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

NCT ID: NCT00524303

Last Updated: 2016-11-11

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 100 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2007-08-31
• Study Completion Date: 2015-08-31

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.

Conditions

Neoplasms, Breast

Keywords

ErbB2 Overexpressing; ErbB2 Positive; Lapatinib; Invasive Breast Cancer

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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

Group Type: ACTIVE_COMPARATOR

Trastuzumab

Intervention Type: DRUG

4mg/kg IV loading dose followed by 2mg/kg IV weekly

Paclitaxel

Intervention Type: DRUG

80mg/m2 IV weekly for 4 (21 day) cycles

FEC75

Intervention Type: DRUG

5FU 500mg/m2 + Epirubicin 75 mg/m2 + cyclophosphamide 500 mg/m2 IV on day 1 of 4 (21 day) cycles

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

Group Type: EXPERIMENTAL

Paclitaxel

Intervention Type: DRUG

80mg/m2 IV weekly for 4 (21 day) cycles

FEC75

Intervention Type: DRUG

5FU 500mg/m2 + Epirubicin 75 mg/m2 + cyclophosphamide 500 mg/m2 IV on day 1 of 4 (21 day) cycles

Lapatinib

Intervention Type: DRUG

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

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

Group Type: EXPERIMENTAL

Trastuzumab

Intervention Type: DRUG

4mg/kg IV loading dose followed by 2mg/kg IV weekly

Paclitaxel

Intervention Type: DRUG

80mg/m2 IV weekly for 4 (21 day) cycles

FEC75

Intervention Type: DRUG

5FU 500mg/m2 + Epirubicin 75 mg/m2 + cyclophosphamide 500 mg/m2 IV on day 1 of 4 (21 day) cycles

Lapatinib

Intervention Type: DRUG

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

Interventions

Trastuzumab

4mg/kg IV loading dose followed by 2mg/kg IV weekly

Intervention Type: DRUG

Paclitaxel

80mg/m2 IV weekly for 4 (21 day) cycles

Intervention Type: DRUG

FEC75

5FU 500mg/m2 + Epirubicin 75 mg/m2 + cyclophosphamide 500 mg/m2 IV on day 1 of 4 (21 day) cycles

Intervention Type: 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

Intervention Type: DRUG

Eligibility 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).

• Minimum Eligible Age: 18 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

GlaxoSmithKline

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

GSK Clinical Trials

Role: STUDY_DIRECTOR

GlaxoSmithKline

Locations

GSK Investigational Site

Fountain Valley, California, United States

GSK Investigational Site

Los Angeles, California, United States

GSK Investigational Site

Denver, Colorado, United States

GSK Investigational Site

Hudson, Florida, United States

GSK Investigational Site

Miami, Florida, United States

GSK Investigational Site

Pembroke Pines, Florida, United States

GSK Investigational Site

Indianapolis, Indiana, United States

GSK Investigational Site

Henderson, Nevada, United States

GSK Investigational Site

Philadelphia, Pennsylvania, United States

GSK Investigational Site

Austin, Texas, United States

GSK Investigational Site

Beaumont, Texas, United States

GSK Investigational Site

Bedford, Texas, United States

GSK Investigational Site

Dallas, Texas, United States

GSK Investigational Site

Dallas, Texas, United States

GSK Investigational Site

Dallas, Texas, United States

GSK Investigational Site

El Paso, Texas, United States

GSK Investigational Site

Houston, Texas, United States

GSK Investigational Site

Lewisville, Texas, United States

GSK Investigational Site

Sugar Land, Texas, United States

GSK Investigational Site

Tyler, Texas, United States

GSK Investigational Site

Norfolk, Virginia, United States

GSK Investigational Site

Seattle, Washington, United States

GSK Investigational Site

Yakima, Washington, United States

Countries

United States

References

O'Shea J, Cremona M, Morgan C, Milewska M, Holmes F, Espina V, Liotta L, O'Shaughnessy J, Toomey S, Madden SF, Carr A, Elster N, Hennessy BT, Eustace AJ. A preclinical evaluation of the MEK inhibitor refametinib in HER2-positive breast cancer cell lines including those with acquired resistance to trastuzumab or lapatinib. Oncotarget. 2017 Jul 22;8(49):85120-85135. doi: 10.18632/oncotarget.19461. eCollection 2017 Oct 17.

Reference Type: DERIVED

PMID: 29156708 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 24304724 (View on PubMed)

Other Identifiers

LPT109096

Identifier Type: -

Identifier Source: org_study_id