Neoplasms, BreastPhase 2NCT02213042
Evaluation of Biomarkers Associated With Response to Subsequent Therapies in Subjects With HER2-Positive Metastatic Breast Cancer
A Phase 2 study testing Lapatinib, Trastuzumab and Aromatase Inhibitors (AIs) in people with Neoplasms, Breast, run by Novartis Pharmaceuticals at 51 sites in 12 countries.
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. Read more about this study
- Who is it for?
- Ages 18 years and older, women only
- Conditions the study is for
- Neoplasms, Breast
- What is being tested?
- Lapatinib, Trastuzumab and Aromatase Inhibitors (AIs)
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 42 participants
- Where
- 51 sitesin 12 countries
- Study dates
- 24 Oct 2014to 4 Jun 2020
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- Women only
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
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- 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)
Who cannot join
- 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.
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- 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
Trial locations and contacts
51 sites in 12 countries.
51 sites in 12 countries
Brazil10 sites
Novartis Investigative Site
Barretos, São Paulo, 14784-400
Novartis Investigative Site
Belo Horizonte, Minas Gerais, 30130-090
Novartis Investigative Site
Itajaí, Santa Catarina, 88301220
Novartis Investigative Site
Porto Alegre, Rio Grande do Sul, 90430-090
Novartis Investigative Site
Porto Alegre, Rio Grande do Sul, 90470-340
Novartis Investigative Site
Porto Alegre, Rio Grande do Sul, 90610-000
Novartis Investigative Site
Salvador, Estado de Bahia, 41825-010
Novartis Investigative Site
São José do Rio Preto, 15090-000
Novartis Investigative Site
São Paulo, São Paulo, 01236030
Novartis Investigative Site
São Paulo, São Paulo, 01317-001
Spain10 sites
Novartis Investigative Site
Barcelona, 08035
Novartis Investigative Site
Barcelona, 08036
Novartis Investigative Site
Donostia / San Sebastian, 20014
Novartis Investigative Site
Madrid, 28034
Novartis Investigative Site
Madrid, 28040
Novartis Investigative Site
Madrid, 28041
Novartis Investigative Site
Málaga, 29010
Novartis Investigative Site
Seville, 41013
Novartis Investigative Site
Valencia, 46010
Novartis Investigative Site
Valencia, 46015
Argentina8 sites
Novartis Investigative Site
Berazategui, Buenos Aires, B1880BBF
Novartis Investigative Site
Buenos Aires, C1025ABI
Novartis Investigative Site
Ciudad Autonoma de Buenos Aires, Buenos Aires, C1125ABD
Novartis Investigative Site
Córdoba, X5004FHP
Novartis Investigative Site
La Rioja, F5300COE
Novartis Investigative Site
Rosario, Santa Fe Province, S2000KZE
Novartis Investigative Site
San Miguel de Tucumán, T4000IAK
Novartis Investigative Site
Viedma, Río Negro Province, R8500ACE
Russia6 sites
Novartis Investigative Site
Kazan', 420029
Novartis Investigative Site
Moscow, 115 478
Novartis Investigative Site
Ryazan, 390011
Novartis Investigative Site
Saint Petersburg, 197022
Novartis Investigative Site
Saint Petersburg, 197758
Novartis Investigative Site
Volzhskiy, 404130
United States3 sites
Novartis Investigative Site
Boston, Massachusetts, 02114
Novartis Investigative Site
Houston, Texas, 77030
Novartis Investigative Site
Mobile, Alabama, 36608
Thailand3 sites
Novartis Investigative Site
Bangkok, 10330
Novartis Investigative Site
Chiang Mai, 50200
Novartis Investigative Site
Phitsanulok, 65000
Austria2 sites
Novartis Investigative Site
Salzburg, A-5020
Novartis Investigative Site
Vienna, 1090
Hong Kong2 sites
Novartis Investigative Site
Pok Fu Lam
Novartis Investigative Site
Pokfulam
Italy2 sites
Novartis Investigative Site
Milan, Lombardy, 20133
Novartis Investigative Site
Milan, Lombardy, 20141
Peru2 sites
Novartis Investigative Site
Arequipa
Novartis Investigative Site
Lima, Lima 34
Philippines2 sites
Novartis Investigative Site
Cebu, 6000
Novartis Investigative Site
Manila, 1000
About this study
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)
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.
Read the detailed 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.
- Conditions
- Neoplasms, Breast
- Being tested
- Lapatinib, Trastuzumab, Aromatase Inhibitors (AIs)
- Keywords
- CLAP016A2206, biomarker, Lapatinib, Prosigna, ErbB2, PAM50, HER2, HER2-overexpressing metastatic breast cancer, HER2-enriched, Trastuzumab
- Medical subject headings
- Breast Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
LapatinibDrug
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
TrastuzumabBiological
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)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.
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: 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. Receives: Drug: Lapatinib; Biological: Trastuzumab; Drug: Aromatase Inhibitors (AIs) |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: 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.
Measured: At screening and at disease progression, assessed up to approx. 3.5 years
Secondary outcomes (4)
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.
Measured: From randomization to disease progression or death, up to approx. 5.6 years
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.
Measured: From enrollment/randomization to the end of study, approximately 5.6 years
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.
Measured: From enrollment/randomization the end of study, approximately 5.6 years
Association Between Biomarkers and PFS
Describe if changes of biomarker expression at disease progression from baseline correlate with PFS.
Measured: From randomization to disease progression or death, up to approx. 5.6 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted11 Aug 2014 (estimated)
- Study start24 Oct 2014
- Primary completion4 Jun 2020
- Study completion4 Jun 2020
Why it stopped: Primary analysis was completed in 2018 and continued minimal data collection from the one participant active in the study was not expected to add meaningful knowledge to the understanding of lapatinib
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Neoplasms, BreastStudies of the same condition, open and under way.
- More trials run by Novartis PharmaceuticalsThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- Participants were randomized to Arms A and B but randomized to Arm C.
- Masking
- None (open label)
- Enrolment
- 42 participants (actual)
Sponsor and investigators
- Lead sponsor
- Novartis Pharmaceuticals
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Novartis Pharmaceuticals, Study director, Novartis Pharmaceuticals
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02213042
- Sponsor's protocol ID
- 117165
- Other IDs
- 2014-001220-30, CLAP016A2206, 2014
- Status last verified
- Sep 2021
- First submitted
- 7 Aug 2014
- Last updated
- 13 Oct 2021
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: 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
Study at a glance
From the registry record, last updated by the sponsor on 13 Oct 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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)
- ClinicalTrials.gov ID
- NCT02213042
- Acronym / sponsor ID
- 117165
- Conditions
- Neoplasms, Breast
- Keywords
- CLAP016A2206, biomarker, Lapatinib, Prosigna, ErbB2, PAM50, HER2, HER2-overexpressing metastatic breast cancer
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Primary analysis was completed in 2018 and continued minimal data collection from the one participant active in the study was not expected to add meaningful knowledge to the understanding of lapatinib
- Enrolment
- 42 participants (actual)
- Lead sponsor
- Novartis PharmaceuticalsIndustry (pharma, biotech, devices)
- Study start
- 24 Oct 2014 (actual)
- Primary completion
- 4 Jun 2020 (actual)
- Study completion
- 4 Jun 2020 (actual)
- First posted
- 11 Aug 2014 (estimated)
- Results
- Posted 16 Sep 2021
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 3
- Model description
- Participants were randomized to Arms A and B but randomized to Arm C.
| Arm | Type | Receives |
|---|---|---|
| Lapatinib 1000mg + Trastuzumab in HER2 Enriched | Active comparator | Drug: Lapatinib, Biological: Trastuzumab, Drug: Aromatase Inhibitors (AIs)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. |
| Trastuzumab in HER2 Enriched | Active comparator | Biological: Trastuzumab, Drug: Aromatase Inhibitors (AIs)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. |
| Lapatinib 1000mg + Trastuzumab in Non- HER2 Enriched | Active comparator | Drug: Lapatinib, Biological: Trastuzumab, Drug: Aromatase Inhibitors (AIs)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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (43 listed)
- 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.
Key exclusion criteria (20 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| LapatinibLapatinib 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 | Drug | Lapatinib 1000mg + Trastuzumab in HER2 Enriched, Lapatinib 1000mg + Trastuzumab in Non- HER2 Enriched |
| TrastuzumabTrastuzumab 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). | Biological | Lapatinib 1000mg + Trastuzumab in HER2 Enriched, Lapatinib 1000mg + Trastuzumab in Non- HER2 Enriched, Trastuzumab in HER2 Enriched |
| 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. | Drug | Lapatinib 1000mg + Trastuzumab in HER2 Enriched, Lapatinib 1000mg + Trastuzumab in Non- HER2 Enriched, Trastuzumab in HER2 Enriched |
Primary outcome
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
Time frame: At screening and at disease progression, assessed up 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.
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
Time frame: At screening and at disease progression, assessed up 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.
Fold Change in Expression Profile of Genes and /or Proteins for Arm C (Non-HER2- Enriched) From Screening to Approx. 3.5 Years
Time frame: At screening and at disease progression, assessed up 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.
4 secondary outcomes
Progression-free Survival (PFS)
Time frame: From randomization to disease progression or death, up to approx. 5.6 years
Overall Response Rate (ORR)
Time frame: From enrollment/randomization to the end of study, approximately 5.6 years
Clinical Benefit Rate (CBR)
Time frame: From enrollment/randomization the end of study, approximately 5.6 years
Association Between Biomarkers and PFS
Time frame: From randomization to disease progression or death, up to approx. 5.6 years
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 13 Oct 2021.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Individual participant dataSharing planned: Yes. 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
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Novartis Pharmaceuticals study director
Novartis Pharmaceuticals
51 sites in 12 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Lapatinib, Trastuzumab and Aromatase Inhibitors (AIs) in people with Neoplasms, Breast, run by Novartis Pharmaceuticals at 51 sites in 12 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 43 inclusion and 20 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 13 Oct 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 51 sites in Brazil, Spain, Argentina, Russia, United States and 7 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 16 Sep 2021). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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 (time frame: At screening and at disease progression, assessed up to approx. 3.5 years). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 13 Oct 2021.