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

Neoplasms, Breast Clinical Trial

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 Details — Status: Terminated

Administrative data

• NCT number: NCT02213042
• Other study ID #: 117165
• Secondary ID: 2014-001220-30CL
• Status: Terminated
• Phase: Phase 2
• Start date: October 24, 2014
• Est. completion date: June 4, 2020

Study information

• Verified date: September 2021
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Description:

This study was designed to address the post-authorization measures as agreed with the Committee for Medicinal Products for Human Use (CHMP). Recruitment of subjects into this study was challenging, and following agreement with the European Medicines Agency (EMA) enrollment into this study was halted after the enrollment of 42 of the 225 planned subjects. The primary endpoint of the study evaluated changes in expression of biomarkers associated with immunomodulation between a pre-treatment biopsy and the disease progression biopsy. Secondary efficacy endpoints included overall response rate, clinical benefit rate and progression-free survival (PFS), as well as safety/tolerability. All subjects received study treatment until disease progression, death, unacceptable toxicity, or subject withdrawal. In case of disease progression during the treatment period, the subject was followed-up for 30 days for safety evaluation. In case of study treatment discontinuation for any reasons other than disease progression, the subject was followed-up for safety and efficacy assessments until disease progression, new anticancer therapy, death, withdrawal of consent or end of study, whichever came first. This study supported a better understanding of the rapidly accumulating evidence for the importance of the immune microenvironment in HER2-positive breast cancer and the observed immunomodulation in the neoadjuvant setting could be confirmed in the advanced setting and supported the putative mechanism of action of HER2 dual blockade and its potential function on the tumor microenvironment. No formal comparisons between treatment arms were undertaken.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 42
• Est. completion date: June 4, 2020
• Est. primary completion date: June 4, 2020
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Breast Neoplasms
• Neoplasms, Breast

Intervention

Drug:
• Lapatinib
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

Biological:
• Trastuzumab
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).

Drug:
• Aromatase Inhibitors (AIs)
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.

Locations

Country	Name	City	State
Argentina	Novartis Investigative Site	Berazategui	Buenos Aires
Argentina	Novartis Investigative Site	Ciudad Autonoma de Buenos Aires	Buenos Aires
Argentina	Novartis Investigative Site	Ciudad Autonoma de Buenos Aires
Argentina	Novartis Investigative Site	Cordoba
Argentina	Novartis Investigative Site	La Rioja
Argentina	Novartis Investigative Site	Rosario	Santa Fe
Argentina	Novartis Investigative Site	San Miguel de Tucuman
Argentina	Novartis Investigative Site	Viedma	Río Negro
Austria	Novartis Investigative Site	Salzburg
Austria	Novartis Investigative Site	Wien
Brazil	Novartis Investigative Site	Barretos	São Paulo
Brazil	Novartis Investigative Site	Belo Horizonte	Minas Gerais
Brazil	Novartis Investigative Site	Itajai	Santa Catarina
Brazil	Novartis Investigative Site	Porto Alegre	Rio Grande Do Sul
Brazil	Novartis Investigative Site	Porto Alegre	Rio Grande Do Sul
Brazil	Novartis Investigative Site	Porto Alegre	Rio Grande Do Sul
Brazil	Novartis Investigative Site	Salvador	Bahía
Brazil	Novartis Investigative Site	Sao Jose do Rio Preto
Brazil	Novartis Investigative Site	Sao Paulo	São Paulo
Brazil	Novartis Investigative Site	Sao Paulo	São Paulo
Hong Kong	Novartis Investigative Site	Pok Fu Lam
Hong Kong	Novartis Investigative Site	Pokfulam
Italy	Novartis Investigative Site	Milano	Lombardia
Italy	Novartis Investigative Site	Milano	Lombardia
Mexico	Novartis Investigative Site	Mexico
Peru	Novartis Investigative Site	Arequipa
Peru	Novartis Investigative Site	Lima
Philippines	Novartis Investigative Site	Cebu
Philippines	Novartis Investigative Site	Manila
Russian Federation	Novartis Investigative Site	Kazan
Russian Federation	Novartis Investigative Site	Moscow
Russian Federation	Novartis Investigative Site	Ryazan
Russian Federation	Novartis Investigative Site	St. Petersburg
Russian Federation	Novartis Investigative Site	St. Petersburg
Russian Federation	Novartis Investigative Site	Volzhskiy
Spain	Novartis Investigative Site	Barcelona
Spain	Novartis Investigative Site	Barcelona
Spain	Novartis Investigative Site	Donostia
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Malaga
Spain	Novartis Investigative Site	Sevilla
Spain	Novartis Investigative Site	Valencia
Spain	Novartis Investigative Site	Valencia
Thailand	Novartis Investigative Site	Bangkok
Thailand	Novartis Investigative Site	Chiangmai
Thailand	Novartis Investigative Site	Phitsanulok
United States	Novartis Investigative Site	Boston	Massachusetts
United States	Novartis Investigative Site	Houston	Texas
United States	Novartis Investigative Site	Mobile	Alabama

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Argentina,  Austria,  Brazil,  Hong Kong,  Italy,  Mexico,  Peru,  Philippines,  Russian Federation,  Spain,  Thailand, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Fold Change in Expression Profile of Genes and/or Proteins for Arm A (LAP+TRAS±AI (HER2-Enriched)) From Screening to Approx. 3.5 Years	Evaluate changes in biomarkers associated with immunomodulation between pre-treatment biopsy and disease progression biopsy within each arm. Biomarker analysis was performed using an mRNA gene expression panel derived from Nanostring platform in a total of 20 subjects who received the study treatment as per the study design and with baseline tumor biopsies available.; For the selected biomarkers associated with immunomodulation, the median fold changes of gene expression level and 95% confidence interval are presented. The fold change was calculated as the ratio of the expression level of a biomarker at disease progression over the baseline.	At screening and at disease progression, assessed up to approx. 3.5 years
Primary	Fold Change in Expression Profile of Genes and /or Proteins for Arm B (TRAS+CHEM±AI (HER2-Enriched)) From Screening to Approx. 3.5 Years	Evaluate changes in biomarkers associated with immunomodulation between pre-treatment biopsy and disease progression biopsy within each arm. Biomarker analysis was performed using an mRNA gene expression panel derived from Nanostring platform in a total of 20 subjects who received the study treatment as per the study design and with baseline tumor biopsies available.; For the selected biomarkers associated with immunomodulation, the median fold changes of gene expression level and 95% confidence interval are presented. The fold change was calculated as the ratio of the expression level of a biomarker at disease progression over the baseline.	At screening and at disease progression, assessed up to approx. 3.5 years
Primary	Fold Change in Expression Profile of Genes and /or Proteins for Arm C (Non-HER2- Enriched) From Screening to Approx. 3.5 Years	Evaluate changes in biomarkers associated with immunomodulation between pre-treatment biopsy and disease progression biopsy within each arm. Biomarker analysis was performed using an mRNA gene expression panel derived from Nanostring platform in a total of 20 subjects who received the study treatment as per the study design and with baseline tumor biopsies available.; For the selected biomarkers associated with immunomodulation, the median fold changes of gene expression level and 95% confidence interval are presented. The fold change was calculated as the ratio of the expression level of a biomarker at disease progression over the baseline.	At screening and at disease progression, assessed up to approx. 3.5 years
Secondary	Progression-free Survival (PFS)	PFS was defined as the time from the date of randomization (for Arm A and B) / treatment start date (for Arm C) to the date of the first documented disease progression or death due to any cause, whichever was earlier. If a subject had not progressed or died at the analysis cutoff date, PFS was censored at the time of the last adequate tumor assessment. PFS was summarized using Kaplan-Meier estimates.	From randomization to disease progression or death, up to approx. 5.6 years
Secondary	Overall Response Rate (ORR)	Overall response rate was defined as the percentage of subjects achieving either a confirmed complete response (CR) or partial response (PR) and was calculated from the Investigator's assessment of response per RECIST 1.1 criteria. . The confirmed CR or PR was derived using the following rules: confirmed CR - at least two determinations of CR at least 4 weeks apart before disease progression; confirmed PR - at least two determinations of PR or better at least 4 weeks apart before progression.	From enrollment/randomization to the end of study, approximately 5.6 years
Secondary	Clinical Benefit Rate (CBR)	CBR is defined as percentage of subjects with a complete response (CR), partial response (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. CR and PR are confirmed responses derived using the following rules: Confirmed CR - at least 2 determinations of CR at least 4 weeks apart before disease progression. Confirmed PR - at least 2 determinations of PR or better at least 4 weeks apart before progression.	From enrollment/randomization the end of study, approximately 5.6 years
Secondary	Association Between Biomarkers and PFS	Describe if changes of biomarker expression at disease progression from baseline correlate with PFS.	From randomization to disease progression or death, up to approx. 5.6 years