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

NCT ID: NCT02213042

Last Updated: 2021-10-13

Study Results

Results available

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Basic Information

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Recruitment Status

TERMINATED

Clinical Phase

PHASE2

Total Enrollment

42 participants

Study Classification

INTERVENTIONAL

Study Start Date

2014-10-24

Study Completion Date

2020-06-04

Brief Summary

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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.

Detailed Description

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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.

Conditions

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Neoplasms, Breast

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Participants were randomized to Arms A and B but randomized to Arm C.
Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

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.

Study Groups

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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 were hormone receptor positive, an aromatase inhibitor of the investigator's choice was required.

Group Type ACTIVE_COMPARATOR

Lapatinib

Intervention Type DRUG

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

Intervention Type BIOLOGICAL

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).

Aromatase Inhibitors (AIs)

Intervention Type DRUG

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.

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 received an aromatase inhibitor at the discretion of the investigator.

Group Type ACTIVE_COMPARATOR

Trastuzumab

Intervention Type BIOLOGICAL

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).

Aromatase Inhibitors (AIs)

Intervention Type DRUG

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.

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 were hormone receptor positive, an aromatase inhibitor of the investigator's choice was required.

Group Type ACTIVE_COMPARATOR

Lapatinib

Intervention Type DRUG

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

Intervention Type BIOLOGICAL

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).

Aromatase Inhibitors (AIs)

Intervention Type DRUG

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.

Interventions

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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

Intervention Type DRUG

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).

Intervention Type BIOLOGICAL

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.

Intervention Type DRUG

Eligibility Criteria

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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
Minimum Eligible Age

18 Years

Eligible Sex

FEMALE

Accepts Healthy Volunteers

No

Sponsors

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Novartis Pharmaceuticals

INDUSTRY

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Novartis Pharmaceuticals

Role: STUDY_DIRECTOR

Novartis Pharmaceuticals

Locations

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Novartis Investigative Site

Mobile, Alabama, United States

Site Status

Novartis Investigative Site

Boston, Massachusetts, United States

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Novartis Investigative Site

Houston, Texas, United States

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Novartis Investigative Site

Berazategui, Buenos Aires, Argentina

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Novartis Investigative Site

Ciudad Autonoma de Buenos Aires, Buenos Aires, Argentina

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Novartis Investigative Site

Viedma, Río Negro Province, Argentina

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Novartis Investigative Site

Rosario, Santa Fe Province, Argentina

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Novartis Investigative Site

Buenos Aires, , Argentina

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Córdoba, , Argentina

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La Rioja, , Argentina

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San Miguel de Tucumán, , Argentina

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Salzburg, , Austria

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Vienna, , Austria

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Novartis Investigative Site

Salvador, Estado de Bahia, Brazil

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Novartis Investigative Site

Belo Horizonte, Minas Gerais, Brazil

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Novartis Investigative Site

Porto Alegre, Rio Grande do Sul, Brazil

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Novartis Investigative Site

Porto Alegre, Rio Grande do Sul, Brazil

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Novartis Investigative Site

Porto Alegre, Rio Grande do Sul, Brazil

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Novartis Investigative Site

Itajaí, Santa Catarina, Brazil

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Novartis Investigative Site

Barretos, São Paulo, Brazil

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Novartis Investigative Site

São Paulo, São Paulo, Brazil

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Novartis Investigative Site

São Paulo, São Paulo, Brazil

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Novartis Investigative Site

São José do Rio Preto, , Brazil

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Novartis Investigative Site

Pok Fu Lam, , Hong Kong

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Novartis Investigative Site

Pokfulam, , Hong Kong

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Novartis Investigative Site

Milan, Lombardy, Italy

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Novartis Investigative Site

Milan, Lombardy, Italy

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Novartis Investigative Site

México, , Mexico

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Novartis Investigative Site

Arequipa, , Peru

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Novartis Investigative Site

Lima, , Peru

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Novartis Investigative Site

Cebu, , Philippines

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Novartis Investigative Site

Manila, , Philippines

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Novartis Investigative Site

Kazan', , Russia

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Novartis Investigative Site

Moscow, , Russia

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Novartis Investigative Site

Ryazan, , Russia

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Novartis Investigative Site

Saint Petersburg, , Russia

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Novartis Investigative Site

Saint Petersburg, , Russia

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Novartis Investigative Site

Volzhskiy, , Russia

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Novartis Investigative Site

Barcelona, , Spain

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Novartis Investigative Site

Barcelona, , Spain

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Novartis Investigative Site

Donostia / San Sebastian, , Spain

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Novartis Investigative Site

Madrid, , Spain

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Novartis Investigative Site

Madrid, , Spain

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Novartis Investigative Site

Madrid, , Spain

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Novartis Investigative Site

Málaga, , Spain

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Novartis Investigative Site

Seville, , Spain

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Novartis Investigative Site

Valencia, , Spain

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Novartis Investigative Site

Valencia, , Spain

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Novartis Investigative Site

Bangkok, , Thailand

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Novartis Investigative Site

Chiang Mai, , Thailand

Site Status

Novartis Investigative Site

Phitsanulok, , Thailand

Site Status

Countries

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United States Argentina Austria Brazil Hong Kong Italy Mexico Peru Philippines Russia Spain Thailand

Provided Documents

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Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

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2014-001220-30

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

CLAP016A2206

Identifier Type: OTHER

Identifier Source: secondary_id

117165

Identifier Type: -

Identifier Source: org_study_id