Breast CancerPhase 2PAMELANCT01973660
PAM50 HER2-enriched Phenotype as a Predictor of Response to Dual HER2 Blockade in HER2-positive Early Breast Cancer
A Phase 2 study testing Lapatinib, Trastuzumab and Endocrine Therapy in people with Breast Cancer, run by SOLTI Breast Cancer Research Group at 22 sites in Spain.
Trial summary
Non-randomized, open label, multicentric translational research study in women with untreated invasive breast carcinoma eligible for primary surgery (Stage I-IIIA). The aim of PAMELA is to test the hypothesis that PAM50 HER2-enriched (HER2-E) subtype better predicts response to neoadjuvant dual anti-HER2 blockade… Read more about this study
- Who is it for?
- Ages 18 years and older, women only
- Conditions the study is for
- Breast Cancer
- What is being tested?
- Lapatinib, Trastuzumab and Endocrine Therapy
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 151 participants
- Where
- 22 sitesSpain
- Study dates
- Oct 2013to Dec 2017
- Phase
- Phase 2
- Are there results?
- None posted in the registry
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
- Written informed consent prior to beginning specific protocol procedures
- Untreated invasive breast carcinoma eligible for primary definitive surgery (stage I-IIIA)
- Histologically confirmed invasive breast carcinoma, with all of the following characteristics: primary tumor ≥1 cm in largest diameter, cN0-2, No evidence of distant metastasis (M0)
- HER2-positive invasive breast cancer by central assessment, defined by ASCO/CAP guidelines
- Female patients
- Age ≥18 years
Show all 12Show fewer
- ECOG performance status of 0 or 1
- Adequate organ function defined as: Absolute neutrophil count (ANC) ≥1.5 × 109/L, Hemoglobin (Hgb) ≥10 g/dL, Platelets >100 000/mm3, Creatinine ≤1.6 mg/dL, ALT and AST ≤2.5 × ULN, Alkaline phosphatase ≤5 ULN, Total bilirubin ≤1.5 mg/dL, Baseline LVEF ≥50% measured by echocardiography (ECHO) or Multiple Gate Acquisition (MUGA) scan
- Negative β-HCG pregnancy test (serum) for premenopausal women of reproductive capacity (those who are biologically capable of having children) and for women less than 12 months after the menopause. All subjects who are biologically capable of having children must agree and commit to the use of a reliable method of birth control from 2 weeks before administration of the first dose of investigational product until 28 days after last dose of investigational product
- Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule
- In the case of multifocal tumor (defined as the presence of two or more tumor foci in the same quadrant of the breast), the largest lesion must be ≥ 1 cm, and "target lesion" must be designated for all subsequent tumor assessments. In all tumor foci should be documented HER2 status as positive
- Availability of enough tumor sample or possibility to take a new biopsy for PAM50 analysis
Who cannot join
- Stage III inoperable breast cancer or known metastatic disease
- Patients for whom upfront chemotherapy including taxanes and anthracyclines is clinically judged appropriate as optimal neoadjuvant treatment
- Prior chemotherapy, radiotherapy or surgery for invasive breast cancer, other than excision of tumor in the contralateral breast, and provided that the patient did not previously receive adjuvant radiotherapy or chemotherapy
- Subjects with a concurrently active second malignancy, other than adequately treated non-melanoma skin cancers, in situ melanoma or in situ cervical cancer. Subjects with other non-mammary malignancies must have been disease-free for at least 5 years
- Known or suspected hypersensitivity reaction to any investigational or therapeutic compound or their incorporated substances
- Concurrent congestive heart failure or LVEF <50%
Show all 17Show fewer
- Clinically significant (i.e. active) cardiovascular disease, including cerebrovascular accident (<6 months before enrollment), unstable angina pectoris, myocardial infarction ≤6 months before enrollment, uncontrolled hypertension (systolic >150 mmHg and/or diastolic >100 mmHg) or high-risk uncontrolled arrhythmias
- Uncontrolled diabetes mellitus, active peptic ulcer disease or uncontrolled epilepsy
- Active uncontrolled infection at the time of enrollment
- History of significant comorbidities that, in the judgment of the investigator, may interfere with the conduction of the study, the evaluation of response, or with informed consent
- Use of any investigational agent or participation in another therapeutic clinical trial concurrently or in the previous 30 days before the enrollment
- Patients who are pregnant or breast-feeding
- Women of child-bearing potential who are unable or unwilling to use contraceptive measures
- Inability or unwillingness to abide by the study protocol or cooperate fully with the investigator
- Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel. Subjects with ulcerative colitis are also excluded
- Concurrent neoadjuvant cancer therapy (chemotherapy, radiation therapy, immunotherapy, biologic therapy other than the trial therapies)
- Concomitant use of CYP3A4 inhibitors or inducers
Trial locations and contacts
22 sites in 1 country.
22 sites in 1 country
Spain22 sites
Hospital Universitario Infanta Cristina
Badajoz, 06071
Vall d'Hebron University Hospital
Barcelona, 08035
Hospital Clínic de Barcelona
Barcelona
Instituto Dexeus
Barcelona
Hospital San Pedro de Alcántara
Cáceres, 10003
Consorcio Hospitalario Provincial de Castellón
Castellon, Castellón
Hospital Universitario Virgen de la Arrixaca
El Palmar, Murcia
Hospital Universitario de Fuenlabrada
Fuenlabrada, Madrid
Institut Català d'Oncologia Hospitalet
L'Hospitalet de Llobregat, Barcelona
Hospital Universitario Arnau de Vilanova de Lleida
Lleida
Hospital Universitario 12 de Octubre
Madrid, 28041
Hospital Clínico San Carlos
Madrid
Hospital Universitario Ramón y Cajal
Madrid
Hospital Son Llàtzer
Palma de Mallorca, Balearic Islands
Hospital Universitario Son Espases
Palma de Mallorca, Balearic Islands
Hospital Universitario Sant Joan de Reus
Reus, Tarragona
Hospital Clínico Universitario de Santiago de Compostela
Santiago de Compostela, Galicia
Hospital Mutua de Terrassa
Terrassa, Barcelona
Hospital de Torrevieja
Torrevieja, Alicante
Hospital Clínico Universitario de Valencia
Valencia
Hospital Universitario Arnau de Vilanova de Valencia
Valencia
Hospital Luis Alcanyís de Xàtiva
Xàtiva, Valencia, 46800
About this study
Official title: PAMELA: PAM50 HER2-enriched Phenotype as a Predictor of Early Response to Neoadjuvant Lapatinib Plus Trastuzumab in Stage I to IIIA HER2-positive Breast Cancer
Non-randomized, open label, multicentric translational research study in women with untreated invasive breast carcinoma eligible for primary surgery (Stage I-IIIA).
The aim of PAMELA is to test the hypothesis that PAM50 HER2-enriched (HER2-E) subtype better predicts response to neoadjuvant dual anti-HER2 blockade, with or without endocrine therapy, compared to traditional clinical HER2 classification. Furthermore, we posit that characterization of gene expression patterns may identify profiles of those who may be safely spared chemotherapy.
Read the detailed description
PAMELA is a non-randomized, open label, multicentric translational research study of neoadjuvant dual HER2 blockade therapy without chemotherapy. Although efficacy and safety will be investigated, the primary goal is to identify profiles predictive of clinical benefit from targeted therapy. Eligible patients must be women with untreated primary HER2-overexpressing and/or amplified breast tumors of more than 1 cm in diameter amenable to definitive surgery (stage I-IIIA).
The PAMELA study is designed to test the hypothesis that the PAM50 HER2-E subtype is able to predict clinical response to neoadjuvant dual HER2 blockade with lapatinib and trastuzumab, with or without endocrine therapy, assessed by pathological complete response in the breast (pCRB) rate at the time of surgery, compared to traditional clinical HER2 classification. Furthermore, we posit that characterization of gene expression patterns may identify profiles of those who may be safely spared chemotherapy.
Patients will first undergo screening, tumor measurement, and mandatory collection of core tumor biopsies for central determination of HER2 and HR status. These biopsies will be used to determine gene expression patterns once the patient is included in the study. Patients will be treated with dual HER2 blockade consisting of lapatinib and trastuzumab for a total of 18 weeks. Patients who are HR-positive will also be given endocrine therapy, letrozole or tamoxifen depending on their menopausal status, for the same 18 weeks. If tumor progression is observed by ultrasound (US) at week 6, tumors will be identified as resistant, and paclitaxel will be added to dual HER2 blockade, maintaining trastuzumab at the same original dose and reducing lapatinib dose for safety reasons. In those patients with HR-positive disease, endocrine therapy will be withdrawn in order to avoid its adverse interactions with chemotherapy.
Two weeks after the first administration of study medication, all patients will undergo mandatory repeat tumor tissue acquisition that will be used for secondary endpoint assessment.
Post treatment tissue acquisition will be obtained at the time of surgery from the specimen excised.
US of the breast and axillary lymph nodes will be performed at baseline, Day 14, week 6, and prior to surgery, and will be correlated with pCR. If tumor progression is observed on week 6, the US will be repeated on week 10 to discard the progression continues despite the addition of paclitaxel at neoadjuvant regimen.
Mammography is required at baseline and prior to surgery, but will not be used for the objective response assessment.
Treatment will be given until definitive surgery, clinical signs of disease progression after paclitaxel addition, unacceptable toxicity or withdrawal of patient consent.
Breast surgery will be carried out 1 to 3 weeks after completion of dual HER2 blockade with or without endocrine therapy, and 2 to 3 weeks after completion of paclitaxel plus dual HER2 blockade, should it had been initiated for progressive disease.
Following surgical excision, adjuvant treatment will be as per investigator´s choice and local standards of care outside the scope of this protocol.
End of study is 30 days (±14 days) after surgery with a safety follow-up visit.
- Conditions
- Breast Cancer
- Being tested
- Lapatinib, Trastuzumab, Endocrine Therapy, Paclitaxel
- Keywords
- Human Epidermal Growth Factor Receptor 2, HER2, HER2 positive, PAM50, lapatinib, trastuzumab, dual HER2 blockade, neoadjuvant
- 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
Also called Tyverb, Tykerb
TrastuzumabDrug
Also called Herceptin, Herclon
Endocrine TherapyDrug
Also called Letrozol, Letrozole, Devazol, Femara, Galdar, Loxifan, Tamoxifen, Tamoxifeno, Nolvadex, Istubal, Valodex
Letrozole or tamoxifen will be prescribed according to patient's menopausal status
PaclitaxelDrug
Also called Abraxane, Taxol
Only administrated if tumor progression is observed by US on week 6
| Study group | Role | What they receive |
|---|---|---|
| Dual HER2 blockade | Experimental | For a total of 18 weeks, HR-negative patients will be given dual blockade consisting of daily lapatinib at 1000 mg and trastuzumab at a loading dose of 8 mg/kg, followed by 6 mg/kg every 3 weeks. Receives: Drug: Lapatinib; Drug: Trastuzumab; Drug: Paclitaxel |
| Dual HER2 blockade plus endocrine therapy | Experimental | For a total of 18 weeks, HR-positive patients will be given letrozole (2.5 mg daily) or tamoxifen (20 mg daily) with concurrent dual blockade consisting of daily lapatinib at 1000 mg and trastuzumab at a loading dose of 8 mg/kg, followed by 6 mg/kg every 3 weeks. Receives: Drug: Lapatinib; Drug: Trastuzumab; Drug: Endocrine Therapy; Drug: Paclitaxel |
What is being measured
The primary outcome is the main question the study is designed to answer.
pCRB to dual HER2 blockade with lapatinib and trastuzumab in all patients, at the time of surgery, predicted by PAM50 HER2-E subtype
Comparison between the PAM50 HER2-E versus non HER2-E cases to achieve pCRB from dual HER2 blockade with lapatinib and trastuzumab at the time of surgery
Measured: At the time of surgery
Secondary outcomes (10)
Pathological complete response in the breast and axilla (pCRBL) to dual HER2 blockade with lapatinib and trastuzumab, in all patients, at the time of surgery, predicted by PAM50 HER2-E subtype
Comparison between the PAM50 HER2-E versus non HER2-E cases to achieve pCRBL from dual HER2 blockade with lapatinib and trastuzumab at the time of surgery
Measured: At the time of surgery
Residual cancer burden in the breast (RCB) to dual HER2 blockade with lapatinib and trastuzumab, in all patients, at the time of surgery, predicted by PAM50 HER2-E subtype
Correlation between PAM50 HER2-E cases and RCB status (0-I versus II-III) after dual HER2 blockade with lapatinib and trastuzumab at the time of surgery
Measured: At the time of surgery
Changes in the percentage of Ki67-positive cells in PAM50 non-Luminal A/B (combined) subtypes
Comparison of the changes in the percentage of Ki67-positive cells in Luminal versus non-Luminal subtypes after 14 days of dual HER2 blockade plus endocrine therapy
Measured: Day 14
Gene expression variations in all patients, in HR-negative and in HR-positive patients
Compare significant changes in gene expression from baseline to Day 14 in the entire study population and separately, in the HR-negative and HR-positive patients
Measured: Day 14
Correlation between PAM50 HER2-E centroid, as a continuous variable, and pCR and/or RCB in the breast to dual HER2 blockade with lapatinib and trastuzumab at the time of surgery
Measured: At the time of surgery
Identification of additional gene expression signatures beyond the PAM50 subtypes that predict pCR and/or RCB to dual HER2 blockade with lapatinib and trastuzumab at the time of surgery
In all patients and in those with HR-positive and HR-negative disease
Measured: At the time of surgery
PAM50 risk of relapse (ROR) score and its ability to predict pCR and/or RCB in the breast to dual HER2 blockade with lapatinib and trastuzumab at the time of surgery in all patients and in those with HR-positive and HR-negative disease
Correlation between the PAM50 ROR and pCR and/or RCB after dual HER2 blockade with lapatinib and trastuzumab at the time of surgery
Measured: At the time of surgery
PAM50 HER-2 subtype (PAM50 HER2-E signature) ability as a continuous variable to predict pCRB to dual HER2 blockade at the time of surgery in patients with HR-positive disease and in patients with HR-negative disease
Measured: At the time of surgery
Changes in gene expression from day 0 to day 14, after dual HER2 blockade, that predict pCRB in all patients and in those with HR-positive and HR-negative disease
Identification of gene expression changes that correlate with pCRB or RCB after dual HER2 blockade treatment
Measured: Day 14
Frequency of adverse events (AE) when lapatinib plus trastuzumab, with or without endocrine therapy, is administered in the neoadjuvant setting
Frequency of adverse events (AE)(assessed by CTCAE v.4.03), including the following parameters:
- All reported AEs and serious AEs
- Neutropenia Grade 3/4
- Febrile neutropenia Grade 3/4
- Neuropathy Grade 3/4
- Myalgia/arthralgia
- Cardiotoxicity (Grade 3/4 or NYHA Class III or IV)
- Frequency of dose reductions and dose delays due to treatment toxicity
Measured: 30 days (+/-14 days) after the surgery
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted31 Oct 2013 (estimated)
- Study startOct 2013
- Primary completionJun 2016
- Study completionDec 2017
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (7)Papers the sponsor has linked to this study.
- Other trials for Breast CancerStudies of the same condition, open and under way.
- 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
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 151 participants (actual)
Sponsor and investigators
- Lead sponsor
- SOLTI Breast Cancer Research Group
- Sponsor type
- University, hospital or other
- Collaborators
- Novartis
- Responsible party
- Sponsor
- Investigators
- Antonio Llombart, MD, PhD, Study chair, Hospital Arnau de Vilanova de ValenciaAleix Prat, MD, PhD, Study chair, Vall d'Hebron Institute of OncologyJavier Cortés, MD, PhD, Study chair, Vall d'Hebron University Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01973660
- Sponsor's protocol ID
- SOLTI-1114
- Other IDs
- 2013-001036-22
- Acronym
- PAMELA
- Status last verified
- Sep 2018
- First submitted
- 25 Oct 2013
- Last updated
- 19 Sep 2018
- Results posted
- No
- Data monitoring committee
- Yes
Publications
Baselga J, Bradbury I, Eidtmann H, Di Cosimo S, de Azambuja E, Aura C, Gomez H, Dinh P, Fauria K, Van Dooren V, Aktan G, Goldhirsch A, Chang TW, Horvath Z, Coccia-Portugal M, Domont J, Tseng LM, Kunz G, Sohn JH, Semiglazov V, Lerzo G, Palacova M, Probachai V, Pusztai L, Untch M, Gelber RD, Piccart-Gebhart M; NeoALTTO Study Team. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2012 Feb 18;379(9816):633-40. doi: 10.1016/S0140-6736(11)61847-3. Epub 2012 Jan 17.
PubMed 22257673Gianni L, Pienkowski T, Im YH, Roman L, Tseng LM, Liu MC, Lluch A, Staroslawska E, de la Haba-Rodriguez J, Im SA, Pedrini JL, Poirier B, Morandi P, Semiglazov V, Srimuninnimit V, Bianchi G, Szado T, Ratnayake J, Ross G, Valagussa P. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol. 2012 Jan;13(1):25-32. doi: 10.1016/S1470-2045(11)70336-9. Epub 2011 Dec 6.
PubMed 22153890Prat A, Parker JS, Fan C, Perou CM. PAM50 assay and the three-gene model for identifying the major and clinically relevant molecular subtypes of breast cancer. Breast Cancer Res Treat. 2012 Aug;135(1):301-6. doi: 10.1007/s10549-012-2143-0. Epub 2012 Jul 3.
PubMed 22752290Rimawi MF, Mayer IA, Forero A, Nanda R, Goetz MP, Rodriguez AA, Pavlick AC, Wang T, Hilsenbeck SG, Gutierrez C, Schiff R, Osborne CK, Chang JC. Multicenter phase II study of neoadjuvant lapatinib and trastuzumab with hormonal therapy and without chemotherapy in patients with human epidermal growth factor receptor 2-overexpressing breast cancer: TBCRC 006. J Clin Oncol. 2013 May 10;31(14):1726-31. doi: 10.1200/JCO.2012.44.8027. Epub 2013 Apr 8.
PubMed 23569315Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature. 2012 Oct 4;490(7418):61-70. doi: 10.1038/nature11412. Epub 2012 Sep 23.
PubMed 23000897Nuciforo P, Pascual T, Cortes J, Llombart-Cussac A, Fasani R, Pare L, Oliveira M, Galvan P, Martinez N, Bermejo B, Vidal M, Pernas S, Lopez R, Munoz M, Garau I, Manso L, Alarcon J, Martinez E, Rodrik-Outmezguine V, Brase JC, Villagrasa P, Prat A, Holgado E. A predictive model of pathologic response based on tumor cellularity and tumor-infiltrating lymphocytes (CelTIL) in HER2-positive breast cancer treated with chemo-free dual HER2 blockade. Ann Oncol. 2018 Jan 1;29(1):170-177. doi: 10.1093/annonc/mdx647.
PubMed 29045543Llombart-Cussac A, Cortes J, Pare L, Galvan P, Bermejo B, Martinez N, Vidal M, Pernas S, Lopez R, Munoz M, Nuciforo P, Morales S, Oliveira M, de la Pena L, Pelaez A, Prat A. HER2-enriched subtype as a predictor of pathological complete response following trastuzumab and lapatinib without chemotherapy in early-stage HER2-positive breast cancer (PAMELA): an open-label, single-group, multicentre, phase 2 trial. Lancet Oncol. 2017 Apr;18(4):545-554. doi: 10.1016/S1470-2045(17)30021-9. Epub 2017 Feb 24.
PubMed 28238593
Study at a glance
From the registry record, last updated by the sponsor on 19 Sep 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- PAMELA: PAM50 HER2-enriched Phenotype as a Predictor of Early Response to Neoadjuvant Lapatinib Plus Trastuzumab in Stage I to IIIA HER2-positive Breast Cancer
- ClinicalTrials.gov ID
- NCT01973660
- Acronym / sponsor ID
- PAMELA / SOLTI-1114
- Conditions
- Breast Cancer
- Keywords
- Human Epidermal Growth Factor Receptor 2, HER2, HER2 positive, PAM50, lapatinib, trastuzumab, dual HER2 blockade, neoadjuvant
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 151 participants (actual)
- Lead sponsor
- SOLTI Breast Cancer Research GroupUniversity, hospital or other
- Collaborators
- Novartis
- Study start
- Oct 2013 (actual)
- Primary completion
- Jun 2016 (actual)
- Study completion
- Dec 2017 (actual)
- First posted
- 31 Oct 2013 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Non-randomized, open label, multicentric translational research study in women with untreated invasive breast carcinoma eligible for primary surgery (Stage I-IIIA).
The aim of PAMELA is to test the hypothesis that PAM50 HER2-enriched (HER2-E) subtype better predicts response to neoadjuvant dual anti-HER2 blockade, with or without endocrine therapy, compared to traditional clinical HER2 classification. Furthermore, we posit that characterization of gene expression patterns may identify profiles of those who may be safely spared chemotherapy.
Detailed description
PAMELA is a non-randomized, open label, multicentric translational research study of neoadjuvant dual HER2 blockade therapy without chemotherapy. Although efficacy and safety will be investigated, the primary goal is to identify profiles predictive of clinical benefit from targeted therapy. Eligible patients must be women with untreated primary HER2-overexpressing and/or amplified breast tumors of more than 1 cm in diameter amenable to definitive surgery (stage I-IIIA).
The PAMELA study is designed to test the hypothesis that the PAM50 HER2-E subtype is able to predict clinical response to neoadjuvant dual HER2 blockade with lapatinib and trastuzumab, with or without endocrine therapy, assessed by pathological complete response in the breast (pCRB) rate at the time of surgery, compared to traditional clinical HER2 classification. Furthermore, we posit that characterization of gene expression patterns may identify profiles of those who may be safely spared chemotherapy.
Patients will first undergo screening, tumor measurement, and mandatory collection of core tumor biopsies for central determination of HER2 and HR status. These biopsies will be used to determine gene expression patterns once the patient is included in the study. Patients will be treated with dual HER2 blockade consisting of lapatinib and trastuzumab for a total of 18 weeks. Patients who are HR-positive will also be given endocrine therapy, letrozole or tamoxifen depending on their menopausal status, for the same 18 weeks. If tumor progression is observed by ultrasound (US) at week 6, tumors will be identified as resistant, and paclitaxel will be added to dual HER2 blockade, maintaining trastuzumab at the same original dose and reducing lapatinib dose for safety reasons. In those patients with HR-positive disease, endocrine therapy will be withdrawn in order to avoid its adverse interactions with chemotherapy.
Two weeks after the first administration of study medication, all patients will undergo mandatory repeat tumor tissue acquisition that will be used for secondary endpoint assessment.
Post treatment tissue acquisition will be obtained at the time of surgery from the specimen excised.
US of the breast and axillary lymph nodes will be performed at baseline, Day 14, week 6, and prior to surgery, and will be correlated with pCR. If tumor progression is observed on week 6, the US will be repeated on week 10 to discard the progression continues despite the addition of paclitaxel at neoadjuvant regimen.
Mammography is required at baseline and prior to surgery, but will not be used for the objective response assessment.
Treatment will be given until definitive surgery, clinical signs of disease progression after paclitaxel addition, unacceptable toxicity or withdrawal of patient consent.
Breast surgery will be carried out 1 to 3 weeks after completion of dual HER2 blockade with or without endocrine therapy, and 2 to 3 weeks after completion of paclitaxel plus dual HER2 blockade, should it had been initiated for progressive disease.
Following surgical excision, adjuvant treatment will be as per investigator´s choice and local standards of care outside the scope of this protocol.
End of study is 30 days (±14 days) after surgery with a safety follow-up visit.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Dual HER2 blockade | Experimental | Drug: Lapatinib, Drug: Trastuzumab, Drug: PaclitaxelFor a total of 18 weeks, HR-negative patients will be given dual blockade consisting of daily lapatinib at 1000 mg and trastuzumab at a loading dose of 8 mg/kg, followed by 6 mg/kg every 3 weeks. |
| Dual HER2 blockade plus endocrine therapy | Experimental | Drug: Lapatinib, Drug: Trastuzumab, Drug: Endocrine Therapy, Drug: PaclitaxelFor a total of 18 weeks, HR-positive patients will be given letrozole (2.5 mg daily) or tamoxifen (20 mg daily) with concurrent dual blockade consisting of daily lapatinib at 1000 mg and trastuzumab at a loading dose of 8 mg/kg, followed by 6 mg/kg every 3 weeks. |
Who may qualify
- Ages
- 18 years and older
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (12 listed)
- Written informed consent prior to beginning specific protocol procedures
- Untreated invasive breast carcinoma eligible for primary definitive surgery (stage I-IIIA)
- Histologically confirmed invasive breast carcinoma, with all of the following characteristics: primary tumor ≥1 cm in largest diameter, cN0-2, No evidence of distant metastasis (M0)
- HER2-positive invasive breast cancer by central assessment, defined by ASCO/CAP guidelines
- Female patients
Key exclusion criteria (17 listed)
- Stage III inoperable breast cancer or known metastatic disease
- Patients for whom upfront chemotherapy including taxanes and anthracyclines is clinically judged appropriate as optimal neoadjuvant treatment
- Prior chemotherapy, radiotherapy or surgery for invasive breast cancer, other than excision of tumor in the contralateral breast, and provided that the patient did not previously receive adjuvant radiotherapy or chemotherapy
- Subjects with a concurrently active second malignancy, other than adequately treated non-melanoma skin cancers, in situ melanoma or in situ cervical cancer. Subjects with other non-mammary malignancies must have been disease-free for at least 5 years
- Known or suspected hypersensitivity reaction to any investigational or therapeutic compound or their incorporated substances
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 |
|---|---|---|
| LapatinibAlso: Tyverb, Tykerb | Drug | Dual HER2 blockade, Dual HER2 blockade plus endocrine therapy |
| TrastuzumabAlso: Herceptin, Herclon | Drug | Dual HER2 blockade, Dual HER2 blockade plus endocrine therapy |
| Endocrine TherapyAlso: Letrozol, Letrozole, Devazol, Femara, Galdar, Loxifan, Tamoxifen, Tamoxifeno, Nolvadex, Istubal, ValodexLetrozole or tamoxifen will be prescribed according to patient's menopausal status | Drug | Dual HER2 blockade plus endocrine therapy |
| PaclitaxelAlso: Abraxane, TaxolOnly administrated if tumor progression is observed by US on week 6 | Drug | Dual HER2 blockade, Dual HER2 blockade plus endocrine therapy |
Primary outcome
pCRB to dual HER2 blockade with lapatinib and trastuzumab in all patients, at the time of surgery, predicted by PAM50 HER2-E subtype
Time frame: At the time of surgery
Comparison between the PAM50 HER2-E versus non HER2-E cases to achieve pCRB from dual HER2 blockade with lapatinib and trastuzumab at the time of surgery
10 secondary outcomes
Pathological complete response in the breast and axilla (pCRBL) to dual HER2 blockade with lapatinib and trastuzumab, in all patients, at the time of surgery, predicted by PAM50 HER2-E subtype
Time frame: At the time of surgery
Residual cancer burden in the breast (RCB) to dual HER2 blockade with lapatinib and trastuzumab, in all patients, at the time of surgery, predicted by PAM50 HER2-E subtype
Time frame: At the time of surgery
Changes in the percentage of Ki67-positive cells in PAM50 non-Luminal A/B (combined) subtypes
Time frame: Day 14
Gene expression variations in all patients, in HR-negative and in HR-positive patients
Time frame: Day 14
Correlation between PAM50 HER2-E centroid, as a continuous variable, and pCR and/or RCB in the breast to dual HER2 blockade with lapatinib and trastuzumab at the time of surgery
Time frame: At the time of surgery
Identification of additional gene expression signatures beyond the PAM50 subtypes that predict pCR and/or RCB to dual HER2 blockade with lapatinib and trastuzumab at the time of surgery
Time frame: At the time of surgery
PAM50 risk of relapse (ROR) score and its ability to predict pCR and/or RCB in the breast to dual HER2 blockade with lapatinib and trastuzumab at the time of surgery in all patients and in those with HR-positive and HR-negative disease
Time frame: At the time of surgery
PAM50 HER-2 subtype (PAM50 HER2-E signature) ability as a continuous variable to predict pCRB to dual HER2 blockade at the time of surgery in patients with HR-positive disease and in patients with HR-negative disease
Time frame: At the time of surgery
Changes in gene expression from day 0 to day 14, after dual HER2 blockade, that predict pCRB in all patients and in those with HR-positive and HR-negative disease
Time frame: Day 14
Frequency of adverse events (AE) when lapatinib plus trastuzumab, with or without endocrine therapy, is administered in the neoadjuvant setting
Time frame: 30 days (+/-14 days) after the surgery
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 19 Sep 2018.
- Background: PubMed 22257673Baselga J, Bradbury I, Eidtmann H, Di Cosimo S, de Azambuja E, Aura C, Gomez H, Dinh P, Fauria K, Van Dooren V, Aktan G, Goldhirsch A, Chang TW, Horvath Z, Coccia-Portugal M, Domont J, Tseng LM, Kunz G, Sohn JH, Semiglazov V, Lerzo G, Palacova M, Probachai V, Pusztai L, Untch M, Gelber RD, Piccart-Gebhart M; NeoALTTO Study Team. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2012 Feb 18;379(9816):633-40. doi: 10.1016/S0140-6736(11)61847-3. Epub 2012 Jan 17.
- Background: PubMed 22153890Gianni L, Pienkowski T, Im YH, Roman L, Tseng LM, Liu MC, Lluch A, Staroslawska E, de la Haba-Rodriguez J, Im SA, Pedrini JL, Poirier B, Morandi P, Semiglazov V, Srimuninnimit V, Bianchi G, Szado T, Ratnayake J, Ross G, Valagussa P. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol. 2012 Jan;13(1):25-32. doi: 10.1016/S1470-2045(11)70336-9. Epub 2011 Dec 6.
- Background: PubMed 22752290Prat A, Parker JS, Fan C, Perou CM. PAM50 assay and the three-gene model for identifying the major and clinically relevant molecular subtypes of breast cancer. Breast Cancer Res Treat. 2012 Aug;135(1):301-6. doi: 10.1007/s10549-012-2143-0. Epub 2012 Jul 3.
- Background: PubMed 23569315Rimawi MF, Mayer IA, Forero A, Nanda R, Goetz MP, Rodriguez AA, Pavlick AC, Wang T, Hilsenbeck SG, Gutierrez C, Schiff R, Osborne CK, Chang JC. Multicenter phase II study of neoadjuvant lapatinib and trastuzumab with hormonal therapy and without chemotherapy in patients with human epidermal growth factor receptor 2-overexpressing breast cancer: TBCRC 006. J Clin Oncol. 2013 May 10;31(14):1726-31. doi: 10.1200/JCO.2012.44.8027. Epub 2013 Apr 8.
- Background: PubMed 23000897Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature. 2012 Oct 4;490(7418):61-70. doi: 10.1038/nature11412. Epub 2012 Sep 23.
- Derived from this study: PubMed 29045543Nuciforo P, Pascual T, Cortes J, Llombart-Cussac A, Fasani R, Pare L, Oliveira M, Galvan P, Martinez N, Bermejo B, Vidal M, Pernas S, Lopez R, Munoz M, Garau I, Manso L, Alarcon J, Martinez E, Rodrik-Outmezguine V, Brase JC, Villagrasa P, Prat A, Holgado E. A predictive model of pathologic response based on tumor cellularity and tumor-infiltrating lymphocytes (CelTIL) in HER2-positive breast cancer treated with chemo-free dual HER2 blockade. Ann Oncol. 2018 Jan 1;29(1):170-177. doi: 10.1093/annonc/mdx647.
- Derived from this study: PubMed 28238593Llombart-Cussac A, Cortes J, Pare L, Galvan P, Bermejo B, Martinez N, Vidal M, Pernas S, Lopez R, Munoz M, Nuciforo P, Morales S, Oliveira M, de la Pena L, Pelaez A, Prat A. HER2-enriched subtype as a predictor of pathological complete response following trastuzumab and lapatinib without chemotherapy in early-stage HER2-positive breast cancer (PAMELA): an open-label, single-group, multicentre, phase 2 trial. Lancet Oncol. 2017 Apr;18(4):545-554. doi: 10.1016/S1470-2045(17)30021-9. Epub 2017 Feb 24.
- SOLTI is a non-profit academic research organization dedicated to conducting innovative breast cancer clinical trials.Link provided by the sponsor.
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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.
Antonio Llombart, MD, PhD study chair
Hospital Arnau de Vilanova de Valencia
Aleix Prat, MD, PhD study chair
Vall d'Hebron Institute of Oncology
Javier Cortés, MD, PhD study chair
Vall d'Hebron University Hospital
22 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Lapatinib, Trastuzumab and Endocrine Therapy in people with Breast Cancer, run by SOLTI Breast Cancer Research Group at 22 sites in Spain.
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 12 inclusion and 17 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: finished, as of the sponsor's last update on 19 Sep 2018. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 22 sites in Spain. 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?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
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?
pCRB to dual HER2 blockade with lapatinib and trastuzumab in all patients, at the time of surgery, predicted by PAM50 HER2-E subtype (time frame: At the time of surgery). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01973660, which also lists 7 linked publications.
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 19 Sep 2018.