Trastuzumab or Lapatinib Ditosylate in Treating Women With Early Breast Cancer (EPHOS-B)

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ClinicalTrials.gov Identifier: NCT01104571

Recruitment Status : Active, not recruiting

First Posted : April 15, 2010

Last Update Posted : September 17, 2018

View this study on Beta.ClinicalTrials.gov

Sponsor:

Collaborators:

University of Manchester

Manchester University NHS Foundation Trust

Cancer Research UK

Novartis

Information provided by (Responsible Party):

Institute of Cancer Research, United Kingdom

Study Description

Brief Summary:

RATIONALE: Monoclonal antibodies, such as trastuzumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Lapatinib ditosylate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether trastuzumab or lapatinib ditosylate is more effective in treating women with early breast cancer.

Update June 2013:

Since the initial development of EPHOS-B in 2007 more evidence in relation to safety and efficacy of anti-HER2 therapies are now available, and in particular, a growing body of evidence that combinations of two anti-HER2 therapies are more effective than monotherapies. Therefore this study has been amended (PART 2) to a 1:1:2 ratio to control, perioperative trastuzumab or the combination of lapatinib and trastuzumab.

PURPOSE: This randomized phase III trial is studying trastuzumab to see how well it works compared with lapatinib ditosylate (and in since June 2013 - compared with a combination of lapatinib and trastuzumab) in treating women with early breast cancer.

Condition or disease	Intervention/treatment	Phase
Breast Cancer	Biological: trastuzumab Drug: lapatinib ditosylate Other: laboratory biomarker analysis Procedure: adjuvant therapy Procedure: neoadjuvant therapy Procedure: therapeutic conventional surgery	Phase 3

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Detailed Description:

OBJECTIVES:

Primary

To determine whether pre-operative treatment of HER-2 positive breast cancer patients with anti-HER2 therapy consisting of trastuzumab (Herceptin®) vs lapatinib ditosylate inhibits proliferation or increases apoptosis.
To compare the effects of trastuzumab (Herceptin®), lapatinib ditosylate and the combination of lapatinib ditosylate and trastuzumab (Herceptin®) on the inhibition of proliferation or increase of apoptosis

Secondary

To determine whether pre-operative anti-HER2 treatment reduces serum angiogenic factors.
To identify molecular predictors of biological response to anti-HER2 therapy

OUTLINE:

This is a multicenter study.Patients are stratified according to center. Patients are randomized to 1 of 3 treatment arms.

PART 1: From Protocol versions 1 to 4:

Arm I (control): Patients receive no neoadjuvant or adjuvant therapy. Approximately 14 days after randomization, patients undergo either breast-conservation surgery or mastectomy.
Arm II (trastuzumab [Herceptin®]): Patients receive neoadjuvant trastuzumab IV over 90 minutes on days 1 and 8. Approximately 11 days after beginning of neoadjuvant therapy, patients undergo either breast-conservation surgery or mastectomy, and receive adjuvant trastuzumab on day 15.
Arm III (lapatinib ditosylate): Patients receive neoadjuvant oral lapatinib ditosylate once daily on days 1-11. Within 24 hours after completion of neoadjuvant therapy, patients undergo either breast-conservation surgery or mastectomy, and receive adjuvant lapatinib ditosylate once daily on days 12-28.

Patients also receive standard adjuvant systemic therapy, including endocrine therapy (for hormone-sensitive disease) and/or chemotherapy and radiotherapy.

PART 2: From Protocol Version 5 (June 2013)

Arm I (control): Patients receive no neoadjuvant or adjuvant therapy. Approximately 14 days after randomization, patients undergo either breast-conservation surgery or mastectomy.
Arm II (trastuzumab [Herceptin®]): Patients receive neoadjuvant trastuzumab IV over 90 minutes on days 1 and 8. Approximately 11 days after beginning of neoadjuvant therapy, patients undergo either breast-conservation surgery or mastectomy, and receive adjuvant trastuzumab on day 15.
Arm III (lapatinib ditosylate and (trastuzumab [Herceptin®] combination): Patients receive oral lapatinib ditosylate once daily on days 1-11. Within 24 hours after completion of neoadjuvant therapy, patients undergo either breast-conservation surgery or mastectomy, and receive adjuvant lapatinib ditosylate once daily on days 12-28. Patients also receive neoadjuvant trastuzumab IV over 90 minutes on days 1 and 8 and receive adjuvant trastuzumab on day 15.

PART 1 and 2:

Patients also receive standard adjuvant systemic therapy, including endocrine therapy (for hormone-sensitive disease) and/or chemotherapy and radiotherapy.

All patients undergo blood and tissue sample collection periodically for biomarker research studies comprising biomarkers of proliferation, apoptosis, and angiogenesis.

After completion of study treatment, patients are followed up every 6 months for 2 years and then annually for 10 years.

Peer Reviewed and Funded by Cancer Research UK

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	257 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	Effect of Perioperative AntiHER-2 Therapy on Early Breast Cancer Study - Biological Phase (EPHOS-B)
Study Start Date :	April 2010
Actual Primary Completion Date :	August 30, 2017
Estimated Study Completion Date :	September 2025

Resource links provided by the National Library of Medicine

MedlinePlus Genetics related topics: Breast cancer

MedlinePlus related topics: Breast Cancer

Drug Information available for: Trastuzumab Lapatinib Lapatinib Ditosylate

U.S. FDA Resources

Arms and Interventions

Arm	Intervention/treatment
Part 1: Control No peri-operative therapy given	Other: laboratory biomarker analysis Procedure: therapeutic conventional surgery therapeutic conventional surgery
Experimental: Part 1: Trastuzumab Trastuzumab 6mg/kg iv given on days 1 & 8 pre-surgery & one dose of 2mg/kg iv between days 15-19 post surgery.	Biological: trastuzumab Trastuzumab 6mg/kg iv given on days 1 & 8 pre-surgery & one dose of 2mg/kg iv between days 15-19 post surgery Other: laboratory biomarker analysis Procedure: adjuvant therapy Procedure: neoadjuvant therapy
Experimental: Part 1: lapatinib Lapatinib 1500mg/day p.o. continuously for 28 days. Should start 11 days (+2 or -1 day) before the scheduled surgery	Drug: lapatinib ditosylate Part 1: Lapatinib 1500mg/day p.o. continuously for 28 days. Should start 11 days (+2 or -1 day) before the scheduled surgery. Part 2: Lapatinib 1000mg/day p.o. continuously for 28 days. Should start 11 days (+2 or -1 day) before the scheduled surgery. Other: laboratory biomarker analysis Procedure: adjuvant therapy Procedure: neoadjuvant therapy
Part 2: Control No peri-operative therapy	Other: laboratory biomarker analysis Procedure: therapeutic conventional surgery therapeutic conventional surgery
Experimental: Part 2: Trastuzumab Trastuzumab 6mg/kg iv given on days 1 & 8 pre-surgery & one dose of 2mg/kg iv between days 15-19 post surgery.	Biological: trastuzumab Trastuzumab 6mg/kg iv given on days 1 & 8 pre-surgery & one dose of 2mg/kg iv between days 15-19 post surgery Other: laboratory biomarker analysis Procedure: adjuvant therapy Procedure: neoadjuvant therapy
Experimental: Part 2: lapatinib-trastuzumab combination Lapatinib 1000mg/day p.o. continuously for 28 days, in combination with trastuzumab 6mg/kg iv given on days 1 & 8 pre-surgery & one dose of 2mg/kg iv between days 15-19 post surgery. Both drugs should start 11 days (+2 or -1 day) before the scheduled surgery.	Biological: trastuzumab Trastuzumab 6mg/kg iv given on days 1 & 8 pre-surgery & one dose of 2mg/kg iv between days 15-19 post surgery Drug: lapatinib ditosylate Part 1: Lapatinib 1500mg/day p.o. continuously for 28 days. Should start 11 days (+2 or -1 day) before the scheduled surgery. Part 2: Lapatinib 1000mg/day p.o. continuously for 28 days. Should start 11 days (+2 or -1 day) before the scheduled surgery. Other: laboratory biomarker analysis Procedure: adjuvant therapy Procedure: neoadjuvant therapy

Outcome Measures

Primary Outcome Measures :

Increase in apoptosis, by change in the tumor (morphological apoptosis and activated caspase 3) measured at diagnosis and at surgery (biological phase) [ Time Frame: 10-13 days ]
Fall in proliferation between diagnosis and surgery by change in proliferation measured by Ki67 immunohistochemical assessment (%) at diagnosis and at surgery (biological phase) [ Time Frame: 10-13 days ]
Relapse-free survival (clinical phase) [ Time Frame: TBC ]

Secondary Outcome Measures :

Changes in the angiogenic serum markers VEGF-A, VEGF R1, and CD105, measured at diagnosis, surgery (plus also tumor CD31) and 28-30 days post surgery (biological phase) [ Time Frame: TBC ]
Pre-treatment and/or surgical expression of molecular markers (EGFR, Her-3, IGF1R, c-myc, AKT, p-ERK, pS6 inase, activated src, or truncated p95HER-2 expression) [ Time Frame: TBC ]
Time to local recurrence (clinical phase) [ Time Frame: TBC ]
Time to distant recurrence (clinical phase) [ Time Frame: TBC ]
Overall survival (clinical phase) [ Time Frame: TBC ]

Eligibility Criteria

Information from the National Library of Medicine

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Ages Eligible for Study:	18 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	Female
Accepts Healthy Volunteers:	No

Criteria

DISEASE CHARACTERISTICS:

Histologically confirmed (by core biopsy) invasive breast cancer
- Newly diagnosed disease
- Resectable disease
HER2-positive disease, defined as 3+ measured by IHC or gene amplification by fluorescent in situ hybridization (FISH)
No evidence of metastatic disease (T4 category) or suspicion of distant metastases
No inflammatory breast cancer
Planned surgery within 1 month of diagnosis, and willing to undergo adjuvant chemotherapy and trastuzumab post-surgery
Must consent to donation of tissue and blood samples
Hormone receptor status known
- Estrogen receptor-positive patients on hormone replacement therapy (HRT) must either continue HRT or must not have taken HRT within the past 3 weeks
- Estrogen receptor-negative patients may enter the trial whether or not they have taken HRT within the past 3 weeks

PATIENT CHARACTERISTICS:

Menopausal status not specified
ECOG performance status (PS) 0-2 OR Karnofsky PS 60-100%
Serum creatinine < 2 times upper limit of normal (ULN) OR creatinine clearance > 30 mg/dL
Bilirubin < 2 times ULN
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective non-hormonal contraception
LVEF ≥ 55% by echocardiography or MUGA
No clinically significant cardiac abnormalities or uncontrolled hypertension
No prior myocardial infarction, heart failure, or significant angina
No prior cancer at any other site that has been treated within the past 6 months (except basal cell carcinoma or cervical carcinoma in situ)
No current active hepatic or biliary disease (except Gilbert syndrome, asymptomatic gallstones, liver metastases, or stable chronic liver disease, per investigator assessment)
No impaired gastrointestinal function that would sufficiently reduce lapatinib ditosylate absorption
No known immediate or delayed hypersensitivity or reaction to drugs chemically related to trastuzumab or lapatinib ditosylate
No altered mental state that would preclude obtaining written informed consent

PRIOR CONCURRENT THERAPY:

See Disease Characteristics
No prior trastuzumab (Herceptin®) therapy within the past 3 months
No prior local cancer treatment (e.g., radiotherapy)
No other concurrent investigational agent or anticancer therapy
No use of herbal (alternative) therapies within 1 day of study entry (vitamin and/or mineral supplements allowed)
No regular use of systemic steroids or other agents that could influence study endpoints (inhaled steroids allowed)
No grapefruit and grapefruit juice for the duration of the study
At least 14 days since prior and no concurrent CYP3A4 inducers
At least 7 days since prior and no concurrent CYP3A4 inhibitors
At least 6 months since prior and no concurrent amiodarone

Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01104571

Locations

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United Kingdom
Wythenshawe Hospital
Manchester, England, United Kingdom, M23 9LJ

Sponsors and Collaborators

Institute of Cancer Research, United Kingdom

University of Manchester

Manchester University NHS Foundation Trust

Cancer Research UK

Novartis

Investigators

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Principal Investigator:	Nigel Bundred	Wythenshawe Hospital

More Information

Additional Information:

ICR-CTSU information on EPHOS-B This link exits the ClinicalTrials.gov site

Cancer Research UK - lay summary of EPHOS-B This link exits the ClinicalTrials.gov site

ISRCTN Registry This link exits the ClinicalTrials.gov site

Publications:

Bundred N, Cameron D, Armstrong A, Brunt AM, Cramer A, Dodwell D, Evans A, Hanby A, Hartup S, Hong A., Horgan K, Khattak I, Morden J, Naik J, Narayanan S, Ooi J, Shaaban A, Smith R, Webster-Smith M, Bliss J; on behalf of the EPHOS-B investigators. Effects of perioperative lapatinib and trastuzumab alone in combination in early HER2+ breast cancer - results from the EPHOS-B trial (CRUK/08/002). Eur J Cancer Supplements. 2016; 57 (Suppl 2): S5 #6LBA.

Bliss JM, Robison LE, Webster-Smith MF, Emson MA, Kilburn LS, Smith IE, Robertson J, Dowsett M, Bundred NJ, Cameron DA, Vidya R, Horgan K, Evans AA, Kokan JS, Pinhel I, A'Hern R; on behalf of the POETIC and EPHOS-B Trialists. A trial model for the future in the search for personalised medicine - the UK POETIC and EPHOS-B perioperative trials experience. Cancer Res. 2011; 71(24 Suppl): Abstract number OT2-03-04.

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Responsible Party:	Institute of Cancer Research, United Kingdom
ClinicalTrials.gov Identifier:	NCT01104571
Other Study ID Numbers:	CDR0000669882 ICR-CTSU-2008-10017 ( Other Identifier: The Institute of Cancer Research Clinical Trials and Statistics Unit ) UM-EPHOS-B CRUK-08-002 ( Other Grant/Funding Number: Cancer Research UK ) MREC-09-H1208-52 ( Other Identifier: Research Ethics Committee ) ISRCTN-15004993 ( Registry Identifier: ISRCTN ) 2008-005466-30 ( EudraCT Number ) EU-21029
First Posted:	April 15, 2010 Key Record Dates
Last Update Posted:	September 17, 2018
Last Verified:	February 2018

Keywords provided by Institute of Cancer Research, United Kingdom:


HER2-positive breast cancer stage IA breast cancer stage IB breast cancer stage II breast cancer	stage IIIA breast cancer estrogen receptor-negative breast cancer estrogen receptor-positive breast cancer

Additional relevant MeSH terms:

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Breast Neoplasms Neoplasms by Site Neoplasms Breast Diseases Skin Diseases Trastuzumab	Lapatinib Antineoplastic Agents, Immunological Antineoplastic Agents Protein Kinase Inhibitors Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action

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