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Neoadjuvant Study With Chemotherapy, Lapatinib And Trastuzumab In Breast Cancer (CHERLOB)

This study has been completed.
Information provided by (Responsible Party):
GlaxoSmithKline Identifier:
First received: January 29, 2007
Last updated: February 22, 2016
Last verified: January 2016
Evaluate the activity of Trastuzumab, Lapatinib, and a combination of both agents with chemotherapy in the preoperative (neoadjuvant) treatment of early breast cancer.

Condition Intervention Phase
Neoplasms, Breast
Drug: lapatinib
Biological: trastuzumab
Drug: paclitaxel
Drug: fluorouracil
Drug: epidoxorubicin
Drug: cyclophosphamide
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Chemotherapy Plus Lapatinib or Trastuzumab or Both in Her2+ Primary Breast Cancer. A Randomized Phase IIb Study With Biomarker Evaluation.

Resource links provided by NLM:

Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:
  • Percentage of Participants With Pathological Complete Response (pCR) in the Breast and in the Lymph Nodes [ Time Frame: At Baseline and surgery (within 5 weeks after the last chemotherapy administration) (assessed up to Study Week 29) ]
    Pathological Complete Response (pCR) is defined by the complete absence of infiltrating tumor cells in the breast and in the lymph nodes. The pathological response in the breast was evaluated according to the criteria of Miller and Payne as follows: Grade 1, no change or some alteration to individual malignant cells, but no reduction in overall cellularity; Grade 2, a minor loss in tumor cells (up to 30%); Grade 3, between an estimated 30% and 90% reduction in tumor cells; Grade 4, marked disappearance of tumor cells, with only a small cluster or a dispersed cell remaining (more than 90% loss); Grade 5, no identifiable malignant cells. Ductal carcinoma in situ (DCIS) may be present. Grades were interpreted as follows: Grade 1-2=no response; Grade 3-4=partial response; Grade 5=complete response. pCR was defined by comparing specimens obtained at Baseline (biopsy) to those obtained upon surgery.

Secondary Outcome Measures:
  • Percentage of Participants With the Indicated Clinical Objective Response (Complete Response and Partial Response), Stable Disease, and Progressive Disease, as Assessed by Ultrasonography [ Time Frame: At Baseline and after primary treatment (within 2 weeks before surgery; up to Study Week 27) ]
    The clinical response was evaluated by comparing the tumor size (largest tumor diameter) before (at Baseline [biopsy]) and after treatment (before surgery), as assessed by ultrasonography examination. The clinical response was scored by Response Evaluation Criteria in Solid Tumors (RECIST) as follows: complete clinical response: the nodule is not detectable and all the ultrasound abnormality detected at diagnosis disappeared (margins circumscribed, round oval shape, parallel orientation, isoechoic echo pattern, no posterior acoustic features, echogenic lesion boundary, and tumor vascularity not present); partial clinical response: the longest diameter of the tumor has been reduced by >50%, and the ultrasound characteristics of the tumor persist; no response (stable disease): the longest diameter of the tumor has been reduced by <50% or has increased by no more than 20% from the starting value; progressive disease: tumor longest diameter has increased >20% from the starting value.

  • Percentage of Participants Who Had Breast-conserving Surgery (BCS), Mastectomy, and Conversion From Mastectomy to BCS [ Time Frame: At Baseline and at surgery (up to Study Week 29) ]
    The percentage of participants who had BCS and mastectomy and who were initiallycandidates for mastectomy and who actually had BCS was measured. At Baseline, the surgeon stated, within 4 weeks before starting the primary treatment, which type of surgical treatment he would perform in the absence of primary therapy and in the case of primary therapy (if the tumor size was reduced by the primary treatment to less than 3 centimeters), and the reasons for these choices. The rules for choosing the type of surgical treatment are reported in the Consensus Conference on Primary Treatment of Early Breast Cancer. The surgeon was to have re-evaluated the participant after primary treatment. In cases in which the type of surgical procedure was different from that originally programmed, the reason for this chance was to have been reported.

  • Time to Treatment Failure From the Start of Primary Therapy [ Time Frame: From randomization up to Study Week 307 ]
    Time to treatment failure (TTF) is defined as the interval of time between the date of randomization and the earliest date of disease progression, premature treatment discontinuation and death due to any cause. The overall disease progression date is the earlier of the two disease progression dates from ultrasonography and mammography assessments. For ultrasonography, disease progression is defined as at least 20% increase in the longest diameter of the primary lesion at pre-surgery comparing to Baseline. For mammography, disease progression is defined as at least 20% increase in the larger nodule dimension at pre-surgery comparing to Baseline. For participants who has neither progressed, pre-maturely withdrawn or died, time to treatment failure will be censored at the latest date of ultrasonography and mammography tumor assessments.

  • Number of Participants With Treatment Failure [ Time Frame: From randomization up to 29 weeks ]
    Treatment failure is defined as the occurrence of local tumor progression (including ipsilateral and controlateral breast), distant tumor progression, permanent treatment discontinuation (either for the experimental or conventional arm), or death due to any cause.

  • Percentage of Inhibition of Biomarkers Ki67, pAKT, pMAPK, Tunel Test, PTEN, and pEGFR After Treatment [ Time Frame: At Baseline and Withdrawal (assessed up to Study Week 29) ]
    The percentage of inhibition of intermediate (EGFR, HER2, pMAPK, pAKT, PTEN, and PI3KCA) and final (TUNEL and Ki67) biomarkers of the proliferation and apoptosis pathways was calculated as the difference between the staining scores before (Baseline [biopsy]) and after treatment (withdrawal).

  • Number of Participants With Any Adverse Event (AE), Including Serious Adverse Events (SAEs), Occurring in >=5% of Participants [ Time Frame: From the first dose of randomized therapy to 30 days after the last dose of randomized therapy (assessed up to Study Week 29) ]
    An AE is defined as any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect. Medical or scientific judgment had been exercised in deciding whether reporting was appropriate in other situations.

  • Number of Variations/Somatic Mutation in PI3KCA at Baseline [ Time Frame: Baseline ]
    Analysis of mutations in the PI3KCA gene was performed from RNA extracted from frozen tumor tissue samples (sections). A gene is either a wild-type (no mutation) or mutated (presence of a mutation). Exons 9 and 20 of the PI3KCA gene were accessed (high frequency mutation at these two spots).

Enrollment: 121
Study Start Date: August 2006
Study Completion Date: June 2012
Primary Completion Date: June 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Arm A
Chemotherapy plus trastuzumab
Biological: trastuzumab
First dose 4mg/kg in 60mins, then weekly 2mg/kg in 30 mins
Other Name: Herceptin
Drug: paclitaxel
80mg/sqm 1 hour infusion for 12 weeks
Other Name: Taxol
Drug: fluorouracil
600mg/sqm iv day 1 q21 days for four coursess
Drug: epidoxorubicin
75mg/sqm iv day 1 q21 days for four courses
Drug: cyclophosphamide
600mg/sqm day 1 q21 days for four courses
Experimental: Arm B
Chemotherapy plus lapatinib
Drug: lapatinib
Arm B 1250mg/d PO Arm C 750mg/d PO
Other Name: Tyverb/Tykerb
Drug: paclitaxel
80mg/sqm 1 hour infusion for 12 weeks
Other Name: Taxol
Drug: fluorouracil
600mg/sqm iv day 1 q21 days for four coursess
Drug: epidoxorubicin
75mg/sqm iv day 1 q21 days for four courses
Drug: cyclophosphamide
600mg/sqm day 1 q21 days for four courses
Active Comparator: Arm C
Chemotherapy plus trastuzumab plus lapatinib
Drug: lapatinib
Arm B 1250mg/d PO Arm C 750mg/d PO
Other Name: Tyverb/Tykerb
Biological: trastuzumab
First dose 4mg/kg in 60mins, then weekly 2mg/kg in 30 mins
Other Name: Herceptin
Drug: paclitaxel
80mg/sqm 1 hour infusion for 12 weeks
Other Name: Taxol
Drug: fluorouracil
600mg/sqm iv day 1 q21 days for four coursess
Drug: epidoxorubicin
75mg/sqm iv day 1 q21 days for four courses
Drug: cyclophosphamide
600mg/sqm day 1 q21 days for four courses


Ages Eligible for Study:   18 Years to 65 Years   (Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No

Inclusion criteria:

  • Histologically confirmed infiltrating primary breast cancer of > 2.0 cm in largest clinical diameter

HER2 positive tumor (either IHC 3+ or FISH+)

  • Availability of tumor tissue suitable for biological and molecular examination before starting primary treatment
  • Age >18, < 65 years
  • ECOG PS 0-1
  • Normal organ and marrow function as defined below:

leukocytes ³ 3000/microL

absolute neutrophil count ³ 1,500/microL

platelets ³ 100,000/microL

total bilirubin <= 1.5x ULN. In case of Gilbert's syndrome, <2 x ULN is allowed

AST (SGOT)/ALT(SGPT)<= 2.5 X institutional upper limit of normal

Alkaline phosphatase <= 2.5 x ULN

Creatinine within normal institutional limits

  • Cardiac ejection fraction within the institutional range of normal as measured by echocardiogram or MUGA scan
  • Eligibility of patients receiving medications or substances known to affect, or with the potential to affect the activity or pharmacokinetics of lapatinib will be determined following review of their use by the Principal Investigator. A list of medications and substances known or with the potential to interact with CYP450 isoenzymes is provided
  • The effects of lapatinib on the developing human fetus at the recommended therapeutic dose are unknown; women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control or abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately, the patient should be apprised of the potential hazard to the fetus and potential risk for loss of the pregnancy
  • Ability to understand and the willingness to sign a written informed consent document
  • Ability to swallow and retain oral medication

Exclusion criteria:

  • Stage IIIB, IIIC, and inflammatory breast cancer
  • Stage IV breast cancer
  • Contraindication to the treatment with anthracycline, paclitaxel and/or trastuzumab
  • Prior treatment with chemotherapy, endocrine therapy or radiotherapy. Prior treatment with EGFR targeting therapies
  • Treatment with any other investigational agents, or with all herbal (alternative) medicines
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to lapatinib
  • Uncontrolled inter-current illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
  • Pregnancy or breastfeeding; (breast feeding should be discontinued to be enrolled in the study)
  • Women of childbearing potential that refusal to adopt adequate contraceptive measures
  • HIV-positive patients receiving combination anti-retroviral therapy
  • GI tract disease resulting in an inability to take oral medication, malabsorption syndrome, a requirement for IV alimentation, prior surgical procedures affecting absorption, uncontrolled inflammatory GI disease (e.g., Crohn's, ulcerative colitis)
  • Concomitant requirement for medication classified as CYP3A4 inducers or inhibitors
  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 identifier: NCT00429299

GSK Investigational Site
Berlin, Germany, 13125
GSK Investigational Site
Carpi (MO), Emilia-Romagna, Italy, 41012
GSK Investigational Site
Forlì, Emilia-Romagna, Italy, 47100
GSK Investigational Site
Modena, Emilia-Romagna, Italy, 41100
GSK Investigational Site
Parma, Emilia-Romagna, Italy, 43100
GSK Investigational Site
Piacenza, Emilia-Romagna, Italy, 29100
GSK Investigational Site
Rimini, Emilia-Romagna, Italy, 47900
GSK Investigational Site
Treviglio (BG), Lombardia, Italy, 24047
GSK Investigational Site
Candiolo (TO), Piemonte, Italy, 10060
GSK Investigational Site
Brindisi, Puglia, Italy, 72100
GSK Investigational Site
Pisa, Toscana, Italy, 56126
GSK Investigational Site
Cremona, Italy, 26100
GSK Investigational Site
Pavia, Italy, 27100
GSK Investigational Site
Perugia, Italy, 06156
GSK Investigational Site
Reggio Emilia, Italy, 42100
GSK Investigational Site
Varese, Italy, 21100
GSK Investigational Site
Warszawa, Poland, 00-909
Sponsors and Collaborators
Study Director: GSK Clinical Trials GlaxoSmithKline
  More Information

Publications automatically indexed to this study by Identifier (NCT Number):
Responsible Party: GlaxoSmithKline Identifier: NCT00429299     History of Changes
Other Study ID Numbers: EGF106988
Study First Received: January 29, 2007
Results First Received: July 21, 2014
Last Updated: February 22, 2016

Keywords provided by GlaxoSmithKline:
neo-adjuvant trastuzumab early breast cancer lapatinib

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasms by Site
Breast Diseases
Skin Diseases
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antimetabolites, Antineoplastic
Protein Kinase Inhibitors
Enzyme Inhibitors
Antibiotics, Antineoplastic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors processed this record on May 23, 2017