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

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborators:
Breast International Group
SOLTI Breast Cancer Research Group
Information provided by (Responsible Party):
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT00553358
First received: November 1, 2007
Last updated: April 24, 2014
Last verified: March 2014
  Purpose

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 will be one year.


Condition Intervention Phase
Neoplasms, Breast
Drug: Lapatinib
Biological: Trastuzumab
Drug: Paclitaxel
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:
  • Number of Participants With Pathological Complete Response (pCR) at the Time of Surgery [ Time Frame: Weeks 20 to 22 ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • Number of Participants With Overall Response at Week 6 [ Time Frame: Week 6 ] [ Designated as safety issue: No ]
    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 lession; progressive disease is defined as a greater than 25% increase in the sum of products of all measurable lesions.

  • Number of Participants With Overall Response at the Time of Surgery [ Time Frame: Time of surgery (Weeks 20 to 22) ] [ Designated as safety issue: No ]
    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 lession; 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) ] [ Designated as safety issue: No ]
    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 absense or presence of distant metastasis.

  • Number of Participants With Actual Indicated Surgery [ Time Frame: At surgery (Weeks 20 to 22) ] [ Designated as safety issue: No ]
    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 quadranectomy/segmentectomy, or a partial mastectomy. Participants who were not assessed as being candidates for non-conservative or conservative surgery were classified as non-operable.

  • Estimate of Treatment Contrast for Change From Baseline in Tumor Size at Week 6 and at Surgery [ Time Frame: Week 6 and surgery (Weeks 20 to 22) ] [ Designated as safety issue: No ]
    Estimate of treatment contrast is defined as the estimate of the difference between treatment groups in the change from baseline 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 ] [ Designated as safety issue: No ]
    Participants with progressive disease at 4 week assessment that were permitted to commence treatment with paclitaxel.

  • Overall Survival [ Time Frame: Following surgery, every 12 months until Year 10 ] [ Designated as safety issue: No ]
    Overall survival was defined as the period from surgery until death (from any cause). Data will be reported when they are mature and available; OS is assessed annually for up to 10 years after the randomization of the last participant into the study.

  • Disease-free Survival (DFS) [ Time Frame: Following surgery, every 12 months until Year 10 ] [ Designated as safety issue: No ]
    DFS was defined as the time from surgery to the first date of breast cancer relapse, second primary tumor (including contralateral breast cancer), or death without documented prior relapse. Data will be reported when they are mature and available, likely when a median of 3 years follow up has been reached.

  • Number of Participants With Metabolic Response of Complete Response (mCR), Partial Response (mPR), or Stable Disease (mSD) as Determined by Positron Emission Tomography/Computed Tomography (PET/CT) [ Time Frame: Baseline, Week 2, and Week 6 ] [ Designated as safety issue: No ]
    European Organisation for Research and Treatment of Cancer recommendations were used to define metabolic response. mCR, complete metabolic response: complete resolution of fludeoxyglucose uptake within tumor, indistinguishable from surrounding normal tissue. mPR, partial metabolic response: reduction of more than 25% of maximum tumor standard uptake value (SUV). mSD, stable metabolic disease: increase of <25% in tumor SUV or decrease of >20% in tumor SUV. mPD, progressive metabolic disease: increase of >25% in tumor SUV or >20% in the extent (longest dimension) or appearance of new metastases.

  • Number of Participants With the Indicated Biomarker Expression [ Time Frame: Baseline, Week 2, and at surgery (Weeks 20 to 22) ] [ Designated as safety issue: No ]
    Biomarker levels (Ki67, p27, Cyclin-D1, ErbB1, ErbB2, ErbB3, pErbB1, pErbB2, Akt and pAkt, S6 and pS6, MAPK and pMAPK, c-myc, IGFR1, p95HER2, PTEN, ER (alpha, beta), PgR,CD34, terminal deoxyneucleotidyl transferase biotin-dUTP nick and labelling technique [TUNEL] and topoisomerase II) were assessed in participants. Blood and tumor tissue samples were collected at Baseline and at Weeks 2 and 20-22; however, data for this outcome measure cannot be presented at this time as they have yet to be evaluated and reviewed.

  • Number of Circulating Tumor Cells (CTC) in the Bloodstream [ Time Frame: Baseline, Week 2 of neo-adjuvant phase (Weeks 1-34), at surgery (Weeks 20 to 22), Week 10 of adjuvant phase, 6 months after completion of adjuvant treatment, and at recurrence ] [ Designated as safety issue: No ]
    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. Data for this outcome measure cannot be presented at this time as they have yet to be evaluated and reviewed.


Enrollment: 455
Study Start Date: January 2008
Estimated Study Completion Date: September 2020
Primary Completion Date: May 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.
Drug: Lapatinib
Small molecule receptor tyrosine kinase inhibitor
Other Name: Lapatinib
Drug: Paclitaxel
antimicrotubule agent
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).
Biological: Trastuzumab
Therapeutic Monoclonal Antibody
Drug: Paclitaxel
antimicrotubule agent
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).
Drug: Lapatinib
Small molecule receptor tyrosine kinase inhibitor
Other Name: Lapatinib
Biological: Trastuzumab
Therapeutic Monoclonal Antibody
Drug: Paclitaxel
antimicrotubule agent

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00553358

  Show 120 Study Locations
Sponsors and Collaborators
GlaxoSmithKline
Breast International Group
SOLTI Breast Cancer Research Group
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline
  More Information

No publications provided by GlaxoSmithKline

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT00553358     History of Changes
Other Study ID Numbers: EGF106903
Study First Received: November 1, 2007
Results First Received: May 26, 2011
Last Updated: April 24, 2014
Health Authority: Spain: Ministry of Health
Lithuania: State Medicine Control Agency - Ministry of Health
Germany: Federal Institute for Drugs and Medical Devices
United States: Food and Drug Administration
United Kingdom: Medicines and Healthcare Products Regulatory Agency

Keywords provided by GlaxoSmithKline:
Early Breast Cancer
Lapatinib
ErbB2+
Neoadjuvant

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasms
Neoplasms by Site
Breast Diseases
Skin Diseases
Paclitaxel
Trastuzumab
Lapatinib
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Protein Kinase Inhibitors
Enzyme Inhibitors

ClinicalTrials.gov processed this record on September 15, 2014