We are updating the design of this site. Learn more.
Show more
ClinicalTrials.gov
ClinicalTrials.gov Menu

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

This study is ongoing, but not recruiting participants.
Sponsor:
ClinicalTrials.gov Identifier:
NCT02213042
First Posted: August 11, 2014
Last Update Posted: October 12, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
  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.


Condition Intervention Phase
Neoplasms, Breast Drug: Lapatinib Biological: Trastuzumab Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Masking: None (Open Label)
Primary Purpose: Treatment
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)

Resource links provided by NLM:


Further study details as provided by Novartis ( Novartis Pharmaceuticals ):

Primary Outcome Measures:
  • 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) ]
    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:
  • Overall response rate (ORR) [ Time Frame: At Study screening, at disease progression (Assessed up to 2 years) ]
    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.

  • Clinical benefit rate (CBR) [ Time Frame: Assessed up to 2 years ]
    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

  • Progression-free survival (PFS) [ Time Frame: From randomization to disease progression or death (Assessed up to 2 years) ]
    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

  • Changes in biomarkers and PFS [ Time Frame: From randomization to disease progression or death (Assessed up to 2 years) ]
    Describe if a change at disease progression in biomarker correlates with PFS

  • 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) ]
    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


Enrollment: 225
Actual Study Start Date: October 24, 2014
Estimated Study Completion Date: September 1, 2018
Estimated Primary Completion Date: March 27, 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Lapatinib 1000mg + Trastuzumab in HER2 Enriched
In 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.
Drug: Lapatinib
Lapatinib is available as 250-mg orange tablets. Subjects randomized to the Lapatinib plus Trastuzumab arm are to receive 1000 mg per day of Lapatinib, so will be instructed to take 4 x 250 mg tablets per day. Lapatinib should be taken either 1 hour (or more) before a meal or 1 hour (or more) after a meal
Biological: Trastuzumab
Trastuzumab is a sterile, white to pale yellow, preservative-free lyophilized powder for IV administration. Trastuzumab will be 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 will be administered q3weekly as a 6 mg/kg maintenance dose. At the discretion of the investigator, weekly Trastuzumab can be given in either of the three treatment arms (loading dose 4mg/kg followed by weekly administration of 2mg/kg)
Active Comparator: Trastuzumab in HER2 Enriched
In 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.
Biological: Trastuzumab
Trastuzumab is a sterile, white to pale yellow, preservative-free lyophilized powder for IV administration. Trastuzumab will be 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 will be administered q3weekly as a 6 mg/kg maintenance dose. At the discretion of the investigator, weekly Trastuzumab can be given in either of the three treatment arms (loading dose 4mg/kg followed by weekly administration of 2mg/kg)
Active Comparator: Lapatinib 1000mg + Trastuzumab in Non- HER2 Enriched
In 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.
Drug: Lapatinib
Lapatinib is available as 250-mg orange tablets. Subjects randomized to the Lapatinib plus Trastuzumab arm are to receive 1000 mg per day of Lapatinib, so will be instructed to take 4 x 250 mg tablets per day. Lapatinib should be taken either 1 hour (or more) before a meal or 1 hour (or more) after a meal
Biological: Trastuzumab
Trastuzumab is a sterile, white to pale yellow, preservative-free lyophilized powder for IV administration. Trastuzumab will be 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 will be administered q3weekly as a 6 mg/kg maintenance dose. At the discretion of the investigator, weekly Trastuzumab can be given in either of the three treatment arms (loading dose 4mg/kg followed by weekly administration of 2mg/kg)

  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02213042


  Show 49 Study Locations
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
  More Information

Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT02213042     History of Changes
Other Study ID Numbers: 117165
First Submitted: August 7, 2014
First Posted: August 11, 2014
Last Update Posted: October 12, 2017
Last Verified: October 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Plan Description:

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com


Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Novartis ( Novartis Pharmaceuticals ):
biomarker
Lapatinib
Prosigna
ErbB2
PAM50
HER2
HER2-overexpressing metastatic breast cancer
HER2-enriched
Trastuzumab

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Lapatinib
Trastuzumab
Aromatase Inhibitors
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Steroid Synthesis Inhibitors
Estrogen Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs