Evaluation of Biomarkers Associated With Response to Subsequent Therapies in Subjects With HER2-Positive Metastatic Breast Cancer
Condition: Neoplasms, Breast
MeSH terms: Breast Neoplasms
Intervention: Lapatinib; Trastuzumab; Aromatase Inhibitors (AIs)
Intervention description: Lapatinib is available as 250-mg orange tablets. Subjects randomized to the Lapatinib plus Trastuzumab arm received 1000 mg per day of Lapatinib, so wre instructed to take 4 x 250 mg tablets per day. Lapatinib was to be taken either 1 hour (or more) before a meal or 1 hour (or more) after a meal; Trastuzumab is a sterile, white to pale yellow, preservative-free lyophilized powder for IV administration. Trastuzumab was administered on Day 1 of the start of Lapatinib or in conjunction with the first cycle of chemotherapy, as an 8 mg/kg loading dose. Subsequently, Trastuzumab was administered q3weekly as a 6 mg/kg maintenance dose. At the discretion of the investigator, weekly Trastuzumab could be given in either of the three treatment arms (loading dose 4mg/kg followed by weekly administration of 2mg/kg).; Subjects who were hormone receptor-positive were required to receive an aromatase inhibitor as combination treatment; however the choice of the aromatase inhibitor selected for each patient was determined by the patients' investigator. The AIs the Investigator could choose from were anastrozole, exemestane, and letrozole and dosing was per product information.
Intervention MeSH terms: Trastuzumab; Lapatinib; Aromatase Inhibitors
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Participants were randomized to Arms A and B but randomized to Arm C.
Masking: None (Open Label)
Masking description: This was a two-cohort, three-arm, open-label Phase II study to evaluate the changes in the expression of biomarkers between pre-treatment and progression biopsy in subjects with Human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. Subjects were allocated to 1 of 2 cohorts depending on the molecular subtype of their biopsy.
Cohort 1 HER2 -enriched included HER2-positive subjects with a HER2-Enriched molecular subtype, and were randomized in a 1:1 ratio to receive either trastuzumab in combination with lapatinib (Arm A) or trastuzumab in combination with chemotherapy (Arm B).
Cohort 2 non-HER2-enriched, included HER2-positive subjects with luminal A, luminal B, and basal-like molecular subtypes and were to receive trastuzumab in combination with lapatinib (Arm C). Subjects with hormone receptor (ER and/or PgR)-positive MBC in this arm were required to be treated with an AI of the Investigator's choice.
Enrollment: 42.0
Sex: Female
Minimum age: 18 Years
Healthy volunteers: No
Keywords: CLAP016A2206; biomarker; Lapatinib; Prosigna; ErbB2; PAM50; HER2; HER2-overexpressing metastatic breast cancer; HER2-enriched; Trastuzumab

Summary:

      This was a multicenter, open-label, Phase II study in subjects with Human epidermal growth
      factor receptor (HER2)-positive metastatic breast cancer who received at least 2 prior lines
      of anti-HER2-targeted therapies of which at least one included a Trastuzumab-containing
      regimen. This study was a post-approval commitment with regulatory authorities. It was
      designed to evaluate whether treatment with Dual blockade promoted changes to biomarkers
      associated with immunomodulation.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Signed written informed consent

          -  Female >=18 years

          -  Histologically or cytologically confirmed invasive breast cancer with distant
             metastasis

          -  Subjects must have at least one measurable lesion per RECIST 1.1

          -  Note: Biopsied lesions should not be used as target lesions.

          -  Documentation of HER2 overexpression or gene amplification, in the invasive component
             of either the primary tumor or metastatic disease site as defined as: 3+ by
             Immunohistochemistry (IHC) and/or

          -  HER2/neu gene amplification by fluorescence, chromogenic, or silver in situ
             hybridization [FISH, CISH or SISH;>=6 HER2/neu gene copies per nucleus or a FISH,
             CISH, or SISH test ratio (HER2 gene copies to chromosome 17 signals) of >=2.0 OR
             HER2/chromosome 17 ratio <=2.0 with average HER2 copy number >=6 signals/cell nucleus]

          -  Centrally determined HER2-positive, hormone receptor status, breast molecular subtype
             by Prediction Analysis of Microarray 50 (PAM50) on the pre-treatment biopsy of
             metastatic lesion obtained during screening

          -  Note: Biopsied lesions should not be used as target lesions.

          -  Progression on at least 2 lines of anti-HER2-targeted therapies for metastatic breast
             cancer (MBC)

          -  Documented radiological disease progression during the most recent treatment regimen
             for metastatic disease

          -  Most recent treatment regimen for metastatic disease must include Trastuzumab and
             chemotherapy.

          -  Note: Trastuzumab emtansine (T-DM1) is considered acceptable as prior
             Trastuzumab/chemotherapy regimen

          -  Agreement to provide 2 tumor biopsies

          -  Prior treatment with pertuzumab, Lapatinib, and/or Trastuzumab emtansine is allowed;
             however, the last treatment for MBC must not include Trastuzumab in combination with
             pertuzumab.

          -  Subjects with radiographically stable Central nervous system (CNS) metastases, defined
             as radiographically stable on the previous 2 brain imaging scans, asymptomatic, and
             off systemic steroids and anticonvulsants for at least 1 month are eligible; treatment
             with prophylactic anticonvulsants is permitted unless listed under Prohibited
             Medications

          -  Discontinuation of all prior chemotherapy, immunotherapy, or biological therapy at
             least 3 weeks prior to the first dose of investigational product is required.

          -  Note: Discontinuation of Trastuzumab is not necessary.

          -  All treatment related toxicities, except alopecia, must have recovered to Grade 1 or
             better (Common Terminology Criteria for Adverse Events (CTCAE); version 4.0) prior to
             administration of the first dose of study treatment.

          -  Baseline Left ventricular ejection fraction (LVEF) >=50% as measured by Echocardiogram
             (ECHO) or Multigated acquisition (MUGA) and above the testing institution's lower
             limit of normal

          -  QT interval corrected (QTc) <450 millisecond (msec) or QTc <480 msec for patients with
             bundle branch block.

          -  The QTc is the QT interval corrected for heart rate according to either Bazett's
             formula (QTcB)

          -  Fridericia's formula (QTcF), or another method, machine or manual overread.

          -  For subject eligibility and withdrawal, QT correction formula QTcB will be used.

          -  For purposes of this data analysis, Bazett's formula will be used as the primary
             method of calculating the corrected QT interval. The QTc should be based on either a
             single Electrocardiogram (ECG) or an average of 3 sequential ECGs obtained within 24
             hours of each other.

          -  The QTc should be based on single or averaged QTc values of triplicate ECGs obtained
             over a brief recording period.

          -  Women of childbearing potential must have a negative serum pregnancy test within 7
             days prior to the first dose of study treatment and agree to use effective
             contraception, during the study and for 30 days following the last dose of study
             treatment.

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

          -  Completion of screening and baseline assessments

          -  Able to swallow and retain orally administered medication and does not have any
             clinically significant gastrointestinal abnormalities that may alter absorption such
             as malabsorption syndrome or major resection of the stomach or bowels.

          -  At least 4 weeks must have elapsed since the last surgery and 2 weeks must have
             elapsed since radiotherapy

          -  Adequate baseline organ function as defined below

          -  Screening laboratory values should be used to confirm subject eligibility. Laboratory
             results may be retested if necessary to confirm eligibility.

          -  Hematologic(These values must be independent of growth factor support and stable for
             at least one week post transfusion)

          -  Absolute neutrophil count >=1.5 x 10^9/litre (L)

          -  Hemoglobin >=9.0 grams/decilitre(g/dL) (after transfusion if needed)

          -  Platelets>=100 x 10^9/L

          -  Hepatic

          -  Albumin >=2.5 g/dL

          -  Serum bilirubin <=1.25 x upper limit of normal (ULN)( These values must be independent
             of growth factor support and stable for at least one week post transfusion)

          -  Alanine aminotransferase; and, Aspartate aminotransferase AST and ALT<=2.5 x ULN

          -  Renal

          -  Calculate creatinine clearance >=40 millilitre/ minute (mL/min) (With the exception of
             those subjects who have Gilbert's syndrome; the bilirubin in these subjects should be
             at their baseline)

        Exclusion Criteria:

          -  Lactating female

          -  Note: Women with potential to have children must be willing to practice acceptable
             methods of birth control during the study

          -  Bone-only disease and/or disease that cannot be biopsied.

          -  Unstable CNS metastases or leptomeningeal carcinomatosis not considered
             radiographically stable

          -  Note: Subjects with radiographically stable CNS metastases are defined as
             radiographically stable on the previous 2 brain imaging studies, asymptomatic, and off
             systemic steroids and anticonvulsants for at least 1 month; treatment with
             prophylactic anticonvulsants is permitted unless listed under prohibited medications

          -  Any serious and/or unstable pre-existing medical, psychiatric disorder, or other
             conditions including concurrent disease that could interfere with subject's safety,
             obtaining informed consent, or compliance with the study procedures.

          -  Serious cardiac illness or medical condition including but not confined to:
             Uncontrolled arrhythmias (e.g. ventricular tachycardia, high-grade atrioventricular
             (AV)-block, supraventricular arrhythmias which are not adequately rate-controlled);

          -  Angina pectoris requiring antianginal medication

          -  History of congestive heart failure or systolic dysfunction (LVEF <50%)

          -  Documented myocardial infarction <6 months from study entry

          -  Evidence of transmural infarction on ECG

          -  Poorly controlled hypertension (e.g. systolic >160milimiter (mm) Mercury (Hg) or
             diastolic >100mm Hg)

          -  Clinically significant valvular heart disease

          -  Current active hepatic or biliary disease (with exception of subjects with Gilbert's
             syndrome, asymptomatic gallstones, liver metastases, or stable chronic liver disease
             per investigator assessment)

          -  Any clinically significant gastrointestinal abnormalities that may alter absorption
             such as malabsorption syndrome or major resection of the stomach or bowels as well as
             subjects with ulcerative colitis are also excluded

          -  Any prohibited medication

          -  Prior treatment with Trastuzumab in combination with Lapatinib or prior treatment with
             an irreversible inhibitor of the intracellular domain of the HER2 receptor such as
             neratinib

          -  Last treatment for metastatic disease including Trastuzumab in combination with
             pertuzumab

          -  Administration of an investigational drug within 30 days or 5 half-lives, whichever is
             longer, preceding the first dose of study treatment

          -  A known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
             chemically related to any of the study drugs or their excipients that, in the opinion
             of the investigator or medical monitor, contraindicates participation