Neo ALTTO (Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimisation) Study

Neoplasms, Breast Clinical Trial

— Neo ALTTO  

Official title:

Neo ALTTO (Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimisation) Study: A Randomised, Multicenter Open-label Phase III Study of Neoadjuvant Lapatinib, Trastuzumab and Their Combination Plus Paclitaxel in Women With HER2/ErbB2 Positive Primary Breast Cancer

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00553358
• Other study ID #: EGF106903
• Secondary ID: 2006-000564-81CL
• Status: Completed
• Phase: Phase 3
• Start date: January 5, 2008
• Est. completion date: December 23, 2019

Study information

• Verified date: August 2021
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a randomised, open label multicenter Phase III study comparing the efficacy of neoadjuvant lapatinib plus paclitaxel, versus trastuzumab plus paclitaxel, versus concomitant lapatinib and trastuzumab plus paclitaxel given as neoadjuvant treatment in HER2/ErbB2 over-expressing and/or amplified primary breast cancer.

Patients will be randomised to receive either: lapatinib 1500 mg daily, trastuzumab 4 mg/kg intravenous (IV) load followed by 2 mg/kg IV weekly, or lapatinib 1000 mg daily with trastuzumab 4 mg/kg IV load followed by 2 mg/kg IV weekly for a total of 6 weeks. After this biological window, patients on monotherapy arms will continue on the same targeted therapy plus weekly paclitaxel 80 mg/m^2 for a further 12 weeks, up to definitive surgery. In the combination arm, patients will receive lapatinib 750 mg daily in combination with trastuzumab 2 mg/kg IV plus weekly paclitaxel 80mg/m^2 IV for a further 12 weeks, up to definitive surgery. After surgery, patients will receive three courses of adjuvant chemotherapy with 5-Fluorouracil Epirubicin Cyclophosphamide (FEC) followed by the same targeted therapy as in the biological window of the neoadjuvant setting for a further 34 weeks (in the combination arm, lapatinib dose will be 1000 mg daily in combination with trastuzumab). The planned total duration of the anti-HER2 therapy one year.

Primary objective is to evaluate and compare the rate of pathological complete response (pCR) at the time of surgery in patients with HER2/ErbB2 overexpressing or amplified operable breast cancer randomised to lapatinib followed by lapatinib plus paclitaxel versus trastuzumab followed by trastuzumab plus paclitaxel versus lapatinib in combination with trastuzumab followed by lapatinib, trastuzumab plus paclitaxel.

Description:

This was a parallel group, three-arm, randomized, multicenter, open-label phase III study. The study compared the efficacy and tolerability of neoadjuvant lapatinib and paclitaxel, versus trastuzumab and paclitaxel, versus the combination of lapatinib with trastuzumab and paclitaxel given as neoadjuvant treatment in HER2/ErbB2 over-expressing and/or amplified primary breast cancer. Subjects were randomized to receive lapatinib, trastuzumab or lapatinib plus trastuzumab for a total of 6 weeks. After this biological window, subjects continued on the same targeted therapy plus weekly paclitaxel for a further 12 weeks, until definitive surgery (total neoadjuvant therapy duration of 18 weeks). Paclitaxel could be initiated at Week 4 if there is evidence of progressive disease (PD) at that time. Within 6 weeks after surgery, subjects received 3 cycles of adjuvant 5-flourouracil, epirubicin and cyclophosphamide (FEC) followed by the same targeted therapy as in the biological window of the neoadjuvant phase for a further 34 weeks (to complete 52 weeks of anti-HER2 therapy).

After completing 52 weeks of (neo-)/adjuvant anti-HER2 therapy, subjects were scheduled to attend post-treatment follow-up every 3 months during the first year (months 12, 15, 18, 21, and 24), every 6months in Years 3 to 5 inclusive, and annually thereafter up to Year 10. Each subject was to be followed for 10 Years. All subjects were to be followed for EFS and OS up to 10 years from last subject randomized.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 455
• Est. completion date: December 23, 2019
• Est. primary completion date: May 27, 2010
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Female gender;

• Age =18 years;

• Performance Status- Eastern Cooperative Oncology Group (ECOG) 0-1

• Histologically confirmed invasive breast cancer:

• Primary tumour greater than 2 cm diameter, measured by clinical examination and mammography or echography,

• Any N,

• No evidence of metastasis (M0) (isolated supraclavicular node involvement allowed);

• Over expression and/or amplification of HER2 in the invasive component of the primary tumour [Wolff et al 2006] and confirmed by a certified laboratory prior to randomisation

• Known hormone receptor status.

• Haematopoietic status:

• Absolute neutrophil count = 1,5 x 10^9/L,

• Platelet count = 100 x 10^9/L,

• Hemoglobin at least 9 g/dl,

• Hepatic status:

• 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,

• Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) = 2.5 times ULN,

• Alkaline phosphatase = 2.5 times ULN,

• Renal status:

• Creatinine = 2.0 mg/dL,

• Cardiovascular:

• Baseline left ventricular ejection fraction (LVEF) ³ 50% measured by echocardiography (ECHO) or Multiple Gate Acquisition (MUGA) scan,

• Negative serum pregnancy test, within 2-weeks (preferably 7 days) prior to randomization (For women of childbearing potential)

• Fertile patients must use effective contraception (barrier method - condoms, diaphragm
• also in conjunction with spermicidal jelly, or total abstinence. Oral, injectable, or implant hormonal contraceptives are not allowed)

• Signed informed consent form (ICF)

• Patient accepts to make available tumour samples for submission to central laboratory to conduct translational studies as part of this protocol

Exclusion Criteria:

• Received any prior treatment for primary invasive breast cancer;

• Previous (less than 10 years) or current history of malignant neoplasms, except for curatively treated:

• Basal and squamous cell carcinoma of the skin;

• Carcinoma in situ of the cervix.

• Patients with a prior malignancy diagnosed more than 10 years prior to randomisation may enter the study. Patients must have been curatively treated with surgery alone. Radiation therapy or systemic therapy (chemotherapy or endocrine) are NOT permitted. Prior diagnoses of breast cancer or melanoma are excluded.

• Diagnosis of inflammatory breast cancer;

• Bilateral cancer;

• This criterion has been deleted from the protocol Version 1. Patients with multi-focal cancer are no longer excluded.

• Known history of uncontrolled or symptomatic angina, clinically significant arrhythmias, congestive heart failure, transmural myocardial infarction, uncontrolled hypertension (=180/110), unstable diabetes mellitus, dyspnoea at rest, or chronic therapy with oxygen;

• Concurrent disease or condition that would make the subject inappropriate for study participation or any serious medical disorder that would interfere with the subject's safety;

• Unresolved or unstable, serious adverse events from prior administration of another investigational drug;

• Active or uncontrolled infection;

• Dementia, altered mental status, or any psychiatric condition that would prevent the understanding or rendering of ICF;

• Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel. Subjects with ulcerative colitis are also excluded;

• Concurrent neoadjuvant cancer therapy (chemotherapy, radiation therapy, immunotherapy, biologic therapy other than the trial therapies);

• Concurrent treatment with an investigational agent or participation in another therapeutic clinical trial;

• Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to trastuzumab or lapatinib or their excipients;

• Pregnant or lactating women;

• Concomitant use of CYP3A4 inhibitors or inducers

Related Conditions & MeSH terms

• Breast Neoplasms
• Neoplasms, Breast

Intervention

Drug:
• Lapatinib
Small molecule receptor tyrosine kinase inhibitor

Biological:
• Trastuzumab
Therapeutic Monoclonal Antibody

Drug:
• Paclitaxel
antimicrotubule agent

Locations

Country	Name	City	State
Argentina	Novartis Investigative Site	Berazategui	Buenos Aires
Argentina	Novartis Investigative Site	Ciudad Autonoma de Buenos Aires	Buenos Aires
Argentina	Novartis Investigative Site	Ciudad Autonoma de Buenos Aires	Buenos Aires
Argentina	Novartis Investigative Site	Quilmes
Argentina	Novartis Investigative Site	Rosario	Santa Fe
Argentina	Novartis Investigative Site	Santa Fe
Argentina	Novartis Investigative Site	Tucuman
Belgium	Novartis Investigative Site	Brussel
Belgium	Novartis Investigative Site	Brussels
Belgium	Novartis Investigative Site	Bruxelles
Belgium	Novartis Investigative Site	Gent
Belgium	Novartis Investigative Site	Leuven
Belgium	Novartis Investigative Site	Namur
Brazil	Novartis Investigative Site	Porto Alegre	Rio Grande Do Sul
Brazil	Novartis Investigative Site	Porto Alegre	Rio Grande Do Sul
Brazil	Novartis Investigative Site	Santo Andre	São Paulo
Brazil	Novartis Investigative Site	Sao Paulo	São Paulo
Canada	Novartis Investigative Site	Montreal	Quebec
Czechia	Novartis Investigative Site	Brno
Czechia	Novartis Investigative Site	Novy Jicin
Czechia	Novartis Investigative Site	Praha 10
France	Novartis Investigative Site	Bayonne
France	Novartis Investigative Site	Bordeaux
France	Novartis Investigative Site	Le Mans
France	Novartis Investigative Site	Levallois-Perret
France	Novartis Investigative Site	Paris
France	Novartis Investigative Site	Reims
France	Novartis Investigative Site	Strasbourg
France	Novartis Investigative Site	Strasbourg
France	Novartis Investigative Site	Toulouse
France	Novartis Investigative Site	Villejuif Cedex
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Celle	Niedersachsen
Germany	Novartis Investigative Site	Dortmund	Nordrhein-Westfalen
Germany	Novartis Investigative Site	Essen	Nordrhein-Westfalen
Germany	Novartis Investigative Site	Frankfurt am Main	Hessen
Germany	Novartis Investigative Site	Freiburg	Baden-Wuerttemberg
Germany	Novartis Investigative Site	Fuerstenwalde	Brandenburg
Germany	Novartis Investigative Site	Fuerth	Bayern
Germany	Novartis Investigative Site	Halle	Sachsen-Anhalt
Germany	Novartis Investigative Site	Hannover	Niedersachsen
Germany	Novartis Investigative Site	Karlsruhe	Baden-Wuerttemberg
Germany	Novartis Investigative Site	Kiel	Schleswig-Holstein
Germany	Novartis Investigative Site	Koeln	Nordrhein-Westfalen
Germany	Novartis Investigative Site	Nuernberg	Bayern
Germany	Novartis Investigative Site	Rostock	Mecklenburg-Vorpommern
Germany	Novartis Investigative Site	Stralsund	Mecklenburg-Vorpommern
Germany	Novartis Investigative Site	Witten	Nordrhein-Westfalen
Hong Kong	Novartis Investigative Site	Hong Kong
Hong Kong	Novartis Investigative Site	Kowloon
Hong Kong	Novartis Investigative Site	Wanchai
Hungary	Novartis Investigative Site	Budapest
India	Novartis Investigative Site	Bangalore
India	Novartis Investigative Site	Hyderabad
India	Novartis Investigative Site	Mumbai
India	Novartis Investigative Site	Nagpur
India	Novartis Investigative Site	New Delhi
India	Novartis Investigative Site	New Delhi
India	Novartis Investigative Site	Pune
Italy	Novartis Investigative Site	Genova	Liguria
Italy	Novartis Investigative Site	Lecco	Lombardia
Italy	Novartis Investigative Site	Milano	Lombardia
Italy	Novartis Investigative Site	Milano	Lombardia
Italy	Novartis Investigative Site	Monza	Lombardia
Italy	Novartis Investigative Site	Roma	Lazio
Italy	Novartis Investigative Site	Sondrio	Lombardia
Italy	Novartis Investigative Site	Trento	Trentino-Alto Adige
Korea, Republic of	Novartis Investigative Site	Seoul
Korea, Republic of	Novartis Investigative Site	Seoul
Korea, Republic of	Novartis Investigative Site	Seoul
Korea, Republic of	Novartis Investigative Site	Seoul
Korea, Republic of	Novartis Investigative Site	Songpa-gu, Seoul
Lithuania	Novartis Investigative Site	Vilnius
Norway	Novartis Investigative Site	Oslo
Norway	Novartis Investigative Site	Oslo
Pakistan	Novartis Investigative Site	Karachi
Peru	Novartis Investigative Site	Lima
Peru	Novartis Investigative Site	Lima
Romania	Novartis Investigative Site	Bucharest
Romania	Novartis Investigative Site	Bucharest
Romania	Novartis Investigative Site	Bucuresti
Romania	Novartis Investigative Site	Cluj-Napoca
Russian Federation	Novartis Investigative Site	Moscow
Russian Federation	Novartis Investigative Site	Ryazan
Russian Federation	Novartis Investigative Site	St. Petersburg
Russian Federation	Novartis Investigative Site	St. Petersburg
South Africa	Novartis Investigative Site	Athlone Park, Amanzimtoti
South Africa	Novartis Investigative Site	Capital Park
South Africa	Novartis Investigative Site	Parktown
South Africa	Novartis Investigative Site	Pretoria	Gauteng
Spain	Novartis Investigative Site	Barcelona
Spain	Novartis Investigative Site	Girona
Spain	Novartis Investigative Site	Lerida
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Mataro
Spain	Novartis Investigative Site	Santiago de Compostela
Spain	Novartis Investigative Site	Sevilla
Spain	Novartis Investigative Site	Toledo
Spain	Novartis Investigative Site	Torrevieja (Alicante)
Spain	Novartis Investigative Site	Valencia
Sweden	Novartis Investigative Site	Goteborg
Taiwan	Novartis Investigative Site	Changhua
Taiwan	Novartis Investigative Site	Tainan
Taiwan	Novartis Investigative Site	Taipei
Taiwan	Novartis Investigative Site	Taipei
Taiwan	Novartis Investigative Site	Taipei
Ukraine	Novartis Investigative Site	Chernivtsi
Ukraine	Novartis Investigative Site	Dnipropetrovsk
Ukraine	Novartis Investigative Site	Kharkiv
Ukraine	Novartis Investigative Site	Kiev
Ukraine	Novartis Investigative Site	Krivoy Rog
Ukraine	Novartis Investigative Site	Kyiv
Ukraine	Novartis Investigative Site	Lviv
Ukraine	Novartis Investigative Site	Odessa
Ukraine	Novartis Investigative Site	Simferopol
United Kingdom	Novartis Investigative Site	Bournemouth
United Kingdom	Novartis Investigative Site	Epping	Essex
United Kingdom	Novartis Investigative Site	London
United Kingdom	Novartis Investigative Site	London
United Kingdom	Novartis Investigative Site	Nottingham

Sponsors (3)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals	Breast International Group, SOLTI Breast Cancer Research Group

Countries where clinical trial is conducted

Argentina,  Belgium,  Brazil,  Canada,  Czechia,  France,  Germany,  Hong Kong,  Hungary,  India,  Italy,  Korea, Republic of,  Lithuania,  Norway,  Pakistan,  Peru,  Romania,  Russian Federation,  South Africa,  Spain,  Sweden,  Taiwan,  Ukraine,  United Kingdom, 

References & Publications (1)

Baselga J, Piccart M, Gelber R, di CosimoS, Viale G, Koehler M, Rojo F. Neo-ALTTO (Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimisation) study [BIG 1-06 /solti/EGF106903]: a phase III translational study for HER2-overexpressing early breast cancer. [Lancet]. 2012;S140-6736(11):

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants With Pathological Complete Response (pCR) at the Time of Surgery	Pathological complete response is defined as no invasive cancer in the breast or only non-invasive in situ cancer in the breast specimen. Surgical breast and axillary node resection specimens were evaluated for pathologic tumor response according to National Surgical Adjuvant Breast and Bowel Project (NSABP) guidelines, which do not take into account the histological nodal status.	Weeks 20 to 22
Secondary	Number of Participants With Overall Response at Week 6	The number of participants with overall response (complete response and/or partial response) was evaluated using World Health Organization (WHO) criteria by clinical examination and by mammography and breast echography with bi-dimensional measurements at Week 6. As per WHO criteria: complete response is defined as the disappearance of all lesions; partial response is defined as a greater than 50% decrease in the sum of products of the greatest length and width of the largest lesion; progressive disease is defined as a greater than 25% increase in the sum of products of all measurable lesions.	Week 6
Secondary	Overall Response at the Time of Surgery	The number of participants with overall response (complete response and/or partial response) was evaluated using WHO criteria by clinical examination and mammography and breast echography with bi-dimensional measurements at the time of surgery (Weeks 20 to 22). As per WHO criteria: complete response is defined as the disappearance of all lesions; partial response is defined as a greater than 50% decrease in the sum of products of the greatest length and width of the largest lesion; progressive disease is defined as a greater than 25% increase in the sum of products of all measurable lesions.	Time of surgery (Weeks 20 to 22)
Secondary	Number of Participants With Negative Lymph Nodes at the Time of Surgery	Participants were assessed for node-negative lymph nodes at the time of surgery. As per the pathological TNM (Tumor, Node, Metastases) classification (pTNM) of malignant tumors: pN, absence or presence and extent of regional lymph node metastasis. Node-negative (pN0) participants had no regional lymph node metastasis. Although not assessed in this measure, pT is the extent of primary tumor, and pM is the absence or presence of distant metastasis.	Time of surgery (Weeks 20 to 22)
Secondary	Number of Participants With Actual Indicated Surgery	Participants were assessed for the type of surgery they underwent for breast cancer. Non-conservative surgery is defined as a radical or modified radical mastectomy. Conservative surgery is comprised of a lumpectomy, a quadrantectomy/segmentectomy, or a partial mastectomy. Participants who were not assessed as being candidates for non-conservative or conservative surgery were classified as non-operable.	At surgery (Weeks 20 to 22)
Secondary	Mean Change From Baseline in Tumor Size at Week 6 and at Surgery	Mean change from baseline in tumor in tumor size. Change from baseline in tumor size was defined as tumor size at Week 6/ surgery (Weeks 20 to 22) minus tumor size at baseline. The difference in treatment arms was estimated for Lapatinib 1500 mg versus Trastuzumab 2 mg/kg and for Lapatinib 1000/750 mg + Trastuzumab 2 mg/kg versus Trastuzumab 2 mg/kg.	Week 6 and surgery (Weeks 20 to 22)
Secondary	Number of Participants Starting Paclitaxel Before Completing 6 Weeks of Treatment With Either Lapatinib or Trastuzumab	Participants with progressive disease at 4 week assessment that were permitted to commence treatment with paclitaxel.	Week 6
Secondary	Event-free Survival (EFS) - Median Clinical Follow-up	Event free survival (EFS) is defined as the time from randomization to first EFS event. For subjects who had breast cancer surgery, EFS events were post-surgery breast cancer relapse, second primary malignancy or death without recurrence. For subjects who did not have breast cancer surgery, EFS events were death during clinical follow-up or non-completion of any neoadjuvant investigational product due to disease progression.	From randomization up to approximately year 10
Secondary	Event-free Survival (EFS) - Events and Censoring	Event free survival (EFS) is defined as the time from randomization to first EFS event. For subjects who had breast cancer surgery, EFS events were post-surgery breast cancer relapse, second primary malignancy or death without recurrence. For subjects who did not have breast cancer surgery, EFS events were death during clinical follow-up or non-completion of any neoadjuvant investigational product due to disease progression.	From randomization up to approximately year 10
Secondary	Overall Survival (OS) - Median Survival Follow-up	Overall survival is defined as the period from randomization until death (from any cause). OS was assessed annually for up to 10 years after the randomization of the last participant into the study.	From randomization up to approximately year 10
Secondary	Overall Survival (OS) - Deaths and Censoring	Overall survival is defined as the period from randomization until death (from any cause). OS was assessed annually for up to 10 years after the randomization of the last participant into the study.	From randomization up to approximately year 10
Secondary	Assess Associations Between Locoregional Pathological Complete Response (pCR) and Event-free Survival (EFS) - Median Clinical Follow-up (EFS Landmark Population)	The landmark date is 30 weeks after a subject's randomization. Subjects with missing pCR status were not included in the landmark analysis.; Clinical follow-up is the period during which the patient is monitored such that all recurrence or second primary malignancy (SPM) or contralateral breast cancer (CBC) events would be reported. Patients are considered in clinical follow-up from randomisation until one of the following occurs: lost to follow-up, withdrawal of consent, end of follow-up due to completion of year 10 visit, termination of study follow-up, or death.	up to year 10
Secondary	Assess Associations Between Locoregional Pathological Complete Response (pCR) and Event-free Survival (EFS) - Number of Participants With EFS Events (EFS Landmark Population)	The landmark date is 30 weeks after a subject's randomization. Subjects with missing pCR status were not included in the landmark analysis.; For patients who had breast cancer surgery, EFS events are post-surgery breast cancer relapse, second primary malignancy or death without recurrence. For patients who do not undergo breast cancer surgery, EFS events are death during clinical follow-up or non-completion of any neo-adjuvant investigational product due to disease progression or second primary malignancy or contralateral breast cancer.	up to year 10
Secondary	Assess Associations Between Locoregional Pathological Complete Response (pCR) and and Overall Survival (OS) - Median Clinical Follow-up (OS Landmark Population)	The landmark date is 30 weeks after a subject's randomization. Subjects with missing pCR status were not included in the landmark analysis.; Patients are considered in survival follow-up from randomisation until one of the following occurs: lost to follow-up, withdrawal of consent, end of follow-up due to completion of year 10 visit, termination of study follow-up, or death. For subjects with no death recorded in the database, time to death is censored.	up to year 10
Secondary	Assess Associations Between Locoregional Pathological Complete Response (pCR) and and Overall Survival (OS) - Number of Participants Who Died (OS Landmark Population)	The landmark date is 30 weeks after a subject's randomization. Subjects with missing pCR status were not included in the landmark analysis. Includes deaths due to any cause.	up to year 10
Secondary	To Assess Safety Via a Comparison of the Three Treatment Arms - to Measure On-treatment Primary Cardiac Endpoints		Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of 31 weeks.
Secondary	Metabolic Response Rate Determined by Positron Emission Tomography/Computed Tomography (PET/CT)	Metabolic Response Rate determined by Positron Emission Tomography/Computed Tomography (PET/CT)	Week 2 and Week 6
Secondary	Percentage of Participants With the Indicated Biomarker Expression - PIK3CA.	Biomarker levels of phosphatidylinositol 3-kinase (PI3K) catalytic subunit (PIK3CA) were assessed in participants at baseline.	Baseline
Secondary	Percentage of Participants With the Indicated Biomarker Expression - PTEN.	Biomarker levels of phosphate and tensin homolog deleted from chromosome 10 (PTEN) were assessed in participants at baseline.	Baseline
Secondary	Ratio (95% CI) of Geometric Means in p95HER2 Expression in HR Positive Patients With pCR vs no pCR	Ratio (95% CI) of geometric means in p95 human epidermal growth factor receptor (p95HER2) expression in hormone-receptor (HR) positive patients with pathological complete response (pCR) vs no pCR	Baseline
Secondary	Percentage of Participants With Circulating Tumor Cells (CTC) in the Bloodstream	Circulating tumor cells (CTCs) are cells that have detached from a primary tumor and circulate in the bloodstream. In the adjuvant phase, after surgery all participants received 3 courses of adjuvant 5-fluorouracil, epirubicin and cyclophosphamide, followed by lapatinib 1500 mg or trastuzumab 2 mg/kg or lapatinib 1000/750 mg plus trastuzumab 2 mg/kg given prior to surgery in the neoadjuvant setting for an additional 34 weeks.	Measurement performed at one or more of the time points: baseline, week 2 or week 18