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

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ClinicalTrials.gov Identifier: NCT00553358
Recruitment Status : Completed
First Posted : November 4, 2007
Results First Posted : October 13, 2011
Last Update Posted : June 3, 2021
Sponsor:
Collaborators:
Breast International Group
SOLTI Breast Cancer Research Group
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Tracking Information
First Submitted Date  ICMJE November 1, 2007
First Posted Date  ICMJE November 4, 2007
Results First Submitted Date  ICMJE May 26, 2011
Results First Posted Date  ICMJE October 13, 2011
Last Update Posted Date June 3, 2021
Actual Study Start Date  ICMJE January 5, 2008
Actual Primary Completion Date May 27, 2010   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 12, 2011)
Number of Participants With Pathological Complete Response (pCR) at the Time of Surgery [ Time Frame: Weeks 20 to 22 ]
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.
Original Primary Outcome Measures  ICMJE
 (submitted: November 1, 2007)
-Rate of pCR at the time of surgery (18 weeks) The planned total duration of the anti-HER2 therapy will be one year. [ Time Frame: The planned total duration of the anti-HER2 therapy will be one year ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 22, 2021)
  • Number of Participants With Overall Response at Week 6 [ Time Frame: 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.
  • Overall Response at the Time of Surgery [ Time Frame: Time of surgery (Weeks 20 to 22) ]
    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.
  • Number of Participants With Negative Lymph Nodes at the Time of Surgery [ Time Frame: Time of surgery (Weeks 20 to 22) ]
    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.
  • Number of Participants With Actual Indicated Surgery [ Time Frame: At surgery (Weeks 20 to 22) ]
    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.
  • Mean Change From Baseline in Tumor Size at Week 6 and at Surgery [ Time Frame: Week 6 and surgery (Weeks 20 to 22) ]
    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.
  • Number of Participants Starting Paclitaxel Before Completing 6 Weeks of Treatment With Either Lapatinib or Trastuzumab [ Time Frame: Week 6 ]
    Participants with progressive disease at 4 week assessment that were permitted to commence treatment with paclitaxel.
  • Event-free Survival (EFS) - Median Clinical Follow-up [ Time Frame: From randomization up to approximately year 10 ]
    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.
  • Event-free Survival (EFS) - Events and Censoring [ Time Frame: From randomization up to approximately year 10 ]
    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.
  • Overall Survival (OS) - Median Survival Follow-up [ Time Frame: From randomization up to approximately year 10 ]
    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.
  • Overall Survival (OS) - Deaths and Censoring [ Time Frame: From randomization up to approximately year 10 ]
    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.
  • Assess Associations Between Locoregional Pathological Complete Response (pCR) and Event-free Survival (EFS) - Median Clinical Follow-up (EFS Landmark Population) [ Time Frame: up to year 10 ]
    The landmark date is 30 weeks after a subject's randomization. Subjects with missing pCR status were not included in the landmark analysis
  • Assess Associations Between Locoregional Pathological Complete Response (pCR) and Event-free Survival (EFS) - Number of Participants With EFS Events (EFS Landmark Population) [ Time Frame: up to year 10 ]
    The landmark date is 30 weeks after a subject's randomization. Subjects with missing pCR status were not included in the landmark analysis
  • Assess Associations Between Locoregional Pathological Complete Response (pCR) and and Overall Survival (OS) - Median Clinical Follow-up (OS Landmark Population) [ Time Frame: up to year 10 ]
    The landmark date is 30 weeks after a subject's randomization. Subjects with missing pCR status were not included in the landmark analysis
  • Assess Associations Between Locoregional Pathological Complete Response (pCR) and and Overall Survival (OS) - Number of Participants With OS Events (OS Landmark Population) [ Time Frame: up to year 10 ]
    The landmark date is 30 weeks after a subject's randomization. Subjects with missing pCR status were not included in the landmark analysis
  • To Assess Safety Via a Comparison of the Three Treatment Arms - to Measure On-treatment Primary Cardiac Endpoints [ Time Frame: 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. ]
  • Metabolic Response Rate Determined by Positron Emission Tomography/Computed Tomography (PET/CT) [ Time Frame: Week 2 and Week 6 ]
    Metabolic Response Rate determined by Positron Emission Tomography/Computed Tomography (PET/CT)
  • Percentage of Participants With the Indicated Biomarker Expression - PIK3CA. [ Time Frame: Baseline ]
    Biomarker levels of phosphatidylinositol 3-kinase (PI3K) catalytic subunit (PIK3CA) were assessed in participants at baseline.
  • Percentage of Participants With the Indicated Biomarker Expression - PTEN. [ Time Frame: Baseline ]
    Biomarker levels of phosphate and tensin homolog deleted from chromosome 10 (PTEN) were assessed in participants at baseline.
  • Ratio (95% CI) of Geometric Means in p95HER2 Expression in HR Positive Patients With pCR vs no pCR [ Time Frame: Baseline ]
    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
  • Percentage of Participants With Circulating Tumor Cells (CTC) in the Bloodstream [ Time Frame: Measurement performed at one or more of the time points: baseline, week 2 or week 18 ]
    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.
Original Secondary Outcome Measures  ICMJE
 (submitted: November 1, 2007)
(from randomisation out to 10 years) -safety and tolerability -objective response rate -% patients with node-negative disease at surgery -conversion to breast conservation -(DFS)(OS) -biomarkers -PET/CT [ Time Frame: The planned total duration of the anti-HER2 therapy will be one year ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Neo ALTTO (Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimisation) Study
Official Title  ICMJE 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
Brief 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.

Detailed 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Neoplasms, Breast
Intervention  ICMJE
  • Drug: Lapatinib
    Small molecule receptor tyrosine kinase inhibitor
  • Biological: Trastuzumab
    Therapeutic Monoclonal Antibody
  • Drug: Paclitaxel
    antimicrotubule agent
Study Arms  ICMJE
  • Experimental: Arm 1 Lapatinib
    1500 mg lapatinib for 6 weeks followed by lapatinib plus weekly paclitaxel for an additional 12 weeks. After definitive surgery, 3 cycles of adjuvant FEC followed by 34 weeks of adjuvant lapatinib.
    Interventions:
    • Drug: Lapatinib
    • Drug: Paclitaxel
  • Active Comparator: Arm 2 Trastuzumab
    4 mg/kg IV loading dose followed by 2 mg/kg IV weekly trastuzumab for 6 weeks followed by 2 mg/kg trastuzumab plus weekly paclitaxel for an additional 12 weeks. After definitive surgery, 3 cycles of adjuvant FEC followed by 34 weeks of adjuvant trastuzumab (8 mg/kg loading dose followed by 6 mg/kg every 3 weeks).
    Interventions:
    • Biological: Trastuzumab
    • Drug: Paclitaxel
  • Experimental: Arm 3 Lapatinib plus Trastuzumab
    1000 mg lapatinib plus 4 mg/kg IV loading dose followed by 2 mg/kg IV weekly trastuzumab for 6 weeks, followed by 750 mg lapatinib plus 2 mg/kg IV weekly trastuzumab plus weekly paclitaxel for an additional 12 weeks. After definitive surgery, 3 cycles of adjuvant FEC followed by 34 weeks of adjuvant lapatinib (1000 mg) in combination with trastuzumab (8 mg/kg loading dose followed by 6 mg/kg every 3 weeks).
    Interventions:
    • Drug: Lapatinib
    • Biological: Trastuzumab
    • Drug: Paclitaxel
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: October 14, 2010)
455
Original Estimated Enrollment  ICMJE
 (submitted: November 1, 2007)
450
Actual Study Completion Date  ICMJE December 23, 2019
Actual Primary Completion Date May 27, 2010   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE 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
Removed Location Countries Czech Republic,   Greece,   Israel,   Portugal
 
Administrative Information
NCT Number  ICMJE NCT00553358
Other Study ID Numbers  ICMJE EGF106903
2006-000564-81 ( EudraCT Number )
CLAP016B2302 ( Other Identifier: Novartis )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description:

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com.

URL: https://www.clinicalstudydatarequest.com/
Responsible Party Novartis ( Novartis Pharmaceuticals )
Study Sponsor  ICMJE Novartis Pharmaceuticals
Collaborators  ICMJE
  • Breast International Group
  • SOLTI Breast Cancer Research Group
Investigators  ICMJE
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
PRS Account Novartis
Verification Date May 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP