Lapatinib +/- Trastuzumab In Addition To Standard Neoadjuvant Breast Cancer Therapy.

• ClinicalTrials.gov Identifier: NCT00524303
• Recruitment Status: Completed
• First Posted: September 3, 2007
• Results First Posted: August 11, 2011
• Last Update Posted: November 11, 2016
• Sponsor: GlaxoSmithKline
• Information provided by (Responsible Party): GlaxoSmithKline

Study Description

Brief Summary:

This study will examine safety and efficacy of Lapatinib in combination with a standard neoadjuvant chemotherapy including 5FU, Epirubicin, Cyclophosphamide and Paclitaxel. Tumor tissue will be obtained at 3 timepoints (optional 4th) to evaluate tumor response to treatment.

Condition or disease	Intervention/treatment	Phase
Neoplasms, Breast	Drug: Trastuzumab; Drug: Paclitaxel; Drug: FEC75; Drug: Lapatinib	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 100 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Randomized Trial of Neoadjuvant Trastuzumab and/or Lapatinib Plus Chemotherapy (Sequential FEC75 and Paclitaxel) in Women With ErbB2- (HER2/Neu-) Overexpressing Invasive Breast Cancer
• Study Start Date: August 2007
• Actual Primary Completion Date: October 2010
• Actual Study Completion Date: August 2015

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Arm 1; Trastuzumab alone for 2 weeks then in combination with FEC75 for 4 (21 Day) cycles and Paclitaxel for 4 (21 day) cycles then continued trastuzumab until time of definitive surgery	Drug: Trastuzumab; 4mg/kg IV loading dose followed by 2mg/kg IV weekly; Drug: Paclitaxel; 80mg/m2 IV weekly for 4 (21 day) cycles; Drug: FEC75; 5FU 500mg/m2 + Epirubicin 75 mg/m2 + cyclophosphamide 500 mg/m2 IV on day 1 of 4 (21 day) cycles
Experimental: Arm 2; Lapatinib alone for 2 weeks then in combination with FEC75 for 4 (21 Day) cycles followed by Paclitaxel for 4 (21 day) cycles then continued lapatinib until time of definitive surgery	Drug: Paclitaxel; 80mg/m2 IV weekly for 4 (21 day) cycles; Drug: FEC75; 5FU 500mg/m2 + Epirubicin 75 mg/m2 + cyclophosphamide 500 mg/m2 IV on day 1 of 4 (21 day) cycles; Drug: Lapatinib; 1250 mg oral daily dose in arm 2, 750 mg oral daily dose for FEC cycles and then 1000 mg oral daily dose during the Paclitaxel cycles in arm 3
Experimental: Arm 3; Trastuzumab + Lapatinib for 2 weeks then added FEC75 for 4 (21 Day) cycles followed by Paclitaxel for 4 (21 day) cycles then continued trastuzumab + lapatinib until time of definitive surgery	Drug: Trastuzumab; 4mg/kg IV loading dose followed by 2mg/kg IV weekly; Drug: Paclitaxel; 80mg/m2 IV weekly for 4 (21 day) cycles; Drug: FEC75; 5FU 500mg/m2 + Epirubicin 75 mg/m2 + cyclophosphamide 500 mg/m2 IV on day 1 of 4 (21 day) cycles; Drug: Lapatinib; 1250 mg oral daily dose in arm 2, 750 mg oral daily dose for FEC cycles and then 1000 mg oral daily dose during the Paclitaxel cycles in arm 3

Outcome Measures

Primary Outcome Measures :

1. Percentage of Participants With Overall Pathological Complete Response (pCR) After 26 Weeks of Therapy [ Time Frame: Week 26 ]
   A pCR in the breast was defined as no pathologic evidence of invasive disease (residual ductal carcinoma in situ [DCIS] or lobular carcinoma in situ [LCIS] was allowed). A pCR in the axillary lymph node(s) was defined as no evidence of breast cancer cells in the lymph node (including subcapsular sinus). Overall pCR was defined as the sum of pCR in the breast and pCR in the lymph nodes. 26 weeks of therapy comprised the 2-week run-in phase, 12 weeks of treatment with FEC, and 12 weeks of treatment with Paclitaxel.

Secondary Outcome Measures :

1. Percentage of Participants With Clinical Complete Response (cCR) at 26 Weeks or at End of Treatment (EOT) or Early Withdrawal [ Time Frame: Week 26 or EOT or Early withdrawal ]
   cCR was defined as the percentage of participants achieving either a Complete Response (CR) or a Partial Response (PR) using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. CR was defined as the disappearance of all target lesions, and PR was defined as at least a 30% decrease in the sum of the longest diameter (LD) of target lesions taking as reference the baseline sum LD.
2. Percentage of Participants (Par.) With Disease-free Survival (DFS) at the End of 5 Years From Randomization [ Time Frame: From first dose date until disease progression, assessed up to a maximum of 5 years ]
   Percentage is the Kaplan Meier estimate of DFS. DFS is time from randomization until disease recurrence (contralateral breast cancer; second primary cancer; progression during neo-adjuvant treatment; or death from any cause). Par. who experienced progression during treatment and were withdrawn were considered to have a DFS event at withdrawal.
3. Number of Participants With the Indicated Electrocardiogram (ECG) Status at Baseline and at EOT or Early Withdrawal [ Time Frame: Baseline and EOT (up to Week 26) or Early withdrawal ]
   12-lead ECGs were performed, and participants were classified as having normal ECG, abnormal- not clinically significant (NCS) ECG, and abnormal-clinically significant (CS) ECG per investigator opinion and reported result.
4. Cumulative Number of Participants With at Least One Decrease of More Than or Equal to 20% in Left Ventricular Ejection Fraction (LVEF) at the Indicated Time Points Compared to LVEF at Baseline [ Time Frame: Weeks 3, 9, and 15; EOT or early withdrawal; and 3- and 6-month survival follow-up after last chemotherapy course ]
   LVEF is the measurement of how much blood is being pumped out of the left ventricle of the heart (the main pumping chamber) with each contraction and is used to determine cardiac function. LVEF was measured by performing echocardiogram (ECHO). If ECHO could not be performed or if the investigator believed that it was not conclusive to evaluate LVEF, then a multigated acquisition (MUGA) scan was performed.

Other Outcome Measures:

1. Mean Intra-tumoral Expression of the Indicated Proteins at Baseline and Day 14 [ Time Frame: Tumor core biopsy taken at Baseline and Treatment Day 14 ]
   Expression (exp) of biomarker proteins (prot) were analyzed to determine if individual prot levels either in the Baseline or Day 14 breast tumor biopsy specimen correlated with breast pCR. A biomarker indicates a change in exp or state of a prot that correlates with the risk or disease progression, or with the susceptibility of the disease to a given treatment. Biomarkers are characteristic biological properties that can be detected and measured in parts of the body like blood or tissue. pCR=yes: participants (par.) had breast pCR. pCR=no: par. did not have breast pCR. Prot exp values are represented as normalized, scaled values; the unit of measurement is unit-less. Raw exp values were processed as follows: background subtraction of the raw exp value, then that value divided by beta-acting exp to normalize the exp value. A Standard Z score was calculated to scale the exp value.
2. Cancer Stem Cells and the Correlation to Response/Non-response to Treatment [ Time Frame: Tumor core biopsy taken at Baseline and Treatment Day 14 ]
   Stem cell data were of poor quality and thus could not be analyzed. Increases or decreases in cancer stem cells and how the changes correlated with response/non-response to treatment were to have been assessed.
3. Transcriptional Profiling of Total RNA and the Correlation to Response/Non-response to Treatment [ Time Frame: Tumor core biopsy taken at Baseline and Treatment Day 14 ]
   Transcriptional data were of poor quality and thus could not be analyzed. Gene pathways that correlate with response/non-response to treatment were to have been evaluated. The unit of measure is unit less; however, the processed values would be considered normalized relative expression level.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Have signed an informed consent form (ICF) and a Patient Authorization Form (HIPAA).
• Have histologically or cytologically confirmed ErbB2- (HER2/neu-) overexpressing invasive breast cancer (T2-4, N0-2).
• ErbB2 overexpressing breast cancer, defined as one of the following definitions:
• 3+ staining by immunohistochemistry (IHC),
• a fluorescent in situ hybridization (FISH) result of more than six HER2 gene copies per nucleus
• a FISH ratio of more than 2.2.
• Have either measurable or evaluable disease.
• Have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-1 (Refer to Section 11.4).
• Have LVEF within the institutional range of normal as measured by either echocardiogram (ECHO) or MUGA scans. The same modality must be used consistently throughout the study.
• Be deemed able to tolerate 8 cycles of preoperative chemotherapy, including 4 cycles with an anthracycline (epirubicin).
• Must be willing to undergo 2 mandatory core biopsies (4 passes each) after diagnosis to obtain tissue for biologic expression profiling. Any subject with clinically palpable residual disease may undergo an optional third biopsy to allow identification of presumed pathways of resistance to therapy. This information might be useful in providing the subject with options for other targeted therapies if definitive surgery confirms residual disease. Definitive local therapy with surgery and radiation therapy as indicated will be performed after completion of 12 weeks of paclitaxel-based chemotherapy.
• Are able to swallow and retain oral medication (intact pill).
• Are able to complete all screening assessments as outlined in the protocol.
• Have adequate organ function as defined in Table 4:

Table 1 Baseline Laboratory Values

Hematologic:

ANC (absolute neutrophil count) >1.5 x 109/L hemoglobin >9 g/dL platelets >75 x 109/L

Hepatic:

albumin >2.5 g/dL serum bilirubin <1.25 x ULN AST / ALT <3 x ULN if no documented liver metastases AST / ALT <3 x ULN with documented liver metastases

Renal:

serum creatinine <2.0 mg/dL

• OR - calculated creatinine clearance >40 mL/min
• Are subjects aged >18 years with any menopausal status:

Non-child-bearing potential (i.e., women with functioning ovaries who have a current documented tubal ligation or hysterectomy, or women who are postmenopausal)

Child-bearing potential (i.e., women with functioning ovaries and no documented impairment of oviductal or uterine function that would cause sterility.) This category includes women with oligomenorrhea (severe), women who are perimenopausal, and young women who have begun to menstruate. These subjects must have a negative serum pregnancy test at screening and agree to one of the following:

Complete abstinence from intercourse from 2 weeks prior to administration of the first dose of study medication until 28 days after the final dose of study medication; or Consistent and correct use of one of the following acceptable methods of birth control: male partner who is sterile prior to the female subject's entry into the study and is the sole sexual partner for that female subject; any intrauterine device (IUD) with a documented failure rate of less than 1% per year; oral contraceptives (either combined or progestogen only) where not contraindicated for this subject population or per local practice.; or barrier methods, including diaphragm or condom with a spermicide.

Please note that breast cancer subjects on this trial cannot receive injectable levonorgestrel or injectable progestogen due to the potential for an adverse effect of anti-hormonal therapies on chemotherapy administered for breast cancer [Albain, 2002]. Progestogen may also affect the proliferative rate of endocrine-responsive tumors.

Exclusion Criteria:

• Have received any prior chemotherapy.
• Had prior therapy with an ErbB1 and/or ErbB2 inhibitor.
• Are receiving concurrent anti-cancer therapy (chemotherapy, immunotherapy, and biologic therapy) while taking study medication.
• Have malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel. Women with ulcerative colitis are also excluded.
• Have a concurrent disease or condition that would make the woman inappropriate for study participation, or any serious medical disorder that would interfere with the woman's safety.
• Have an active or uncontrolled infection.
• Have dementia, altered mental status, or any psychiatric condition that would prohibit the understanding or rendering of informed consent.
• Have active cardiac disease, defined as one or more of the following:

History of uncontrolled or symptomatic angina History of arrhythmias requiring medications, or clinically significant Myocardial infarction <6 months from study entry Uncontrolled or symptomatic congestive heart failure Ejection fraction below the institutional normal limit Any other cardiac condition, which in the opinion of the treating physician, would make this protocol unreasonably hazardous for the patient

• Are pregnant or breastfeeding.
• Have received concurrent treatment with an investigational agent or participate in another clinical trial.
• Have received concurrent treatment with prohibited medications (refer to Section 5.8.2 for details on prohibited medications).
• Have used an investigational drug within 30 days or 5 half-lives, whichever is longer, preceding the first dose of study medication.
• Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to any of the agents used in this study or their excipients.
• Are receiving therapeutic anti-coagulation therapy (i.e. warfarin, heparin).

Contacts and Locations

Locations

United States, California

GSK Investigational Site

Fountain Valley, California, United States, 92708

GSK Investigational Site

Los Angeles, California, United States, 90057

United States, Colorado

GSK Investigational Site

Denver, Colorado, United States, 80220

United States, Florida

GSK Investigational Site

Hudson, Florida, United States, 34667

GSK Investigational Site

Miami, Florida, United States, 33176

GSK Investigational Site

Pembroke Pines, Florida, United States, 33028

United States, Indiana

GSK Investigational Site

Indianapolis, Indiana, United States, 46219

United States, Nevada

GSK Investigational Site

Henderson, Nevada, United States, 89052

United States, Pennsylvania

GSK Investigational Site

Philadelphia, Pennsylvania, United States, 19107

United States, Texas

GSK Investigational Site

Austin, Texas, United States, 78731

GSK Investigational Site

Beaumont, Texas, United States, 77702-1449

GSK Investigational Site

Bedford, Texas, United States, 76022

GSK Investigational Site

Dallas, Texas, United States, 75231

GSK Investigational Site

Dallas, Texas, United States, 75246

GSK Investigational Site

Dallas, Texas, United States, 75320-2510

GSK Investigational Site

El Paso, Texas, United States, 79915

GSK Investigational Site

Houston, Texas, United States, 77024

GSK Investigational Site

Lewisville, Texas, United States, 75067

GSK Investigational Site

Sugar Land, Texas, United States, 77479

GSK Investigational Site

Tyler, Texas, United States, 75702

United States, Virginia

GSK Investigational Site

Norfolk, Virginia, United States, 23502

United States, Washington

GSK Investigational Site

Seattle, Washington, United States, 98117

GSK Investigational Site

Yakima, Washington, United States, 98902

Sponsors and Collaborators

GlaxoSmithKline

Investigators

• Study Director: GSK Clinical Trials; GlaxoSmithKline

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Holmes FA, Espina V, Liotta LA, Nagarwala YM, Danso M, McIntyre KJ, Osborne CR, Anderson T, Krekow L, Blum JL, Pippen J, Florance A, Mahoney J, O'Shaughnessy JA. Pathologic complete response after preoperative anti-HER2 therapy correlates with alterations in PTEN, FOXO, phosphorylated Stat5, and autophagy protein signaling. BMC Res Notes. 2013 Dec 5;6:507. doi: 10.1186/1756-0500-6-507.

• Responsible Party: GlaxoSmithKline
• ClinicalTrials.gov Identifier: NCT00524303
• Other Study ID Numbers: LPT109096
• First Posted: September 3, 2007
• Results First Posted: August 11, 2011
• Last Update Posted: November 11, 2016
• Last Verified: March 2016

Keywords provided by GlaxoSmithKline:

ErbB2 Overexpressing; ErbB2 Positive; Lapatinib; Invasive Breast Cancer

Additional relevant MeSH terms:

Breast Neoplasms; Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Paclitaxel; Trastuzumab; Lapatinib; Antineoplastic Agents, Phytogenic; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents, Immunological; Protein Kinase Inhibitors; Enzyme Inhibitors