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

NCT02213042 | Terminated Phase 2 Results FDA Drug

• 3 other identifiers: 1171652014-001220-30CLAP016A2206
• Study Type: interventional
• Target: 42
• Locations: 12 countries
• Sites: 51

Brief 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.

Conditions

Neoplasms, Breast

Keywords

CLAP016A2206; biomarker; Lapatinib; Prosigna; ErbB2; PAM50; HER2; HER2-overexpressing metastatic breast cancer; HER2-enriched; Trastuzumab

Outcome Measures

Primary Outcomes (3)

• 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

• 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

• 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 Outcomes (4)

• Progression-free Survival (PFS)

  From randomization to disease progression or death, up to approx. 5.6 years

• Overall Response Rate (ORR)

  From enrollment/randomization to the end of study, approximately 5.6 years

• Clinical Benefit Rate (CBR)

  From enrollment/randomization the end of study, approximately 5.6 years

• Association Between Biomarkers and PFS

  From randomization to disease progression or death, up to approx. 5.6 years

Study Arms (3)

Lapatinib 1000mg + Trastuzumab in HER2 Enriched

ACTIVE COMPARATOR

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.

Drug: Lapatinib; Biological: Trastuzumab; Drug: Aromatase Inhibitors (AIs)

Trastuzumab in HER2 Enriched

ACTIVE COMPARATOR

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.

Biological: Trastuzumab; Drug: Aromatase Inhibitors (AIs)

Lapatinib 1000mg + Trastuzumab in Non- HER2 Enriched

ACTIVE COMPARATOR

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.

Drug: Lapatinib; Biological: Trastuzumab; Drug: Aromatase Inhibitors (AIs)

Interventions

Lapatinib 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

Lapatinib 1000mg + Trastuzumab in HER2 Enriched; Lapatinib 1000mg + Trastuzumab in Non- HER2 Enriched

Trastuzumab 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).

Lapatinib 1000mg + Trastuzumab in HER2 Enriched; Lapatinib 1000mg + Trastuzumab in Non- HER2 Enriched; Trastuzumab in HER2 Enriched

Aromatase Inhibitors (AIs) 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 HER2 Enriched; Lapatinib 1000mg + Trastuzumab in Non- HER2 Enriched; Trastuzumab in HER2 Enriched

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (51)

Novartis Investigative Site

Mobile, Alabama, 36608, United States

Location

Novartis Investigative Site

Boston, Massachusetts, 02114, United States

Location

Novartis Investigative Site

Houston, Texas, 77030, United States

Location

Novartis Investigative Site

Berazategui, Buenos Aires, B1880BBF, Argentina

Location

Novartis Investigative Site

Ciudad Autonoma de Buenos Aires, Buenos Aires, C1125ABD, Argentina

Location

Novartis Investigative Site

Viedma, Río Negro Province, R8500ACE, Argentina

Location

Novartis Investigative Site

Rosario, Santa Fe Province, S2000KZE, Argentina

Location

Novartis Investigative Site

Buenos Aires, C1025ABI, Argentina

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Novartis Investigative Site

Córdoba, X5004FHP, Argentina

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Novartis Investigative Site

La Rioja, F5300COE, Argentina

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Novartis Investigative Site

San Miguel de Tucumán, T4000IAK, Argentina

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Novartis Investigative Site

Salzburg, A-5020, Austria

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Novartis Investigative Site

Vienna, 1090, Austria

Location

Novartis Investigative Site

Salvador, Estado de Bahia, 41825-010, Brazil

Location

Novartis Investigative Site

Belo Horizonte, Minas Gerais, 30130-090, Brazil

Location

Novartis Investigative Site

Porto Alegre, Rio Grande do Sul, 90430-090, Brazil

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Novartis Investigative Site

Porto Alegre, Rio Grande do Sul, 90470-340, Brazil

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Novartis Investigative Site

Porto Alegre, Rio Grande do Sul, 90610-000, Brazil

Location

Novartis Investigative Site

Itajaí, Santa Catarina, 88301220, Brazil

Location

Novartis Investigative Site

Barretos, São Paulo, 14784-400, Brazil

Location

Novartis Investigative Site

São Paulo, São Paulo, 01236030, Brazil

Location

Novartis Investigative Site

São Paulo, São Paulo, 01317-001, Brazil

Location

Novartis Investigative Site

São José do Rio Preto, 15090-000, Brazil

Location

Novartis Investigative Site

Pok Fu Lam, Hong Kong

Location

Novartis Investigative Site

Pokfulam, Hong Kong

Location

Novartis Investigative Site

Milan, Lombardy, 20133, Italy

Location

Novartis Investigative Site

Milan, Lombardy, 20141, Italy

Location

Novartis Investigative Site

México, 06760, Mexico

Location

Novartis Investigative Site

Arequipa, Peru

Location

Novartis Investigative Site

Lima, Lima 34, Peru

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Novartis Investigative Site

Cebu, 6000, Philippines

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Novartis Investigative Site

Manila, 1000, Philippines

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Novartis Investigative Site

Kazan', 420029, Russia

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Novartis Investigative Site

Moscow, 115 478, Russia

Location

Novartis Investigative Site

Ryazan, 390011, Russia

Location

Novartis Investigative Site

Saint Petersburg, 197022, Russia

Location

Novartis Investigative Site

Saint Petersburg, 197758, Russia

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Novartis Investigative Site

Volzhskiy, 404130, Russia

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Novartis Investigative Site

Barcelona, 08035, Spain

Location

Novartis Investigative Site

Barcelona, 08036, Spain

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Novartis Investigative Site

Donostia / San Sebastian, 20014, Spain

Location

Novartis Investigative Site

Madrid, 28034, Spain

Location

Novartis Investigative Site

Madrid, 28040, Spain

Location

Novartis Investigative Site

Madrid, 28041, Spain

Location

Novartis Investigative Site

Málaga, 29010, Spain

Location

Novartis Investigative Site

Seville, 41013, Spain

Location

Novartis Investigative Site

Valencia, 46010, Spain

Location

Novartis Investigative Site

Valencia, 46015, Spain

Location

Novartis Investigative Site

Bangkok, 10330, Thailand

Location

Novartis Investigative Site

Chiang Mai, 50200, Thailand

Location

Novartis Investigative Site

Phitsanulok, 65000, Thailand

Location

MeSH Terms

Conditions

Breast Neoplasms

Interventions

Lapatinib; Trastuzumab; Aromatase Inhibitors

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Quinazolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Steroid Synthesis Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses; Estrogen Antagonists; Hormone Antagonists; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs

Results Point of Contact

• Title: Study Director
• Organization: Novartis Pharmaceuticals

novartis.email@novartis.com

862-778-8300

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Masking Details: 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.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Participants were randomized to Arms A and B but randomized to Arm C.

Study Record Dates

• First Submitted: August 7, 2014
• First Posted: August 11, 2014
• Study Start: October 24, 2014
• Primary Completion: June 4, 2020
• Study Completion: June 4, 2020
• Last Updated: October 13, 2021
• Results First Posted: September 16, 2021

Record last verified: 2021-09

Data Sharing

• IPD Sharing: Will share

Locations

TH (3); PE (2); AU (2); RU (6); AR (8); ME (1); BR (10); PH (2); IT (2); ES (10); HK (2); US (3)