Clinical Trials /

Evaluation of Biomarkers Associated With Response to Subsequent Therapies in Subjects With HER2-Positive Metastatic Breast Cancer

NCT02213042

Description:

This is 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 is a post-approval commitment with regulatory authorities. It is designed to evaluate whether treatment with Dual blockade promotes changes to biomarkers associated with immunomodulation. The primary endpoint of the study will be to evaluate changes in expression of biomarkers associated with immunomodulation between a pre-treatment biopsy and the disease progression biopsy. Secondary efficacy endpoints include overall response rate; clinical benefit rate; and progression-free survival (PFS); as well as safety/tolerability. All subjects will receive study treatment until disease progression, death, unacceptable toxicity, or subject withdrawal. In case of disease progression during the treatment period, the subject will be followed-up for 30 days for safety evaluation. In case of study treatment discontinuation for any reasons other than disease progression, the subject will be followed-up for safety and efficacy assessments until disease progression, new anticancer therapy, death, withdrawal of consent or end of study, whichever comes first. This study will support a better understanding if the rapidly accumulating evidence for the importance of the immune microenvironment in HER2-positive breast cancer and the observed immunomodulation in the neoadjuvant setting can be confirmed in the advanced setting and support the putative mechanism of action of HER2 dual blockade and its potential function on the tumor microenvironment. No formal comparisons between treatment arms will be undertaken.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Evaluation of Biomarkers Associated With Response to Subsequent Therapies in Subjects With HER2-Positive Metastatic Breast Cancer
  • Official Title: An Open-Label, Phase II, Study to Evaluate Biomarkers Associated With Response to Subsequent Therapies in Subjects With HER2-Positive Metastatic Breast Cancer Receiving Treatment With Trastuzumab in Combination With Lapatinib or Chemotherapy (EGF117165)

Clinical Trial IDs

  • ORG STUDY ID: 117165
  • NCT ID: NCT02213042

Conditions

  • Neoplasms, Breast

Interventions

DrugSynonymsArms
LapatinibLapatinib 1000mg + Trastuzumab in Non- HER2 Enriched
TrastuzumabLapatinib 1000mg + Trastuzumab in Non- HER2 Enriched

Purpose

This is 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 is a post-approval commitment with regulatory authorities. It is designed to evaluate whether treatment with Dual blockade promotes changes to biomarkers associated with immunomodulation. The primary endpoint of the study will be to evaluate changes in expression of biomarkers associated with immunomodulation between a pre-treatment biopsy and the disease progression biopsy. Secondary efficacy endpoints include overall response rate; clinical benefit rate; and progression-free survival (PFS); as well as safety/tolerability. All subjects will receive study treatment until disease progression, death, unacceptable toxicity, or subject withdrawal. In case of disease progression during the treatment period, the subject will be followed-up for 30 days for safety evaluation. In case of study treatment discontinuation for any reasons other than disease progression, the subject will be followed-up for safety and efficacy assessments until disease progression, new anticancer therapy, death, withdrawal of consent or end of study, whichever comes first. This study will support a better understanding if the rapidly accumulating evidence for the importance of the immune microenvironment in HER2-positive breast cancer and the observed immunomodulation in the neoadjuvant setting can be confirmed in the advanced setting and support the putative mechanism of action of HER2 dual blockade and its potential function on the tumor microenvironment. No formal comparisons between treatment arms will be undertaken.

Trial Arms

NameTypeDescriptionInterventions
Lapatinib 1000mg + Trastuzumab in HER2 EnrichedActive ComparatorIn subjects with HER2-overexpressing MBC with a molecular subtype of HER2 Enriched, Lapatinib 1000mg once daily orally along with Trastuzumab (loading dose of 8 milligram/ kilogram (mg/kg) followed by the maintenance dose of 6 mg/kg Intravenous (IV) Every 3 weeks (q3weekly)) or Lapatinib 1000 milligram (mg) once daily orally along with Weekly Trastuzumab (loading dose of 4 mg/kg) followed by maintenance dose of 2 mg/kg IV weekly. For subjects who are hormone receptor positive, an aromatase inhibitor of the investigator's choice is required.
  • Lapatinib
Trastuzumab in HER2 EnrichedActive ComparatorIn subjects with HER2-overexpressing MBC with a molecular subtype of HER2 Enriched, Trastuzumab (loading dose of 8 mg/kg followed by the maintenance dose of 6 mg/kg IV q3weekly) along with chemotherapy of the investigator's choice or Weekly Trastuzumab (loading dose of 4 mg/kg) followed by maintenance dose of 2 mg/kg IV weekly along with chemotherapy of the investigators choice. Subjects randomized to this arm and hormone receptor positive will receive an aromatase inhibitor at the discretion of the investigator.
    Lapatinib 1000mg + Trastuzumab in Non- HER2 EnrichedActive ComparatorIn subjects with HER2-overexpressing MBC with a molecular subtype of Non- HER2 Enriched (luminal A, luminal B or Basal type), Lapatinib 1000mg once daily orally along with Trastuzumab (loading dose of 8 milligram/ kilogram (mg/kg) followed by the maintenance dose of 6 mg/kg Intravenous (IV) Every 3 weeks (q3weekly)) or Lapatinib 1000 milligram (mg) once daily orally along with Weekly Trastuzumab (loading dose of 4 mg/kg) followed by maintenance dose of 2 mg/kg IV weekly. For subjects who are hormone receptor positive, an aromatase inhibitor of the investigator's choice is required.
    • Lapatinib

    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
          
    Maximum Eligible Age:N/A
    Minimum Eligible Age:18 Years
    Eligible Gender:Female
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:Evaluate changes in biomarkers associated with immunomodulation between pre-treatment biopsy and disease progression biopsy
    Time Frame:At screening and at disease progression (Assessed up to 2 years)
    Safety Issue:
    Description:Changes in gene and/or protein expression of pre-specified biomarkers associated with immunomodulation between the pre-treatment biopsy and disease progression biopsy within each arm.

    Secondary Outcome Measures

    Measure:Overall response rate (ORR)
    Time Frame:At Study screening, at disease progression (Assessed up to 2 years)
    Safety Issue:
    Description:ORR is defined as percentage of subjects with a complete response (CR) or partial response (PR) according to the investigator assessment of response per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria.
    Measure:Clinical benefit rate (CBR)
    Time Frame:Assessed up to 2 years
    Safety Issue:
    Description:CBR is defined as percentage of subjects with a CR, PR, or maintaining stable disease (SD) for at least 24 weeks while on study according to the investigator assessment of response per RECIST 1.1 criteria
    Measure:Progression-free survival (PFS)
    Time Frame:From randomization to disease progression or death (Assessed up to 2 years)
    Safety Issue:
    Description:PFS is defined as the interval of time between randomization and disease progression or death due to any cause according to the investigator assessment of response per RECIST 1.1 criteria
    Measure:Changes in biomarkers and PFS
    Time Frame:From randomization to disease progression or death (Assessed up to 2 years)
    Safety Issue:
    Description:Describe if a change at disease progression in biomarker correlates with PFS
    Measure:Safety and tolerability of Trastuzumab in combination with Lapatinib and of Trastuzumab in combination with chemotherapy
    Time Frame:From first dose of study treatment to 30 days following discontinuation of study treatment (Assessed up to 2 years)
    Safety Issue:
    Description:Investigator or site staff will be responsible for detecting, documenting and reporting any untoward medical occurrence in a subject or subject clinical investigation, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product for both treatment arms

    Details

    Phase:Phase 2
    Primary Purpose:Interventional
    Overall Status:Active, not recruiting
    Lead Sponsor:Novartis Pharmaceuticals

    Trial Keywords

    • biomarker
    • Lapatinib
    • Prosigna
    • ErbB2
    • PAM50
    • HER2
    • HER2-overexpressing metastatic breast cancer
    • HER2-enriched
    • Trastuzumab

    Last Updated

    October 10, 2017