Trial document





This study has been imported from ClinicalTrials.gov without additional data checks.
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  DRKS00003651

Trial Description

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Title

A Randomised, Multi-centre, Open-label, Phase III Study of Adjuvant Lapatinib, Trastuzumab, Their Sequence and Their Combination in Patients With HER2/ErbB2 Positive Primary Breast Cancer

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Trial Acronym

ALTTO

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URL of the Trial

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Brief Summary in Lay Language

This is a randomised, open label multi-centre phase III study comparing the activity of
lapatinib alone versus trastuzumab alone versus trastuzumab followed by lapatinib versus
lapatinib concomitantly with trastuzumab in the adjuvant treatment of patients with ErbB2
overexpressing and/or amplified breast cancer. Patients will be enrolled according to one
of two design schemas, with Design 2 having two chemotherapy options (Design 2 and 2B), and
will be randomised to one of four treatment regimens within each design schema.

The primary objective of this study is to compare disease-free survival (DFS) in patients
with HER2 overexpressing and/or amplified breast cancer randomised to trastuzumab for one
year versus lapatinib for one year versus trastuzumab (12 or 18 weeks, according to assigned
design) followed by a six-week treatment-free interval followed by lapatinib (28 or 34
weeks, according to assigned design) versus trastuzumab in combination with lapatinib for
one year (52 weeks). Secondary objectives include treatment comparisons with respect to
overall survival, time to recurrence, time to distant recurrence, safety and tolerability,
incidence of brain metastasis, and analyses conducted separately for cohorts of patients
defined by presence or absence of cMyc oncogene amplification, expression level of PTEN and
presence or absence of the p95HER2 receptor. On August 18, 2011, the ALTTO Independent Data
Monitoring Committee (IDMC) met to review the first planned interim analysis. The IDMC
reported that the comparison of lapatinib alone versus trastuzumab alone crossed the
futility boundary, indicating that the lapatinib alone arm was unlikely to meet the
pre-specified criteria to demonstrate non-inferiority to trastuzumab alone with respect to
disease-free survival (DFS). The IDMC also stated that the other three arms (trastuzumab
alone, sequential trastuzumab/lapatinib arm and the combination arm) should continue as
planned with no changes.

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Brief Summary in Scientific Language

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Organizational Data

  •   DRKS00003651
  •   2012/05/04
  •   2007/06/20
  •   no
  •   [---]*
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Secondary IDs

  •   NCT00490139  (ClinicalTrials.gov)
  •   EGF106708  (GlaxoSmithKline)
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Health Condition or Problem studied

  •   Neoplasms, Breast
  •   C50 -  Malignant neoplasm of breast
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Interventions/Observational Groups

  •   Drug: Lapatinib
  •   Biological: Trastuzumab
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Characteristics

  •   Interventional
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  •   Randomized controlled trial
  •   Open (masking not used)
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  •   Active control
  •   Treatment
  •   Parallel
  •   III
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Primary Outcome

- Disease-free survival; time frame: Approximately 6-10 years

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Secondary Outcome

- Overall survival; time frame: Approximately 6-10 years
- Time to recurrence; time frame: Approximately 6-10 years
- Time to distant recurrence; time frame: Approximately 6-10 years
- Incidence of brain metastases as first site of breast cancer recurrence; time frame: Approximately 6-10 years
- Safety and Tolerability; time frame: Approximately 6-10 years
- Conduct analyses separately for cohorts defined by the presence or absence of cMyc gene amplification; time frame: Approximately 6-10 years
- Conduct analyses separately for cohorts defined by the expression levels of PTEN; time frame: Approximately 6-10 years
- Conduct analyses separately for cohorts defined by the presence or absence of p95HER2 domain; time frame: Approximately 6-10 years

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Countries of Recruitment

  •   United States
  •   Argentina
  •   Australia
  •   Austria
  •   Belgium
  •   Brazil
  •   Bulgaria
  •   Canada
  •   Chile
  •   China
  •   Croatia
  •   Czech Republic
  •   Denmark
  •   Estonia
  •   France
  •   Germany
  •   Greece
  •   Hong Kong
  •   Hungary
  •   India
  •   Ireland
  •   Israel
  •   Italy
  •   Japan
  •   Korea, Republic of
  •   Malaysia
  •   Mexico
  •   Netherlands
  •   New Zealand
  •   Norway
  •   Pakistan
  •   Peru
  •   Philippines
  •   Poland
  •   Romania
  •   Russian Federation
  •   Singapore
  •   Slovakia
  •   Slovenia
  •   South Africa
  •   Spain
  •   Switzerland
  •   Taiwan, Province of China
  •   Thailand
  •   Ukraine
  •   United Kingdom
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Locations of Recruitment

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Recruitment

  •   [---]*
  •   2007/05/31
  •   8400
  •   Multicenter trial
  •   International
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Inclusion Criteria

  •   Both, male and female
  •   18   Years
  •   no maximum age
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Additional Inclusion Criteria

- Age ≥ 18 years

- Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1;

- Non-metastatic operable primary invasive adenocarcinoma of the breast fulfilling the
following:

1. Histologically confirmed

2. Adequately excised (exceptions: patients who have 'non-resectable' deep margin
invasion are eligible provided they have had or will receive radiotherapy
encompassing the region concerned; patients with histologically documented
infiltration of the skin (pT4) are eligible provided they have undergone or will
receive radiotherapy encompassing the tumour bed);

3. Axilla dissected; sentinel node sampling is allowed provided that axillary
dissection follows confirmation of a positive sentinel node; sentinel node
sampling alone is NOT acceptable after neoadjuvant chemotherapy (in patients
receiving neoadjuvant chemotherapy lymph node status will be considered unknown,
regardless of the results of post-chemotherapy axillary dissection);

4. Axillary node positive patient OR node negative patient with a tumour greater
than or equal to 1.0 cm in greatest diameter. For clarification, isolated tumour
cells (ITC) are considered pN0 and micrometastases are considered pN1

- Known hormone receptor status (ER/PgR or ER alone)

- For Designs 1 and 2: Patients must have received at least four cycles of an approved
anthracycline-based (neo-) adjuvant chemotherapy regimen or listed as an exception in
Table 5 of the protocol.

For Design 1: Randomization must be performed no longer than 12 weeks from day 1 of the
last chemotherapy cycle after obtaining a post-chemotherapy LVEF ≥ 50. Study treatment
must start no more than 14 days after randomization For Design 2: Randomization must be
performed no longer than 6 weeks from day 1 of the last anthracycline-containing
chemotherapy cycle after obtaining a post-anthracycline chemotherapy LVEF ≥ 50. Study
treatment must start no more than 14 days after randomization and must be concurrent with
taxanes.

For Design 2B: Randomisation must be performed no longer than 8 weeks from definitive
surgery. Non-anthracycline platinum containing regimen (docetaxel and carboplatin) and
study treatment must start concomitantly and no more than 14 days after randomisation.

- Baseline LVEF ≥50% measured by echocardiography or MUGA scan. For Design 1 and Design
2 - after completion of all anthracycline-based (neo-) adjuvant chemotherapy and
prior to the targeted therapy(ies); for Design 2B - prior to targeted therapy(ies)
and chemotherapy (docetaxel and carboplatin)

- Over expression and/or amplification of HER2 in the invasive component of the primary
tumour (in case of neoadjuvant treatment, tissue sample used for HER2 testing should
be collected before neoadjuvant treatment starts), according to one of the following
definitions [Wolff et al 2007] and confirmed by central laboratory prior to
randomization:

- 3+ over expression by IHC (> 30% of invasive tumour cells);

- 2+ or 3+ (in 30% or less neoplastic cells) over expression by IHC AND in situ
hybridization (FISH/CISH) test demonstrating HER2 gene amplification;

- HER2 gene amplification by FISH/CISH ( > 6 HER2 gene copies per nucleus, or a FISH
ratio [HER2 gene copies to chromosome 17 signals] of > than 2.2.) Patients with a
negative or equivocal overall result (FISH test ratio of ≤ 2.2, ≤ 6.0 HER2 gene
copies per nucleus) and staining scores of 0, 1+, 2+ or 3+ (in 30% or less neoplastic
cells) by IHC are not eligible for participation in the trial.

Equivocal local results may be submitted for a final determination by the central
laboratory.

- Completion of all necessary baseline laboratory and radiological investigations

- Signed written informed consent (approved by an Independent Ethics Committee (IEC)
and obtained prior to any study specific screening procedures).

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Exclusion Criteria

- History of any prior (ipsi- and/or contralateral) invasive breast carcinoma;

- Past (less than 10 years) or current history of malignant neoplasms, except for
curatively treated 1) basal and squamous cell carcinoma of the skin or 2) carcinoma
in situ of the cervix.

NOTE: Patients with a prior malignancy diagnosed greater than 10 years in the past who
have been curatively treated with surgery ONLY, WITHOUT radiation therapy or systemic
therapy (chemotherapy or endocrine) are eligible for the study. Patients with any prior
diagnosis of breast cancer or melanoma, at any time, are excluded from this study.

- Any clinically staged T4 tumour, including inflammatory breast cancer;

- Bilateral tumours;

- This exclusion criterion has been removed as of protocol amendment 1.

NOTE: multifocal/multicentric tumours are permitted:

- If the patient is node-negative: one of the lesions must be equal or greater than 1.0
cm (sum of the lesion diameters is not acceptable) AND must have positive HER2 status
centrally-confirmed;

- If patient is node-positive: lesion size does not matter BUT one of the lesions must
have HER2 positivity centrally-confirmed. If several lesions are found to be HER2
positive locally, the largest lesion should be considered for central review.

- Maximum cumulative dose of doxorubicin >360mg/m² or maximum cumulative dose of
epirubicin >720mg/m² or any prior anthracyclines unrelated to the present breast
cancer;

- (Neo-) or adjuvant chemotherapy using peripheral stem cell or bone marrow stem cell
support;

- Any prior mediastinal irradiation except internal mammary node irradiation for the
present breast cancer;

- Patients with positive or suspicious internal mammary nodes identified by sentinel
node technique which have not been irradiated or will not be irradiated, or patients
with supraclavicular lymph node involvement (confirmed by fine needle aspirate or
biopsy);

- Prior use of anti-HER2 therapy for any reason or other prior biologic or
immunotherapy for breast cancer;

- Concurrent anti-cancer treatment, except hormonal therapy or radiotherapy for the
present breast cancer;

- Concurrent anti-cancer treatment in another investigational trial with hormone
therapy or immunotherapy unless approved by the Executive Committee:

- Serious cardiac illness or medical conditions including but not confined to:

History of documented congestive heart failure (CHF) or systolic dysfunction (LVEF <50%);
High-risk uncontrolled arrhythmias (ventricular tachycardia, high-grade AV-block,
supraventricular arrhythmias which are not adequately rate-controlled); Angina pectoris
requiring antianginal medication; Clinically significant valvular heart disease; Evidence
of transmural infarction on ECG; Poorly controlled hypertension (e.g. systolic >180mm Hg
or diastolic >100mm Hg);

- Other concurrent serious diseases that may interfere with planned treatment including
severe pulmonary conditions/illness;

- Any of the following abnormal laboratory tests immediately prior to randomization:

serum total bilirubin >1.5 x upper limit of normal (ULN), in the case of known Gilbert's
syndrome, a higher serum total bilirubin (<2 X ULN) is allowed; alanine amino transferase
(ALAT) or aspartate amino transferase (ASAT) >2.5 x ULN; alkaline phosphatase (ALP) > 2.5
x ULN; serum creatinine >2.0 x ULN; total white blood cell count (WBC) <2.5 x 10^9/L;
absolute neutrophil count <1.5 x 10^9/L; platelets <100 x 10^9/L.

- Unresolved or unstable serious adverse events from prior adjuvant chemotherapy or
radiotherapy;

- Malabsorption syndrome, any disease significantly affecting gastrointestinal
function, or resection of the stomach or small bowel, or persons unable to swallow
oral medication. Subjects with ulcerative colitis are also excluded;

- Pregnant, lactating or women of childbearing potential without a negative pregnancy
test - urine or serum - within 7 days prior to randomization, irrespective of the
method of contraception used, including tubal ligation;

- Women of childbearing potential and male participants with partners of child bearing
potential, including women whose last menstrual period was <12 months ago (unless
surgically sterile) who are unable or unwilling to use adequate contraceptive
measures during study treatment (adequate contraceptive measures: intra-uterine
device, barrier method - condoms, diaphragm - also in conjunction with spermicidal
jelly, or total abstinence. Oral, injectable, or implant hormonal contraceptives are
not indicated in this patient population);

- Concomitant use of CYP3A4 inhibitors or inducers.

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Addresses

  • start of 1:1-Block address primary-sponsor
    • GlaxoSmithKline
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  • start of 1:1-Block address scientific-contact
    • GlaxoSmithKline
    • GSK Clinical Trials 
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  • start of 1:1-Block address public-contact
    • GlaxoSmithKline
    • GSK Clinical Trials 
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Sources of Monetary or Material Support

  • start of 1:1-Block address materialSupport
    • Bitte wenden Sie sich an den Sponsor / Please refer to primary sponsor
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Status

  •   Recruiting complete, follow-up continuing
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Trial Publications, Results and other Documents

  • [---]*
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The parameters in ClinicalTrials.gov and DRKS are not identical. Therefore the data import from ClinicalTrials.gov required adjustments. For full details please see the DRKS FAQs .
  •   4
  •   2013/10/30
* This entry means the parameter is not applicable or has not been set.