Trial Review

Did you know?

The ANZCTR now automatically displays published trial results and simplifies the addition of trial documents such as unpublished protocols and statistical analysis plans.

These enhancements will offer a more comprehensive view of trials, regardless of whether their results are positive, negative, or inconclusive.

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT00490139




Registration number
NCT00490139
Ethics application status
Date submitted
20/06/2007
Date registered
22/06/2007
Date last updated
23/07/2021

Titles & IDs
Public title
ALTTO (Adjuvant Lapatinib And/Or Trastuzumab Treatment Optimisation) Study; BIG 2-06/N063D
Scientific 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
Secondary ID [1] 0 0
CLAP016B2301
Secondary ID [2] 0 0
EGF106708
Universal Trial Number (UTN)
Trial acronym
ALTTO
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Neoplasms, Breast 0 0
Condition category
Condition code
Cancer 0 0 0 0
Breast

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Lapatinib
Treatment: Other - Trastuzumab

Active comparator: Arm 1: Trastuzumab - Design 1: Trastuzumab 8mg/kg IV loading dose followed by 6mg/kg IV every 3 weeks for a total of 52 weeks.

Design 2: Either paclitaxel 80mg/m2 IV weekly for 12 weeks OR docetaxel 75mg/m2 IV every 3 weeks for 4 cycles administered concomitantly with trastuzumab 4mg/kg IV loading dose followed by 2mg/kg IV weekly. After completion of chemotherapy, trastuzumab administered every 3 weeks (6mg/kg IV without loading dose) for an additional 40 weeks (52 weeks total).

Design 2B: Docetaxel 75mg/m2 and carboplatin AUC 6 every 3 weeks for 6 cycles (18 weeks) administered concomitantly with trastuzumab 4mg/kg IV loading dose followed by 2mg/kg IV weekly. After completion of chemotherapy, trastuzumab (6mg/kg without loading dose) every 3 weeks for an additional 40 weeks (52 weeks total).

Experimental: Arm 2: Lapatinib - Based on the IDMC results from 18 August 2011, any patient enrolled onto Arm 2 should be considered for a new treatment strategy based on discussion with their physician.

Design 1: Lapatinib 1500mg oral daily for a total of 52 weeks.

Design 2: Either paclitaxel 80mg/m2 IV weekly for 12 weeks OR docetaxel 75mg/m2 IV every 3 weeks for 4 cycles administered concomitantly with oral lapatinib at 750mg daily. After completion of chemotherapy, oral lapatinib administered at 1500mg daily for an additional 40 weeks (52 weeks total).

Design 2B: Docetaxel 75mg/m2 and carboplatin AUC 6 every 3 weeks for 6 cycles (18 weeks) administered concomitantly with oral lapatinib at 750mg daily. After completion of chemotherapy, the dose of lapatinib will be increased to 1500mg oral daily for an additional 40 weeks (52 weeks total).

Experimental: Arm 3: Trastuzumab followed by Lapatinib - Design 1: Trastuzumab (4mg/kg IV loading dose followed by 2mg/kg IV weekly) for 12 weeks followed by a 6 week treatment-free interval followed by oral lapatinib 1500mg daily for 34 weeks (52 weeks total).

Design 2: Trastuzumab (4mg/kg IV loading dose followed by 2mg/kg IV weekly) for 12 weeks administered concomitantly and either paclitaxel 80mg/m2 IV weekly for 12 weeks OR docetaxel 75mg/m2 every 21 days for 4 cycles; followed by a 6 week treatment-free interval followed by oral lapatinib 1500mg daily for 34 weeks (52 weeks total).

Design 2B: Docetaxel 75mg/m2 and carboplatin AUC 6 every 3 weeks for 6 cycles (18 weeks) administered concomitantly with trastuzumab (4mg/kg IV loading dose followed by 2mg/kg IV weekly) followed by a 6 week treatment-free interval followed by oral lapatinib 1500 mg daily for 28 weeks (52 weeks total).

Experimental: Arm 4: Lapatinib in combination with Trastuzumab - Design 1: Oral lapatinib 1000 mg daily concurrent with trastuzumab 8 mg/kg IV loading dose followed by 6mg/kg IV every 3 weeks (52 weeks total).

Design 2: Trastuzumab (4mg/kg loading dose followed by 2mg/kg IV weekly) concurrent with oral lapatinib 750 mg daily and either paclitaxel 80mg/m2 IV weekly for 12 weeks OR docetaxel 75mg/m2 every 21 days for 4 cycles (12 weeks). After completion of chemotherapy, the dose of lapatinib will be increased to 1000mg daily concurrently with trastuzumab every 3 weeks (6mg/kg without loading dose) for an additional 40 weeks (52 weeks total).

Design 2B: Docetaxel 75mg/m2 and carboplatin AUC 6 every 3 weeks for 6 cycles (18 weeks) administered concurrently with oral lapatinib 750mg plus weekly trastuzumab (4mg/kg IV loading dose followed by 2mg/kg IV. After the completion of chemotherapy, trastuzumab will be administered every 3 weeks (6mg/kg without loading dose) concurrent with lapatinib 1000mg daily for an additional 40 weeks (52 weeks total).


Treatment: Drugs: Lapatinib
Small molecule inhibitor

Treatment: Other: Trastuzumab
Antibody
Intervention code [1] 0 0
Treatment: Drugs
Intervention code [2] 0 0
Treatment: Other
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Disease-free Survival (DFS)
Timepoint [1] 0 0
From randomization until the date of the first occurrence of disease recurrence, a contralateral invasive breast cancer, a second primary cancer, or death from any cause (median follow-up of 4.5 years)
Secondary outcome [1] 0 0
Overall Survival (OS)
Timepoint [1] 0 0
From randomization until death due to any cause (median follow-up of 4.5 years)
Secondary outcome [2] 0 0
Time to Recurrence
Timepoint [2] 0 0
From randomization until the date of the first occurrence of a disease recurrence (median follow-up of 4.5 years)
Secondary outcome [3] 0 0
Time to Distant Recurrence
Timepoint [3] 0 0
From randomization until the date of the first occurrence of distant recurrence (median follow-up of 4.5 years)
Secondary outcome [4] 0 0
Time to Central Nervous System Recurrence
Timepoint [4] 0 0
From randomization until the first central nervous system recurrence (median follow-up of 4.5 years)
Secondary outcome [5] 0 0
DFS Ignoring Non-breast Second Primary Malignancies
Timepoint [5] 0 0
From randomization until the date of the first occurrence of disease recurrence, a contralateral invasive breast cancer, a second primary cancer, or death from any cause (median follow-up of 4.5 years)

Eligibility
Key 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).
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key 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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Phase 3
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
16/05/2007
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
1/07/2021
Sample size
Target
Accrual to date
Final
8382
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,TAS,VIC,WA
Recruitment hospital [1] 0 0
Novartis Investigative Site - Camperdown
Recruitment hospital [2] 0 0
Novartis Investigative Site - Coffs Harbour
Recruitment hospital [3] 0 0
Novartis Investigative Site - Concord
Recruitment hospital [4] 0 0
Novartis Investigative Site - Kingswood
Recruitment hospital [5] 0 0
Novartis Investigative Site - Liverpool
Recruitment hospital [6] 0 0
Novartis Investigative Site - North Sydney
Recruitment hospital [7] 0 0
Novartis Investigative Site - Port Macquarie
Recruitment hospital [8] 0 0
Novartis Investigative Site - Randwick
Recruitment hospital [9] 0 0
Novartis Investigative Site - Taree
Recruitment hospital [10] 0 0
Novartis Investigative Site - Tweed Heads
Recruitment hospital [11] 0 0
Novartis Investigative Site - Wagga Wagga
Recruitment hospital [12] 0 0
Novartis Investigative Site - Waratah
Recruitment hospital [13] 0 0
Novartis Investigative Site - Westmead
Recruitment hospital [14] 0 0
Novartis Investigative Site - Nambour
Recruitment hospital [15] 0 0
Novartis Investigative Site - South Brisbane
Recruitment hospital [16] 0 0
Novartis Investigative Site - Woolloongabba
Recruitment hospital [17] 0 0
Novartis Investigative Site - Adelaide
Recruitment hospital [18] 0 0
Novartis Investigative Site - Bedford Park
Recruitment hospital [19] 0 0
Novartis Investigative Site - Woodville
Recruitment hospital [20] 0 0
Novartis Investigative Site - Hobart
Recruitment hospital [21] 0 0
Novartis Investigative Site - Box Hill
Recruitment hospital [22] 0 0
Novartis Investigative Site - East Bentleigh
Recruitment hospital [23] 0 0
Novartis Investigative Site - East Melbourne
Recruitment hospital [24] 0 0
Novartis Investigative Site - Fitzroy
Recruitment hospital [25] 0 0
Novartis Investigative Site - Footscray
Recruitment hospital [26] 0 0
Novartis Investigative Site - Frankston
Recruitment hospital [27] 0 0
Novartis Investigative Site - Heidelberg
Recruitment hospital [28] 0 0
Novartis Investigative Site - Melbourne
Recruitment hospital [29] 0 0
Novartis Investigative Site - Parkville
Recruitment hospital [30] 0 0
Novartis Investigative Site - Ringwood East
Recruitment hospital [31] 0 0
Novartis Investigative Site - Wendouree
Recruitment hospital [32] 0 0
Novartis Investigative Site - Bunbury
Recruitment hospital [33] 0 0
Novartis Investigative Site - Nedlands
Recruitment hospital [34] 0 0
Novartis Investigative Site - Subiaco
Recruitment hospital [35] 0 0
Novartis Investigative Site - Campbelltown
Recruitment hospital [36] 0 0
Novartis Investigative Site - Lismore
Recruitment hospital [37] 0 0
Novartis Investigative Site - Murdoch
Recruitment postcode(s) [1] 0 0
2050 - Camperdown
Recruitment postcode(s) [2] 0 0
2450 - Coffs Harbour
Recruitment postcode(s) [3] 0 0
2139 - Concord
Recruitment postcode(s) [4] 0 0
2747 - Kingswood
Recruitment postcode(s) [5] 0 0
2170 - Liverpool
Recruitment postcode(s) [6] 0 0
2060 - North Sydney
Recruitment postcode(s) [7] 0 0
2444 - Port Macquarie
Recruitment postcode(s) [8] 0 0
2031 - Randwick
Recruitment postcode(s) [9] 0 0
2430 - Taree
Recruitment postcode(s) [10] 0 0
2485 - Tweed Heads
Recruitment postcode(s) [11] 0 0
2650 - Wagga Wagga
Recruitment postcode(s) [12] 0 0
2298 - Waratah
Recruitment postcode(s) [13] 0 0
2145 - Westmead
Recruitment postcode(s) [14] 0 0
4560 - Nambour
Recruitment postcode(s) [15] 0 0
4101 - South Brisbane
Recruitment postcode(s) [16] 0 0
4102 - Woolloongabba
Recruitment postcode(s) [17] 0 0
5000 - Adelaide
Recruitment postcode(s) [18] 0 0
5042 - Bedford Park
Recruitment postcode(s) [19] 0 0
5011 - Woodville
Recruitment postcode(s) [20] 0 0
7000 - Hobart
Recruitment postcode(s) [21] 0 0
3128 - Box Hill
Recruitment postcode(s) [22] 0 0
3165 - East Bentleigh
Recruitment postcode(s) [23] 0 0
3002 - East Melbourne
Recruitment postcode(s) [24] 0 0
3065 - Fitzroy
Recruitment postcode(s) [25] 0 0
3011 - Footscray
Recruitment postcode(s) [26] 0 0
3199 - Frankston
Recruitment postcode(s) [27] 0 0
3084 - Heidelberg
Recruitment postcode(s) [28] 0 0
3002 - Melbourne
Recruitment postcode(s) [29] 0 0
3050 - Parkville
Recruitment postcode(s) [30] 0 0
3135 - Ringwood East
Recruitment postcode(s) [31] 0 0
3355 - Wendouree
Recruitment postcode(s) [32] 0 0
6230 - Bunbury
Recruitment postcode(s) [33] 0 0
6009 - Nedlands
Recruitment postcode(s) [34] 0 0
6008 - Subiaco
Recruitment postcode(s) [35] 0 0
2560 - Campbelltown
Recruitment postcode(s) [36] 0 0
2480 - Lismore
Recruitment postcode(s) [37] 0 0
6150 - Murdoch
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Alabama
Country [2] 0 0
United States of America
State/province [2] 0 0
Alaska
Country [3] 0 0
United States of America
State/province [3] 0 0
Arizona
Country [4] 0 0
United States of America
State/province [4] 0 0
Arkansas
Country [5] 0 0
United States of America
State/province [5] 0 0
California
Country [6] 0 0
United States of America
State/province [6] 0 0
Colorado
Country [7] 0 0
United States of America
State/province [7] 0 0
Connecticut
Country [8] 0 0
United States of America
State/province [8] 0 0
Delaware
Country [9] 0 0
United States of America
State/province [9] 0 0
District of Columbia
Country [10] 0 0
United States of America
State/province [10] 0 0
Florida
Country [11] 0 0
United States of America
State/province [11] 0 0
Georgia
Country [12] 0 0
United States of America
State/province [12] 0 0
Hawaii
Country [13] 0 0
United States of America
State/province [13] 0 0
Idaho
Country [14] 0 0
United States of America
State/province [14] 0 0
Illinois
Country [15] 0 0
United States of America
State/province [15] 0 0
Indiana
Country [16] 0 0
United States of America
State/province [16] 0 0
Iowa
Country [17] 0 0
United States of America
State/province [17] 0 0
Kansas
Country [18] 0 0
United States of America
State/province [18] 0 0
Kentucky
Country [19] 0 0
United States of America
State/province [19] 0 0
Louisiana
Country [20] 0 0
United States of America
State/province [20] 0 0
Maine
Country [21] 0 0
United States of America
State/province [21] 0 0
Maryland
Country [22] 0 0
United States of America
State/province [22] 0 0
Massachusetts
Country [23] 0 0
United States of America
State/province [23] 0 0
Michigan
Country [24] 0 0
United States of America
State/province [24] 0 0
Minnesota
Country [25] 0 0
United States of America
State/province [25] 0 0
Mississippi
Country [26] 0 0
United States of America
State/province [26] 0 0
Missouri
Country [27] 0 0
United States of America
State/province [27] 0 0
Montana
Country [28] 0 0
United States of America
State/province [28] 0 0
Nebraska
Country [29] 0 0
United States of America
State/province [29] 0 0
Nevada
Country [30] 0 0
United States of America
State/province [30] 0 0
New Hampshire
Country [31] 0 0
United States of America
State/province [31] 0 0
New Jersey
Country [32] 0 0
United States of America
State/province [32] 0 0
New Mexico
Country [33] 0 0
United States of America
State/province [33] 0 0
New York
Country [34] 0 0
United States of America
State/province [34] 0 0
North Carolina
Country [35] 0 0
United States of America
State/province [35] 0 0
North Dakota
Country [36] 0 0
United States of America
State/province [36] 0 0
Ohio
Country [37] 0 0
United States of America
State/province [37] 0 0
Oklahoma
Country [38] 0 0
United States of America
State/province [38] 0 0
Oregon
Country [39] 0 0
United States of America
State/province [39] 0 0
Pennsylvania
Country [40] 0 0
United States of America
State/province [40] 0 0
Rhode Island
Country [41] 0 0
United States of America
State/province [41] 0 0
South Carolina
Country [42] 0 0
United States of America
State/province [42] 0 0
South Dakota
Country [43] 0 0
United States of America
State/province [43] 0 0
Tennessee
Country [44] 0 0
United States of America
State/province [44] 0 0
Texas
Country [45] 0 0
United States of America
State/province [45] 0 0
Utah
Country [46] 0 0
United States of America
State/province [46] 0 0
Vermont
Country [47] 0 0
United States of America
State/province [47] 0 0
Virginia
Country [48] 0 0
United States of America
State/province [48] 0 0
Washington
Country [49] 0 0
United States of America
State/province [49] 0 0
West Virginia
Country [50] 0 0
United States of America
State/province [50] 0 0
Wisconsin
Country [51] 0 0
United States of America
State/province [51] 0 0
Wyoming
Country [52] 0 0
Argentina
State/province [52] 0 0
Buenos Aires
Country [53] 0 0
Argentina
State/province [53] 0 0
Santa Fe
Country [54] 0 0
Argentina
State/province [54] 0 0
Ciudad Autonoma de Buenos Aires
Country [55] 0 0
Argentina
State/province [55] 0 0
Mendoza
Country [56] 0 0
Argentina
State/province [56] 0 0
Quilmes
Country [57] 0 0
Argentina
State/province [57] 0 0
Tucuman
Country [58] 0 0
Austria
State/province [58] 0 0
Guessing
Country [59] 0 0
Austria
State/province [59] 0 0
Linz
Country [60] 0 0
Austria
State/province [60] 0 0
Rankweil
Country [61] 0 0
Austria
State/province [61] 0 0
Salzburg
Country [62] 0 0
Austria
State/province [62] 0 0
Steyr
Country [63] 0 0
Austria
State/province [63] 0 0
Vienna
Country [64] 0 0
Austria
State/province [64] 0 0
Villach
Country [65] 0 0
Austria
State/province [65] 0 0
Wien
Country [66] 0 0
Austria
State/province [66] 0 0
Wolfsberg
Country [67] 0 0
Belgium
State/province [67] 0 0
Aalst
Country [68] 0 0
Belgium
State/province [68] 0 0
Antwerpen
Country [69] 0 0
Belgium
State/province [69] 0 0
Bonheiden
Country [70] 0 0
Belgium
State/province [70] 0 0
Brasschaat
Country [71] 0 0
Belgium
State/province [71] 0 0
Brugge
Country [72] 0 0
Belgium
State/province [72] 0 0
Brussels
Country [73] 0 0
Belgium
State/province [73] 0 0
Brussel
Country [74] 0 0
Belgium
State/province [74] 0 0
Bruxelles
Country [75] 0 0
Belgium
State/province [75] 0 0
Charleroi
Country [76] 0 0
Belgium
State/province [76] 0 0
Edegem
Country [77] 0 0
Belgium
State/province [77] 0 0
Genk
Country [78] 0 0
Belgium
State/province [78] 0 0
Gent
Country [79] 0 0
Belgium
State/province [79] 0 0
Haine Saint Paul
Country [80] 0 0
Belgium
State/province [80] 0 0
Hasselt
Country [81] 0 0
Belgium
State/province [81] 0 0
Huy
Country [82] 0 0
Belgium
State/province [82] 0 0
Kortrijk
Country [83] 0 0
Belgium
State/province [83] 0 0
Leuven
Country [84] 0 0
Belgium
State/province [84] 0 0
Liege
Country [85] 0 0
Belgium
State/province [85] 0 0
Mons
Country [86] 0 0
Belgium
State/province [86] 0 0
Namur
Country [87] 0 0
Belgium
State/province [87] 0 0
Roeselare
Country [88] 0 0
Belgium
State/province [88] 0 0
Sint-Niklaas
Country [89] 0 0
Belgium
State/province [89] 0 0
Tournai
Country [90] 0 0
Belgium
State/province [90] 0 0
Turnhout
Country [91] 0 0
Belgium
State/province [91] 0 0
Verviers
Country [92] 0 0
Belgium
State/province [92] 0 0
Wilrijk
Country [93] 0 0
Belgium
State/province [93] 0 0
Yvoir
Country [94] 0 0
Brazil
State/province [94] 0 0
Bahía
Country [95] 0 0
Brazil
State/province [95] 0 0
Minas Gerais
Country [96] 0 0
Brazil
State/province [96] 0 0
Rio Grande Do Sul
Country [97] 0 0
Brazil
State/province [97] 0 0
São Paulo
Country [98] 0 0
Brazil
State/province [98] 0 0
Rio de Janeiro
Country [99] 0 0
Bulgaria
State/province [99] 0 0
Shumen
Country [100] 0 0
Bulgaria
State/province [100] 0 0
Sofia
Country [101] 0 0
Bulgaria
State/province [101] 0 0
Varna
Country [102] 0 0
Canada
State/province [102] 0 0
British Columbia
Country [103] 0 0
Canada
State/province [103] 0 0
New Brunswick
Country [104] 0 0
Canada
State/province [104] 0 0
Ontario
Country [105] 0 0
Canada
State/province [105] 0 0
Prince Edward Island
Country [106] 0 0
Canada
State/province [106] 0 0
Quebec
Country [107] 0 0
Canada
State/province [107] 0 0
Saskatchewan
Country [108] 0 0
Chile
State/province [108] 0 0
Región De La Araucania
Country [109] 0 0
Chile
State/province [109] 0 0
Región De Los Lagos
Country [110] 0 0
Chile
State/province [110] 0 0
Región Metro De Santiago
Country [111] 0 0
Chile
State/province [111] 0 0
Valparaíso
Country [112] 0 0
Chile
State/province [112] 0 0
Arica
Country [113] 0 0
China
State/province [113] 0 0
Guangdong
Country [114] 0 0
China
State/province [114] 0 0
Beijing
Country [115] 0 0
China
State/province [115] 0 0
Shanghai
Country [116] 0 0
China
State/province [116] 0 0
Tianjin
Country [117] 0 0
Croatia
State/province [117] 0 0
Varazdin
Country [118] 0 0
Croatia
State/province [118] 0 0
Zagreb
Country [119] 0 0
Czechia
State/province [119] 0 0
Brno
Country [120] 0 0
Czechia
State/province [120] 0 0
Ceske Budejovice
Country [121] 0 0
Czechia
State/province [121] 0 0
Chomutov
Country [122] 0 0
Czechia
State/province [122] 0 0
Jihlava
Country [123] 0 0
Czechia
State/province [123] 0 0
Novy Jicin
Country [124] 0 0
Czechia
State/province [124] 0 0
Olomouc
Country [125] 0 0
Czechia
State/province [125] 0 0
Pardubice
Country [126] 0 0
Czechia
State/province [126] 0 0
Praha 10
Country [127] 0 0
Czechia
State/province [127] 0 0
Praha 2
Country [128] 0 0
Czechia
State/province [128] 0 0
Praha 4
Country [129] 0 0
Czechia
State/province [129] 0 0
Praha 5
Country [130] 0 0
Czechia
State/province [130] 0 0
Praha 8
Country [131] 0 0
Czechia
State/province [131] 0 0
Usti nad Labem
Country [132] 0 0
Denmark
State/province [132] 0 0
Aalborg
Country [133] 0 0
Denmark
State/province [133] 0 0
Arhus C
Country [134] 0 0
Denmark
State/province [134] 0 0
Esbjerg
Country [135] 0 0
Denmark
State/province [135] 0 0
Herlev
Country [136] 0 0
Denmark
State/province [136] 0 0
Hilleroed
Country [137] 0 0
Denmark
State/province [137] 0 0
Koebenhavn Oe
Country [138] 0 0
Denmark
State/province [138] 0 0
Naestved
Country [139] 0 0
Denmark
State/province [139] 0 0
Odense
Country [140] 0 0
Denmark
State/province [140] 0 0
Roskilde
Country [141] 0 0
Denmark
State/province [141] 0 0
Vejle
Country [142] 0 0
Denmark
State/province [142] 0 0
Viborg
Country [143] 0 0
Estonia
State/province [143] 0 0
Tallinn
Country [144] 0 0
Estonia
State/province [144] 0 0
Tartu
Country [145] 0 0
France
State/province [145] 0 0
ANGERS Cedex 2
Country [146] 0 0
France
State/province [146] 0 0
Annecy
Country [147] 0 0
France
State/province [147] 0 0
Avignon
Country [148] 0 0
France
State/province [148] 0 0
Bayonne
Country [149] 0 0
France
State/province [149] 0 0
Bethune
Country [150] 0 0
France
State/province [150] 0 0
Bordeaux
Country [151] 0 0
France
State/province [151] 0 0
Brive La Gaillarde
Country [152] 0 0
France
State/province [152] 0 0
Bron
Country [153] 0 0
France
State/province [153] 0 0
Caen Cedex 05
Country [154] 0 0
France
State/province [154] 0 0
Caen
Country [155] 0 0
France
State/province [155] 0 0
Clermont Ferrand
Country [156] 0 0
France
State/province [156] 0 0
Coudekerque Branche
Country [157] 0 0
France
State/province [157] 0 0
Dijon Cedex
Country [158] 0 0
France
State/province [158] 0 0
Dijon
Country [159] 0 0
France
State/province [159] 0 0
Draguignan
Country [160] 0 0
France
State/province [160] 0 0
Grenoble Cedex 9
Country [161] 0 0
France
State/province [161] 0 0
Grenoble Cedex
Country [162] 0 0
France
State/province [162] 0 0
Hyeres
Country [163] 0 0
France
State/province [163] 0 0
La Seyne Sur Mer
Country [164] 0 0
France
State/province [164] 0 0
Le Chesnay
Country [165] 0 0
France
State/province [165] 0 0
Le Havre
Country [166] 0 0
France
State/province [166] 0 0
Le Mans
Country [167] 0 0
France
State/province [167] 0 0
Lille
Country [168] 0 0
France
State/province [168] 0 0
Lyon
Country [169] 0 0
France
State/province [169] 0 0
Marseille Cedex 09
Country [170] 0 0
France
State/province [170] 0 0
Marseille cedex 5
Country [171] 0 0
France
State/province [171] 0 0
Marseille
Country [172] 0 0
France
State/province [172] 0 0
Metz cedex 01
Country [173] 0 0
France
State/province [173] 0 0
Mont de Marsan
Country [174] 0 0
France
State/province [174] 0 0
Montauban
Country [175] 0 0
France
State/province [175] 0 0
Montbeliard
Country [176] 0 0
France
State/province [176] 0 0
Mulhouse
Country [177] 0 0
France
State/province [177] 0 0
Nancy
Country [178] 0 0
France
State/province [178] 0 0
Nice Cedex 2
Country [179] 0 0
France
State/province [179] 0 0
Nimes cedex 9
Country [180] 0 0
France
State/province [180] 0 0
Paris Cedex 10
Country [181] 0 0
France
State/province [181] 0 0
Paris Cedex 14
Country [182] 0 0
France
State/province [182] 0 0
Paris Cedex 5
Country [183] 0 0
France
State/province [183] 0 0
Perigueux
Country [184] 0 0
France
State/province [184] 0 0
Perin Sur Mer
Country [185] 0 0
France
State/province [185] 0 0
Perpignan
Country [186] 0 0
France
State/province [186] 0 0
Reims
Country [187] 0 0
France
State/province [187] 0 0
Rouen cedex 1
Country [188] 0 0
France
State/province [188] 0 0
Rouen
Country [189] 0 0
France
State/province [189] 0 0
Saint Gregoire
Country [190] 0 0
France
State/province [190] 0 0
Saint Jean
Country [191] 0 0
France
State/province [191] 0 0
Saint-Cloud
Country [192] 0 0
France
State/province [192] 0 0
Saint-Herblain
Country [193] 0 0
France
State/province [193] 0 0
Saint-Martin Boulogne
Country [194] 0 0
France
State/province [194] 0 0
Saint-Priest en Jarez Cedex
Country [195] 0 0
France
State/province [195] 0 0
Strasbourg
Country [196] 0 0
France
State/province [196] 0 0
Toulouse
Country [197] 0 0
France
State/province [197] 0 0
Tours cedex
Country [198] 0 0
France
State/province [198] 0 0
Valenciennes
Country [199] 0 0
France
State/province [199] 0 0
Vandoeuvre-Les-Nancy
Country [200] 0 0
France
State/province [200] 0 0
Villejuif Cedex
Country [201] 0 0
Germany
State/province [201] 0 0
Baden-Wuerttemberg
Country [202] 0 0
Germany
State/province [202] 0 0
Bayern
Country [203] 0 0
Germany
State/province [203] 0 0
Brandenburg
Country [204] 0 0
Germany
State/province [204] 0 0
Bremen
Country [205] 0 0
Germany
State/province [205] 0 0
Hessen
Country [206] 0 0
Germany
State/province [206] 0 0
Mecklenburg-Vorpommern
Country [207] 0 0
Germany
State/province [207] 0 0
Niedersachsen
Country [208] 0 0
Germany
State/province [208] 0 0
Nordrhein-Westfalen
Country [209] 0 0
Germany
State/province [209] 0 0
Rheinland-Pfalz
Country [210] 0 0
Germany
State/province [210] 0 0
Saarland
Country [211] 0 0
Germany
State/province [211] 0 0
Sachsen-Anhalt
Country [212] 0 0
Germany
State/province [212] 0 0
Sachsen
Country [213] 0 0
Germany
State/province [213] 0 0
Schleswig-Holstein
Country [214] 0 0
Germany
State/province [214] 0 0
Thueringen
Country [215] 0 0
Germany
State/province [215] 0 0
Berlin
Country [216] 0 0
Germany
State/province [216] 0 0
Friedrichshafen
Country [217] 0 0
Germany
State/province [217] 0 0
Hamburg
Country [218] 0 0
Germany
State/province [218] 0 0
Wuerzburg
Country [219] 0 0
Greece
State/province [219] 0 0
Athens
Country [220] 0 0
Greece
State/province [220] 0 0
Heraklion,Crete
Country [221] 0 0
Greece
State/province [221] 0 0
Patra
Country [222] 0 0
Greece
State/province [222] 0 0
Thessaloniki
Country [223] 0 0
Hong Kong
State/province [223] 0 0
Kowloon
Country [224] 0 0
Hong Kong
State/province [224] 0 0
Tuen Mun
Country [225] 0 0
Hungary
State/province [225] 0 0
Budapest
Country [226] 0 0
Hungary
State/province [226] 0 0
Gyor
Country [227] 0 0
Hungary
State/province [227] 0 0
Szeged
Country [228] 0 0
Hungary
State/province [228] 0 0
Szombathely
Country [229] 0 0
India
State/province [229] 0 0
Gurgaon
Country [230] 0 0
India
State/province [230] 0 0
Hyderabad
Country [231] 0 0
India
State/province [231] 0 0
Kolkatta (w.b.)
Country [232] 0 0
India
State/province [232] 0 0
Mangalore
Country [233] 0 0
India
State/province [233] 0 0
Mumbai
Country [234] 0 0
India
State/province [234] 0 0
Nagpur
Country [235] 0 0
India
State/province [235] 0 0
New Delhi
Country [236] 0 0
India
State/province [236] 0 0
Trivandrum
Country [237] 0 0
Ireland
State/province [237] 0 0
Dublin
Country [238] 0 0
Ireland
State/province [238] 0 0
Galway
Country [239] 0 0
Ireland
State/province [239] 0 0
Limerick
Country [240] 0 0
Ireland
State/province [240] 0 0
Sligo
Country [241] 0 0
Ireland
State/province [241] 0 0
Tallaght, Dublin
Country [242] 0 0
Ireland
State/province [242] 0 0
Wilton, Cork
Country [243] 0 0
Israel
State/province [243] 0 0
Beer-Sheva
Country [244] 0 0
Israel
State/province [244] 0 0
Haifa
Country [245] 0 0
Israel
State/province [245] 0 0
Holon
Country [246] 0 0
Israel
State/province [246] 0 0
Jerusalem
Country [247] 0 0
Israel
State/province [247] 0 0
Kfar Saba
Country [248] 0 0
Israel
State/province [248] 0 0
Netanya
Country [249] 0 0
Israel
State/province [249] 0 0
Ramat Gan
Country [250] 0 0
Israel
State/province [250] 0 0
Rehovot
Country [251] 0 0
Israel
State/province [251] 0 0
Tel Aviv
Country [252] 0 0
Italy
State/province [252] 0 0
Basilicata
Country [253] 0 0
Italy
State/province [253] 0 0
Campania
Country [254] 0 0
Italy
State/province [254] 0 0
Emilia-Romagna
Country [255] 0 0
Italy
State/province [255] 0 0
Friuli-Venezia-Giulia
Country [256] 0 0
Italy
State/province [256] 0 0
Lazio
Country [257] 0 0
Italy
State/province [257] 0 0
Liguria
Country [258] 0 0
Italy
State/province [258] 0 0
Lombardia
Country [259] 0 0
Italy
State/province [259] 0 0
Marche
Country [260] 0 0
Italy
State/province [260] 0 0
Piemonte
Country [261] 0 0
Italy
State/province [261] 0 0
Puglia
Country [262] 0 0
Italy
State/province [262] 0 0
Sardegna
Country [263] 0 0
Italy
State/province [263] 0 0
Sicilia
Country [264] 0 0
Italy
State/province [264] 0 0
Toscana
Country [265] 0 0
Italy
State/province [265] 0 0
Trentino-Alto Adige
Country [266] 0 0
Italy
State/province [266] 0 0
Chieti
Country [267] 0 0
Italy
State/province [267] 0 0
Cosenza
Country [268] 0 0
Japan
State/province [268] 0 0
Aichi
Country [269] 0 0
Japan
State/province [269] 0 0
Chiba
Country [270] 0 0
Japan
State/province [270] 0 0
Ehime
Country [271] 0 0
Japan
State/province [271] 0 0
Fukuoka
Country [272] 0 0
Japan
State/province [272] 0 0
Ibaraki
Country [273] 0 0
Japan
State/province [273] 0 0
Kanagawa
Country [274] 0 0
Japan
State/province [274] 0 0
Kyoto
Country [275] 0 0
Japan
State/province [275] 0 0
Osaka
Country [276] 0 0
Japan
State/province [276] 0 0
Saitama
Country [277] 0 0
Japan
State/province [277] 0 0
Tokyo
Country [278] 0 0
Korea, Republic of
State/province [278] 0 0
Gyeonggi-do
Country [279] 0 0
Korea, Republic of
State/province [279] 0 0
Incheon
Country [280] 0 0
Korea, Republic of
State/province [280] 0 0
Seoul
Country [281] 0 0
Korea, Republic of
State/province [281] 0 0
Suwon-si, Gyeonggi-do
Country [282] 0 0
Malaysia
State/province [282] 0 0
Kubang Kerian
Country [283] 0 0
Malaysia
State/province [283] 0 0
Sarawak
Country [284] 0 0
Mexico
State/province [284] 0 0
Estado De México
Country [285] 0 0
Mexico
State/province [285] 0 0
Yucatán
Country [286] 0 0
Mexico
State/province [286] 0 0
Chihuahua
Country [287] 0 0
Mexico
State/province [287] 0 0
Mexico City
Country [288] 0 0
Mexico
State/province [288] 0 0
Mexico D.F.
Country [289] 0 0
Mexico
State/province [289] 0 0
Mexico DF
Country [290] 0 0
Netherlands
State/province [290] 0 0
Amersfoort
Country [291] 0 0
Netherlands
State/province [291] 0 0
Amsterdam
Country [292] 0 0
Netherlands
State/province [292] 0 0
Arnhem
Country [293] 0 0
Netherlands
State/province [293] 0 0
Blaricum
Country [294] 0 0
Netherlands
State/province [294] 0 0
Delft
Country [295] 0 0
Netherlands
State/province [295] 0 0
Den Haag
Country [296] 0 0
Netherlands
State/province [296] 0 0
Eindhoven
Country [297] 0 0
Netherlands
State/province [297] 0 0
Gouda
Country [298] 0 0
Netherlands
State/province [298] 0 0
Hoofddorp
Country [299] 0 0
Netherlands
State/province [299] 0 0
Leeuwarden
Country [300] 0 0
Netherlands
State/province [300] 0 0
Leiden
Country [301] 0 0
Netherlands
State/province [301] 0 0
Leidschendam
Country [302] 0 0
Netherlands
State/province [302] 0 0
Purmerend
Country [303] 0 0
Netherlands
State/province [303] 0 0
Rotterdam
Country [304] 0 0
Netherlands
State/province [304] 0 0
Sittard-geleen
Country [305] 0 0
Netherlands
State/province [305] 0 0
Tilburg
Country [306] 0 0
Netherlands
State/province [306] 0 0
Utrecht
Country [307] 0 0
New Zealand
State/province [307] 0 0
Hamilton
Country [308] 0 0
New Zealand
State/province [308] 0 0
Palmerston North
Country [309] 0 0
New Zealand
State/province [309] 0 0
Wellington
Country [310] 0 0
Norway
State/province [310] 0 0
Forde
Country [311] 0 0
Norway
State/province [311] 0 0
Oslo
Country [312] 0 0
Norway
State/province [312] 0 0
Tromso
Country [313] 0 0
Pakistan
State/province [313] 0 0
Karachi
Country [314] 0 0
Pakistan
State/province [314] 0 0
Lahore
Country [315] 0 0
Pakistan
State/province [315] 0 0
Rawalpindi
Country [316] 0 0
Peru
State/province [316] 0 0
Callao
Country [317] 0 0
Peru
State/province [317] 0 0
Lima
Country [318] 0 0
Philippines
State/province [318] 0 0
Cebu
Country [319] 0 0
Philippines
State/province [319] 0 0
Quezon City
Country [320] 0 0
Philippines
State/province [320] 0 0
Sampaloc Manila
Country [321] 0 0
Philippines
State/province [321] 0 0
San Juan
Country [322] 0 0
Poland
State/province [322] 0 0
Bydgoszcz
Country [323] 0 0
Poland
State/province [323] 0 0
Elblag
Country [324] 0 0
Poland
State/province [324] 0 0
Gdansk
Country [325] 0 0
Poland
State/province [325] 0 0
Gliwice
Country [326] 0 0
Poland
State/province [326] 0 0
Krakow
Country [327] 0 0
Poland
State/province [327] 0 0
Olsztyn
Country [328] 0 0
Poland
State/province [328] 0 0
Opole
Country [329] 0 0
Poland
State/province [329] 0 0
Rzeszow
Country [330] 0 0
Poland
State/province [330] 0 0
Szczecin
Country [331] 0 0
Poland
State/province [331] 0 0
Warszawa
Country [332] 0 0
Poland
State/province [332] 0 0
Wroclaw
Country [333] 0 0
Romania
State/province [333] 0 0
Bucharest
Country [334] 0 0
Romania
State/province [334] 0 0
Bucuresti
Country [335] 0 0
Romania
State/province [335] 0 0
Cluj-Napoca
Country [336] 0 0
Romania
State/province [336] 0 0
Iasi
Country [337] 0 0
Russian Federation
State/province [337] 0 0
Arkhangelsk
Country [338] 0 0
Russian Federation
State/province [338] 0 0
Chelyabinsk
Country [339] 0 0
Russian Federation
State/province [339] 0 0
Irkutsk
Country [340] 0 0
Russian Federation
State/province [340] 0 0
Kazan
Country [341] 0 0
Russian Federation
State/province [341] 0 0
Kirov
Country [342] 0 0
Russian Federation
State/province [342] 0 0
Moscow
Country [343] 0 0
Russian Federation
State/province [343] 0 0
Novosibirsk
Country [344] 0 0
Russian Federation
State/province [344] 0 0
Omsk
Country [345] 0 0
Russian Federation
State/province [345] 0 0
Orenburg
Country [346] 0 0
Russian Federation
State/province [346] 0 0
Ryazan
Country [347] 0 0
Russian Federation
State/province [347] 0 0
Samara
Country [348] 0 0
Russian Federation
State/province [348] 0 0
St. Petersburg
Country [349] 0 0
Russian Federation
State/province [349] 0 0
Voronezh
Country [350] 0 0
Singapore
State/province [350] 0 0
Singapore
Country [351] 0 0
Slovakia
State/province [351] 0 0
Bratislava
Country [352] 0 0
Slovakia
State/province [352] 0 0
Kosice
Country [353] 0 0
Slovakia
State/province [353] 0 0
Poprad
Country [354] 0 0
Slovakia
State/province [354] 0 0
Rimavska Sobota
Country [355] 0 0
Slovakia
State/province [355] 0 0
Zilina
Country [356] 0 0
Slovenia
State/province [356] 0 0
Ljubljana
Country [357] 0 0
South Africa
State/province [357] 0 0
Capital Park
Country [358] 0 0
South Africa
State/province [358] 0 0
Groenkloof, Pretoria, 0001
Country [359] 0 0
South Africa
State/province [359] 0 0
Johannesburg
Country [360] 0 0
South Africa
State/province [360] 0 0
Observatory
Country [361] 0 0
South Africa
State/province [361] 0 0
Panorama
Country [362] 0 0
South Africa
State/province [362] 0 0
Parktown
Country [363] 0 0
South Africa
State/province [363] 0 0
Pretoria
Country [364] 0 0
South Africa
State/province [364] 0 0
Saxonwold, Johannesburg
Country [365] 0 0
Spain
State/province [365] 0 0
Alcoy/Alicante
Country [366] 0 0
Spain
State/province [366] 0 0
Barakaldo (Vizcaya)
Country [367] 0 0
Spain
State/province [367] 0 0
Barcelona
Country [368] 0 0
Spain
State/province [368] 0 0
Burgos
Country [369] 0 0
Spain
State/province [369] 0 0
Cadiz
Country [370] 0 0
Spain
State/province [370] 0 0
Castellon
Country [371] 0 0
Spain
State/province [371] 0 0
Cordoba
Country [372] 0 0
Spain
State/province [372] 0 0
Coria
Country [373] 0 0
Spain
State/province [373] 0 0
Elda
Country [374] 0 0
Spain
State/province [374] 0 0
Granada
Country [375] 0 0
Spain
State/province [375] 0 0
Hospitalet de Llobregat (Barcelona)
Country [376] 0 0
Spain
State/province [376] 0 0
Huesca
Country [377] 0 0
Spain
State/province [377] 0 0
La Laguna (Santa Cruz De Tenerife)
Country [378] 0 0
Spain
State/province [378] 0 0
Lerida
Country [379] 0 0
Spain
State/province [379] 0 0
Lugo
Country [380] 0 0
Spain
State/province [380] 0 0
Madrid
Country [381] 0 0
Spain
State/province [381] 0 0
Malaga
Country [382] 0 0
Spain
State/province [382] 0 0
Mataro
Country [383] 0 0
Spain
State/province [383] 0 0
Mostoles (Madrid)
Country [384] 0 0
Spain
State/province [384] 0 0
Murcia
Country [385] 0 0
Spain
State/province [385] 0 0
Palma de Mallorca
Country [386] 0 0
Spain
State/province [386] 0 0
Pamplona
Country [387] 0 0
Spain
State/province [387] 0 0
Salamanca
Country [388] 0 0
Spain
State/province [388] 0 0
San Sebastian
Country [389] 0 0
Spain
State/province [389] 0 0
Santander
Country [390] 0 0
Spain
State/province [390] 0 0
Santiago
Country [391] 0 0
Spain
State/province [391] 0 0
Segovia
Country [392] 0 0
Spain
State/province [392] 0 0
Sevilla
Country [393] 0 0
Spain
State/province [393] 0 0
Tarrasa, Barcelona
Country [394] 0 0
Spain
State/province [394] 0 0
Toledo
Country [395] 0 0
Spain
State/province [395] 0 0
Valencia
Country [396] 0 0
Spain
State/province [396] 0 0
Zamora
Country [397] 0 0
Spain
State/province [397] 0 0
Zaragoza
Country [398] 0 0
Switzerland
State/province [398] 0 0
Aarau
Country [399] 0 0
Switzerland
State/province [399] 0 0
Basel
Country [400] 0 0
Switzerland
State/province [400] 0 0
Bellinzona
Country [401] 0 0
Switzerland
State/province [401] 0 0
Bern
Country [402] 0 0
Switzerland
State/province [402] 0 0
Chur
Country [403] 0 0
Switzerland
State/province [403] 0 0
Lausanne
Country [404] 0 0
Switzerland
State/province [404] 0 0
Locarno
Country [405] 0 0
Switzerland
State/province [405] 0 0
St Gallen
Country [406] 0 0
Switzerland
State/province [406] 0 0
Thun
Country [407] 0 0
Switzerland
State/province [407] 0 0
Zuerich
Country [408] 0 0
Switzerland
State/province [408] 0 0
Zurich
Country [409] 0 0
Taiwan
State/province [409] 0 0
Kaohsiung
Country [410] 0 0
Taiwan
State/province [410] 0 0
Taichung
Country [411] 0 0
Taiwan
State/province [411] 0 0
Tainan County
Country [412] 0 0
Taiwan
State/province [412] 0 0
Taipei
Country [413] 0 0
Thailand
State/province [413] 0 0
Bangkok
Country [414] 0 0
Thailand
State/province [414] 0 0
Chiangmai
Country [415] 0 0
Thailand
State/province [415] 0 0
Hatyai, Songkhla
Country [416] 0 0
Thailand
State/province [416] 0 0
Khon Kaen
Country [417] 0 0
Thailand
State/province [417] 0 0
Phitsanulok
Country [418] 0 0
Ukraine
State/province [418] 0 0
Chernivtsi
Country [419] 0 0
Ukraine
State/province [419] 0 0
Donetsk
Country [420] 0 0
Ukraine
State/province [420] 0 0
Ivano-Frankivsk
Country [421] 0 0
Ukraine
State/province [421] 0 0
Kharkiv
Country [422] 0 0
Ukraine
State/province [422] 0 0
Kyiv
Country [423] 0 0
Ukraine
State/province [423] 0 0
Lviv
Country [424] 0 0
Ukraine
State/province [424] 0 0
Simferopol
Country [425] 0 0
Ukraine
State/province [425] 0 0
Uzhgorod
Country [426] 0 0
Ukraine
State/province [426] 0 0
Uzhorod
Country [427] 0 0
United Kingdom
State/province [427] 0 0
Essex
Country [428] 0 0
United Kingdom
State/province [428] 0 0
Gloucestershire
Country [429] 0 0
United Kingdom
State/province [429] 0 0
Kent
Country [430] 0 0
United Kingdom
State/province [430] 0 0
Lancashire
Country [431] 0 0
United Kingdom
State/province [431] 0 0
Middlesex
Country [432] 0 0
United Kingdom
State/province [432] 0 0
Midlothian
Country [433] 0 0
United Kingdom
State/province [433] 0 0
Oxfordshire
Country [434] 0 0
United Kingdom
State/province [434] 0 0
Ashford
Country [435] 0 0
United Kingdom
State/province [435] 0 0
Blackpool
Country [436] 0 0
United Kingdom
State/province [436] 0 0
Bournemouth
Country [437] 0 0
United Kingdom
State/province [437] 0 0
Brighton
Country [438] 0 0
United Kingdom
State/province [438] 0 0
Cheltenham
Country [439] 0 0
United Kingdom
State/province [439] 0 0
Cottingham
Country [440] 0 0
United Kingdom
State/province [440] 0 0
Dorchester
Country [441] 0 0
United Kingdom
State/province [441] 0 0
Exeter
Country [442] 0 0
United Kingdom
State/province [442] 0 0
Grimsby
Country [443] 0 0
United Kingdom
State/province [443] 0 0
Guildford
Country [444] 0 0
United Kingdom
State/province [444] 0 0
Gwynedd
Country [445] 0 0
United Kingdom
State/province [445] 0 0
Ipswich
Country [446] 0 0
United Kingdom
State/province [446] 0 0
Lancaster
Country [447] 0 0
United Kingdom
State/province [447] 0 0
Leeds
Country [448] 0 0
United Kingdom
State/province [448] 0 0
Lindley, Huddersfield
Country [449] 0 0
United Kingdom
State/province [449] 0 0
Liverpool
Country [450] 0 0
United Kingdom
State/province [450] 0 0
London
Country [451] 0 0
United Kingdom
State/province [451] 0 0
Maidstone
Country [452] 0 0
United Kingdom
State/province [452] 0 0
Margate
Country [453] 0 0
United Kingdom
State/province [453] 0 0
Newcastle upon Tyne
Country [454] 0 0
United Kingdom
State/province [454] 0 0
Nottingham
Country [455] 0 0
United Kingdom
State/province [455] 0 0
Plymouth
Country [456] 0 0
United Kingdom
State/province [456] 0 0
Poole, Dorset
Country [457] 0 0
United Kingdom
State/province [457] 0 0
Portsmouth
Country [458] 0 0
United Kingdom
State/province [458] 0 0
Romford
Country [459] 0 0
United Kingdom
State/province [459] 0 0
Sheffield
Country [460] 0 0
United Kingdom
State/province [460] 0 0
Shrewsbury
Country [461] 0 0
United Kingdom
State/province [461] 0 0
Southport
Country [462] 0 0
United Kingdom
State/province [462] 0 0
St Helens
Country [463] 0 0
United Kingdom
State/province [463] 0 0
Stoke on Trent
Country [464] 0 0
United Kingdom
State/province [464] 0 0
Sutton
Country [465] 0 0
United Kingdom
State/province [465] 0 0
Swansea
Country [466] 0 0
United Kingdom
State/province [466] 0 0
Whitchurch, Cardiff
Country [467] 0 0
United Kingdom
State/province [467] 0 0
Worthing

Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
Novartis Pharmaceuticals
Address
Country
Other collaborator category [1] 0 0
Other
Name [1] 0 0
North Central Cancer Treatment Group
Address [1] 0 0
Country [1] 0 0
Other collaborator category [2] 0 0
Government body
Name [2] 0 0
National Cancer Institute (NCI)
Address [2] 0 0
Country [2] 0 0
Other collaborator category [3] 0 0
Other
Name [3] 0 0
Breast International Group
Address [3] 0 0
Country [3] 0 0
Other collaborator category [4] 0 0
Other
Name [4] 0 0
Canadian Cancer Trials Group
Address [4] 0 0
Country [4] 0 0

Ethics approval
Ethics application status

Summary
Brief summary
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.
Trial website
https://clinicaltrials.gov/study/NCT00490139
Trial related presentations / publications
Nader-Marta G, Debien V, Eiger D, Tsourti Z, Caparica R, Kassapian M, Napoleone S, Hultsch S, Korde L, Wang Y, Chumsri S, Pritchard KI, Untch M, Bellet-Ezquerra M, Dornelles Rosa D, Moreno-Aspitia A, Piccart M, Dafni U, de Azambuja E. Outcomes of patients with small and node-negative HER2-positive early breast cancer treated with adjuvant chemotherapy and anti-HER2 therapy-a sub-analysis of the ALTTO study. Br J Cancer. 2022 Nov;127(10):1799-1807. doi: 10.1038/s41416-022-01963-8. Epub 2022 Sep 1.
Moreno-Aspitia A, Holmes EM, Jackisch C, de Azambuja E, Boyle F, Hillman DW, Korde L, Fumagalli D, Izquierdo MA, McCullough AE, Wolff AC, Pritchard KI, Untch M, Guillaume S, Ewer MS, Shao Z, Sim SH, Aziz Z, Demetriou G, Mehta AO, Andersson M, Toi M, Lang I, Xu B, Smith IE, Barrios CH, Baselga J, Gelber RD, Piccart-Gebhart M; ALTTO Steering Committee and Investigators. Updated results from the international phase III ALTTO trial (BIG 2-06/Alliance N063D). Eur J Cancer. 2021 May;148:287-296. doi: 10.1016/j.ejca.2021.01.053. Epub 2021 Mar 23.
Sonnenblick A, Agbor-Tarh D, de Azambuja E, Hultsch S, Izquierdo M, Liu M, Pruneri G, Harbeck N, Piccart M, Moreno-Aspita A, Granit RZ, Rouas G, Fahoum I, Sotiriou C. STAT3 activation in HER2-positive breast cancers: Analysis of data from a large prospective trial. Int J Cancer. 2021 Mar 15;148(6):1529-1535. doi: 10.1002/ijc.33385. Epub 2020 Nov 23.
Eiger D, Ponde NF, Agbor-Tarh D, Moreno-Aspitia A, Piccart M, Hilbers FS, Werner O, Chumsri S, Dueck A, Kroep JR, Gomez H, Lang I, Rodeheffer RJ, Ewer MS, Suter T, de Azambuja E. Long-term cardiac outcomes of patients with HER2-positive breast cancer treated in the adjuvant lapatinib and/or trastuzumab Treatment Optimization Trial. Br J Cancer. 2020 May;122(10):1453-1460. doi: 10.1038/s41416-020-0786-x. Epub 2020 Mar 16.
Holmes EM, Bradbury I, Williams LS, Korde L, de Azambuja E, Fumagalli D, Moreno-Aspitia A, Baselga J, Piccart-Gebhart M, Dueck AC, Gelber RD; ALTTO Trial Study Team. Are we assuming too much with our statistical assumptions? Lessons learned from the ALTTO trial. Ann Oncol. 2019 Sep 1;30(9):1507-1513. doi: 10.1093/annonc/mdz195.
McCullough AE, Dell'orto P, Reinholz MM, Gelber RD, Dueck AC, Russo L, Jenkins RB, Andrighetto S, Chen B, Jackisch C, Untch M, Perez EA, Piccart-Gebhart MJ, Viale G. Central pathology laboratory review of HER2 and ER in early breast cancer: an ALTTO trial [BIG 2-06/NCCTG N063D (Alliance)] ring study. Breast Cancer Res Treat. 2014 Feb;143(3):485-92. doi: 10.1007/s10549-013-2827-0. Epub 2014 Jan 7.
Public notes

Contacts
Principal investigator
Name 0 0
Novartis Pharmaceuticals
Address 0 0
Novartis Pharmaceuticals
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/study/NCT00490139