Clinical trial NCT00429299: Neoadjuvant Study With Chemotherapy, Lapatinib And Trastuzumab In Breast Cancer
Official title: Chemotherapy Plus Lapatinib or Trastuzumab or Both in Her2+ Primary Breast Cancer. A Randomized Phase IIb Study With Biomarker Evaluation.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Neoplasms, Breast
Keywords: neo-adjuvant trastuzumab early breast cancer lapatinib
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2007-01-31
Enrollment: 121
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Evaluate the activity of Trastuzumab, Lapatinib, and a combination of both agents with chemotherapy in the preoperative (neoadjuvant) treatment of early breast cancer.


Eligibility criteria: 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

Primary outcomes:
measure: Percentage of Participants With Pathological Complete Response (pCR) in the Breast and in the Lymph Nodes
timeFrame: At Baseline and surgery (within 5 weeks after the last chemotherapy administration) (assessed up to Study Week 29)
Secondary outcomes:
measure: Percentage of Participants With the Indicated Clinical Objective Response (Complete Response and Partial Response), Stable Disease, and Progressive Disease, as Assessed by Ultrasonography
timeFrame: At Baseline and after primary treatment (within 2 weeks before surgery; up to Study Week 27)
measure: Percentage of Participants Who Had Breast-conserving Surgery (BCS), Mastectomy, and Conversion From Mastectomy to BCS
timeFrame: At Baseline and at surgery (up to Study Week 29)
measure: Time to Treatment Failure From the Start of Primary Therapy
timeFrame: From randomization up to Study Week 307
measure: Number of Participants With Treatment Failure
timeFrame: From randomization up to 29 weeks
measure: Percentage of Inhibition of Biomarkers Ki67, pAKT, pMAPK, Tunel Test, PTEN, and pEGFR After Treatment
timeFrame: At Baseline and Withdrawal (assessed up to Study Week 29)
measure: Number of Participants With Any Adverse Event (AE), Including Serious Adverse Events (SAEs), Occurring in >=5% of Participants
timeFrame: From the first dose of randomized therapy to 30 days after the last dose of randomized therapy (assessed up to Study Week 29)
measure: Number of Variations/Somatic Mutation in PI3KCA at Baseline
timeFrame: Baseline
Other outcomes:
Locations:
city: Berlin
country: Germany
facility: GSK Investigational Site
city: Carpi (MO)
country: Italy
facility: GSK Investigational Site
state: Emilia-Romagna
city: Forlì
country: Italy
facility: GSK Investigational Site
state: Emilia-Romagna
city: Modena
country: Italy
facility: GSK Investigational Site
state: Emilia-Romagna
city: Parma
country: Italy
facility: GSK Investigational Site
state: Emilia-Romagna
city: Piacenza
country: Italy
facility: GSK Investigational Site
state: Emilia-Romagna
city: Rimini
country: Italy
facility: GSK Investigational Site
state: Emilia-Romagna
city: Treviglio (BG)
country: Italy
facility: GSK Investigational Site
state: Lombardia
city: Candiolo (TO)
country: Italy
facility: GSK Investigational Site
state: Piemonte
city: Brindisi
country: Italy
facility: GSK Investigational Site
state: Puglia
city: Pisa
country: Italy
facility: GSK Investigational Site
state: Toscana
city: Cremona
country: Italy
facility: GSK Investigational Site
city: Pavia
country: Italy
facility: GSK Investigational Site
city: Perugia
country: Italy
facility: GSK Investigational Site
city: Reggio Emilia
country: Italy
facility: GSK Investigational Site
city: Varese
country: Italy
facility: GSK Investigational Site
city: Warszawa
country: Poland
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Guarneri V, Frassoldati A, Bottini A, Cagossi K, Bisagni G, Sarti S, Ravaioli A, Cavanna L, Giardina G, Musolino A, Untch M, Orlando L, Artioli F, Boni C, Generali DG, Serra P, Bagnalasta M, Marini L, Piacentini F, D'Amico R, Conte P. Preoperative chemotherapy plus trastuzumab, lapatinib, or both in human epidermal growth factor receptor 2-positive operable breast cancer: results of the randomized phase II CHER-LOB study. J Clin Oncol. 2012 Jun 1;30(16):1989-95. doi: 10.1200/JCO.2011.39.0823. Epub 2012 Apr 9.
citation: Guarneri V, Dieci MV, Griguolo G, Miglietta F, Girardi F, Bisagni G, Generali DG, Cagossi K, Sarti S, Frassoldati A, Gianni L, Cavanna L, Pinotti G, Musolino A, Piacentini F, Cinieri S, Prat A, Conte P; of the CHER-Lob study team. Trastuzumab-lapatinib as neoadjuvant therapy for HER2-positive early breast cancer: Survival analyses of the CHER-Lob trial. Eur J Cancer. 2021 Aug;153:133-141. doi: 10.1016/j.ejca.2021.05.018. Epub 2021 Jun 19.
citation: Guarneri V, Dieci MV, Frassoldati A, Maiorana A, Ficarra G, Bettelli S, Tagliafico E, Bicciato S, Generali DG, Cagossi K, Bisagni G, Sarti S, Musolino A, Ellis C, Crescenzo R, Conte P. Prospective Biomarker Analysis of the Randomized CHER-LOB Study Evaluating the Dual Anti-HER2 Treatment With Trastuzumab and Lapatinib Plus Chemotherapy as Neoadjuvant Therapy for HER2-Positive Breast Cancer. Oncologist. 2015 Sep;20(9):1001-10. doi: 10.1634/theoncologist.2015-0138. Epub 2015 Aug 5.
citation: Guarneri V, Generali DG, Frassoldati A, Artioli F, Boni C, Cavanna L, Tagliafico E, Maiorana A, Bottini A, Cagossi K, Bisagni G, Piacentini F, Ficarra G, Bettelli S, Roncaglia E, Nuzzo S, Swaby R, Ellis C, Holford C, Conte P. Double-blind, placebo-controlled, multicenter, randomized, phase IIb neoadjuvant study of letrozole-lapatinib in postmenopausal hormone receptor-positive, human epidermal growth factor receptor 2-negative, operable breast cancer. J Clin Oncol. 2014 Apr 1;32(10):1050-7. doi: 10.1200/JCO.2013.51.4737. Epub 2014 Mar 3.