: Wels
country: Austria
facility: Klinikum Wels - Grieskirchen GmbH
city: Wien
country: Austria
facility: Brustzentrum Hanusch-KH
city: Aachen
country: Germany
facility: Marienhospital
city: Bamberg
country: Germany
facility: Klinikum am Bruderwald
city: Bayreuth
country: Germany
facility: Klinikum Bayreuth
city: Berlin
country: Germany
facility: HELIOS Klinikum
city: Bietigheim
country: Germany
facility: Klinikum Bietigheim
city: Boblingen
country: Germany
facility: Klinikum Sindelfingen-Böblingen
city: Bonn
country: Germany
facility: Johanniter Krankenhaus
city: Bonn
country: Germany
facility: Universitätsfrauenklinik
city: Celle
country: Germany
facility: Krankenhaus Celle
city: Deggendorf
country: Germany
facility: Klinikum Deggendorf
city: Dresden
country: Germany
facility: Diakonissen Krankenhaus
city: Dresden
country: Germany
facility: Gemeinschaftspraxis
city: Dresden
country: Germany
facility: Krankenhaus St. Joseph-Stift
city: Erkelenz
country: Germany
facility: Praxis Dr. Adhami
city: Frankfurt am Main
country: Germany
facility: Klinikum der J. W. Goethe Universität
city: Frankfurt am Main
country: Germany
facility: Klinikum Frankfurt Höchst GmbH
city: Frankfurt am Main
country: Germany
facility: Onkologische Gemeinschaftspraxis
city: Freudenstadt
country: Germany
facility: Kreiskrankenhaus
city: Fulda
country: Germany
facility: Klinikum Fulda
city: Goslar
country: Germany
facility: Onkologische Schwerpunktpraxis
city: Halle
country: Germany
facility: Krankenhaus St. Elisabeth und St. Barbara
city: Halle
country: Germany
facility: Universitätsfrauenklinik
city: Hameln
country: Germany
facility: Klinikum Hameln
city: Hannover
country: Germany
facility: Henriettenstiftung
city: Hannover
country: Germany
facility: Medizinische Hochschule
city: Heidelberg
country: Germany
facility: Universität Heidelberg
city: Heilbronn
country: Germany
facility: Klinikum Heilbronn
city: Hildesheim
country: Germany
facility: Gemienschaftspraxis
city: Homburg
country: Germany
facility: Universitätsfrauenklinik
city: Karlsruhe
country: Germany
facility: St. Vincentius Kliniken
city: Karlsruhe
country: Germany
facility: Städtisches Klinikum
city: Kassel
country: Germany
facility: Elisabeth Krankenhaus
city: Kempten
country: Germany
facility: Klinikum Kempten
city: Köln
country: Germany
facility: St. Elisabeth-KKH
city: Limburg
country: Germany
facility: St. Vincenz Krankenhaus
city: Lohsa
country: Germany
facility: Onkologische Tagesklinik
city: Ludwigsburg
country: Germany
facility: Klinikum Ludwigsburg
city: Ludwigsfelde
country: Germany
facility: Ev. Krankenhaus
city: Mainz
country: Germany
facility: St. Vincenz und Elisabeth-Hospital
city: Mainz
country: Germany
facility: Universitätsfrauenklinik
city: Mannheim
country: Germany
facility: Universitätsfrauenklinik
city: Marktredwitz
country: Germany
facility: Klinikum Fichtelgebirge
city: Memmingen
country: Germany
facility: Onkologische Praxis
city: Münster
country: Germany
facility: Gemeinschaftspraxis Münster
city: Neumarkt
country: Germany
facility: Praxis am Klinikum Neumarkt
city: Pinneberg
country: Germany
facility: Onkologische Praxis
city: Reutlingen
country: Germany
facility: Klinikum am Steinenberg
city: Rheinfelden
country: Germany
facility: Klinikum Rheinfelden
city: Schwerin
country: Germany
facility: Klinikum Schwerin
city: Troisdorf
country: Germany
facility: Gesellschaft für onkologische Studien
city: Tuttlingen
country: Germany
facility: Klinikum Tuttlingen
city: Tübingen
country: Germany
facility: Universitätsfrauenklinik
city: Ulm
country: Germany
facility: Universitätsfrauenklinik
city: Villingen
country: Germany
facility: Klinikum Villingen-Schwenningen
city: Weiden
country: Germany
facility: Klinikum Weiden
city: Weinheim
country: Germany
facility: Klinikum Weinheim
city: Wiesbaden
country: Germany
facility: Asklepios Paulinen Klinik
city: Wiesbaden
country: Germany
facility: St. Josefs-Hospital
city: Worms
country: Germany
facility: Stadtkrankenhaus
city: Gävle
country: Sweden
facility: Central Hospital
city: Göteborg
country: Sweden
facility: Sahlgrenska University Hospital
city: Karlstad
country: Sweden
facility: Central 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: Stockholm
country: Sweden
facility: Karolinska University Hospital, Dept of Oncology
city: Sundsvall
country: Sweden
facility: Central Hospital
city: Umeå
country: Sweden
facility: Norrlands University Hospital
city: Uppsala
country: Sweden
facility: Uppsala Academic Hospital
city: Örebro
country: Sweden
facility: Örebro University Hospital
Study officials:
affiliation: Karolinska University Hospital
name: Jonas Bergh, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Increasing the dose intensity of chemotherapy by more frequent administration or sequential scheduling: a patient-level meta-analysis of 37 298 women with early breast cancer in 26 randomised trials. Lancet. 2019 Apr 6;393(10179):1440-1452. doi: 10.1016/S0140-6736(18)33137-4. Epub 2019 Feb 8.
citation: Matikas A, Papakonstantinou A, Loibl S, Steger GG, Untch M, Johansson H, Tsiknakis N, Hellstrom M, Greil R, Mobus V, Gnant M, Bergh J, Foukakis T. Benefit from dose-dense adjuvant chemotherapy for breast cancer: subgroup analyses from the randomised phase 3 PANTHER trial. Lancet Reg Health Eur. 2024 Dec 3;49:101162. doi: 10.1016/j.lanepe.2024.101162. eCollection 2025 Feb.
citation: Matikas A, Mobus V, Greil R, Andersson A, Steger GG, Untch M, Fornander T, Malmstrom P, Schmatloch S, Johansson H, Hellstrom M, Brandberg Y, Gnant M, Loibl S, Foukakis T, Bergh J; SweBCG, ABCSG and GBG. Tailored Dose-Dense Versus Standard Adjuvant Chemotherapy for High-Risk Early Breast Cancer: End-of-Study Results of the Randomized PANTHER Trial. J Clin Oncol. 2024 Sep 10;42(26):3077-3082. doi: 10.1200/JCO.24.00178. Epub 2024 Jul 17.
citation: Zerdes I, Simonetti M, Matikas A, Harbers L, Acs B, Boyaci C, Zhang N, Salgkamis D, Agartz S, Moreno-Ruiz P, Bai Y, Rimm DL, Hartman J, Mezheyeuski A, Bergh J, Crosetto N, Foukakis T. Interplay between copy number alterations and immune profiles in the early breast cancer Scandinavian Breast Group 2004-1 randomized phase II trial: results from a feasibility study. NPJ Breast Cancer. 2021 Nov 19;7(1):144. doi: 10.1038/s41523-021-00352-3.
citation: Brandberg Y, Johansson H, Hellstrom M, Gnant M, Mobus V, Greil R, Foukakis T, Bergh J; Swedish Breast Cancer Group, the Austrian Breast, Colorectal Cancer Study Group, the German Breast Cancer Group. Long-term (up to 16 months) health-related quality of life after adjuvant tailored dose-dense chemotherapy vs. standard three-weekly chemotherapy in women with high-risk early breast cancer. Breast Cancer Res Treat. 2020 May;181(1):87-96. doi: 10.1007/s10549-020-05602-9. Epub 2020 Mar 31.
citation: Papakonstantinou A, Matikas A, Bengtsson NO, Malmstrom P, Hedayati E, Steger G, Untch M, Hubbert L, Johansson H, Hellstrom M, Gnant M, Loibl S, Greil R, Moebus V, Foukakis T, Bergh J. Efficacy and safety of tailored and dose-dense adjuvant chemotherapy and trastuzumab for resected HER2-positive breast cancer: Results from the phase 3 PANTHER trial. Cancer. 2020 Mar 15;126(6):1175-1182. doi: 10.1002/cncr.32653. Epub 2019 Dec 18.
citation: Papakonstantinou A, Hedayati E, Hellstrom M, Johansson H, Gnant M, Steger G, Greil R, Untch M, Moebus V, Loibl S, Foukakis T, Bergh J, Matikas A. Neutropenic complications in the PANTHER phase III study of adjuvant tailored dose-dense chemotherapy in early breast cancer. Acta Oncol. 2020 Jan;59(1):75-81. doi: 10.1080/0284186X.2019.1670353. Epub 2019 Oct 4.
citation: Matikas A, Foukakis T, Moebus V, Greil R, Bengtsson NO, Steger GG, Untch M, Johansson H, Hellstrom M, Malmstrom P, Gnant M, Loibl S, Bergh J. Dose tailoring of adjuvant chemotherapy for breast cancer based on hematologic toxicities: further results from the prospective PANTHER study with focus on obese patients. Ann Oncol. 2019 Jan 1;30(1):109-114. doi: 10.1093/annonc/mdy475.
citation: Matikas A, Margolin S, Hellstrom M, Johansson H, Bengtsson NO, Karlsson L, Edlund P, Karlsson P, Lidbrink E, Linderholm B, Lindman H, Malmstrom P, Villman K, Foukakis T, Bergh J. Long-term safety and survival outcomes from the Scandinavian Breast Group 2004-1 randomized phase II trial of tailored dose-dense adjuvant chemotherapy for early breast cancer. Breast Cancer Res Treat. 2018 Apr;168(2):349-355. doi: 10.1007/s10549-017-4599-4. Epub 2017 Nov 30.
citation: Foukakis T, von Minckwitz G, Bengtsson NO, Brandberg Y, Wallberg B, Fornander T, Mlineritsch B, Schmatloch S, Singer CF, Steger G, Egle D, Karlsson E, Carlsson L, Loibl S, Untch M, Hellstrom M, Johansson H, Anderson H, Malmstrom P, Gnant M, Greil R, Mobus V, Bergh J; Swedish Breast Cancer Group (SweBCG), the German Breast Group (GBG), and the Austrian Breast & Colorectal Cancer Study Group (ABCSG). Effect of Tailored Dose-Dense Chemotherapy vs Standard 3-Weekly Adjuvant Chemotherapy on Recurrence-Free Survival Among Women With High-Risk Early Breast Cancer: A Randomized Clinical Trial. JAMA. 2016 Nov 8;316(18):1888-1896. doi: 10.1001/jama.2016.15865.
citation: Bergh J. Oral presentation, ASCO Annual Meeting 2016.
citation: Margolin S, Bengtsson NO, Carlsson L, Edlund P, Hellstrom M, Karlsson P, Lidbrink E, Linderholm B, Lindman H, Malmstrom P, Pettersson Skold D, Soderberg M, Villman K, Bergh J; Scandinavian Breast Group Study SBG 2004-1. A randomised feasibility/phase II study (SBG 2004-1) with dose-dense/tailored epirubicin, cyclophoshamide (EC) followed by docetaxel (T) or fixed dosed dose-dense EC/T versus T, doxorubicin and C (TAC) in node-positive breast cancer. Acta Oncol. 2011 Jan;50(1):35-41. doi: 10.3109/0284186X.2010.535847.