PAM50 HER2-enriched Phenotype as a Predictor of Response to Dual HER2 Blockade in HER2-positive Early Breast Cancer

NCT01973660 | Completed Phase 2 DMC

• 2 other identifiers: SOLTI-11142013-001036-22
• Study Type: interventional
• Target: 151
• Locations: 1 country
• Sites: 22

Brief 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, 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.

Conditions

Breast Cancer

Keywords

Human Epidermal Growth Factor Receptor 2; HER2; HER2 positive; PAM50; lapatinib; trastuzumab; dual HER2 blockade; neoadjuvant

Outcome Measures

Primary Outcomes (1)

• 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

  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

  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

  At the time of surgery

• Changes in the percentage of Ki67-positive cells in PAM50 non-Luminal A/B (combined) subtypes

  Day 14

• Gene expression variations in all patients, in HR-negative and in HR-positive patients

  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

  At the time of surgery

Study Arms (2)

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.

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.

Drug: Lapatinib; Drug: Trastuzumab; Drug: Endocrine Therapy; Drug: Paclitaxel

Interventions

Lapatinib DRUG

Also known as: Tyverb, Tykerb

Dual HER2 blockade; Dual HER2 blockade plus endocrine therapy

Trastuzumab DRUG

Also known as: Herceptin, Herclon

Dual HER2 blockade; Dual HER2 blockade plus endocrine therapy

Endocrine Therapy DRUG

Letrozole or tamoxifen will be prescribed according to patient's menopausal status

Also known as: Letrozol, Letrozole, Devazol, Femara, Galdar, Loxifan, Tamoxifen, Tamoxifeno, Nolvadex, Istubal, Valodex

Dual HER2 blockade plus endocrine therapy

Paclitaxel DRUG

Only administrated if tumor progression is observed by US on week 6

Also known as: Abraxane, Taxol

Dual HER2 blockade; Dual HER2 blockade plus endocrine therapy

Eligibility Criteria

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

You may qualify if:

• 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
• 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

You may not qualify if:

• 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%
• 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

Sponsors & Collaborators

• SOLTI Breast Cancer Research Group: lead
• Novartis: collaborator

Study Sites (22)

Hospital de Torrevieja

Torrevieja, Alicante, Spain

Location

Hospital Son Llàtzer

Palma de Mallorca, Balearic Islands, Spain

Location

Hospital Universitario Son Espases

Palma de Mallorca, Balearic Islands, Spain

Location

Institut Català d'Oncologia Hospitalet

L'Hospitalet de Llobregat, Barcelona, Spain

Location

Hospital Mutua de Terrassa

Terrassa, Barcelona, Spain

Location

Consorcio Hospitalario Provincial de Castellón

Castellon, Castellón, Spain

Location

Hospital Clínico Universitario de Santiago de Compostela

Santiago de Compostela, Galicia, Spain

Location

Hospital Universitario de Fuenlabrada

Fuenlabrada, Madrid, Spain

Location

Hospital Universitario Virgen de la Arrixaca

El Palmar, Murcia, Spain

Location

Hospital Universitario Sant Joan de Reus

Reus, Tarragona, Spain

Location

Hospital Luis Alcanyís de Xàtiva

Xàtiva, Valencia, 46800, Spain

Location

Hospital Universitario Infanta Cristina

Badajoz, 06071, Spain

Location

Vall d'Hebron University Hospital

Barcelona, 08035, Spain

Location

Hospital Clínic de Barcelona

Barcelona, Spain

Location

Instituto Dexeus

Barcelona, Spain

Location

Hospital San Pedro de Alcántara

Cáceres, 10003, Spain

Location

Hospital Universitario Arnau de Vilanova de Lleida

Lleida, Spain

Location

Hospital Universitario 12 de Octubre

Madrid, 28041, Spain

Location

Hospital Clínico San Carlos

Madrid, Spain

Location

Hospital Universitario Ramón y Cajal

Madrid, Spain

Location

Hospital Clínico Universitario de Valencia

Valencia, Spain

Location

Hospital Universitario Arnau de Vilanova de Valencia

Valencia, Spain

Location

Related Publications (7)

• 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.

  PMID: 22257673 BACKGROUND

• Gianni 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.

  PMID: 22153890 BACKGROUND

• Prat 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.

  PMID: 22752290 BACKGROUND

• Rimawi 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.

  PMID: 23569315 BACKGROUND

• Cancer 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.

  PMID: 23000897 BACKGROUND

• Nuciforo 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.

  PMID: 29045543 DERIVED

• Llombart-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.

  PMID: 28238593 DERIVED

Related Links

• SOLTI is a non-profit academic research organization dedicated to conducting innovative breast cancer clinical trials.

MeSH Terms

Conditions

Breast Neoplasms

Interventions

Lapatinib; Trastuzumab; Letrozole; Tamoxifen; Paclitaxel; Albumin-Bound Paclitaxel

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; Nitriles; Organic Chemicals; Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Stilbenes; Benzylidene Compounds; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Diterpenes; Terpenes; Albumins

Study Officials

• Antonio Llombart, MD, PhD

  Hospital Arnau de Vilanova de Valencia

  STUDY CHAIR

• Aleix Prat, MD, PhD

  Vall d'Hebron Institute of Oncology (VHIO)

  STUDY CHAIR

• Javier Cortés, MD, PhD

  Vall d'Hebron University Hospital

  STUDY CHAIR

Study Design

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

Study Record Dates

• First Submitted: October 25, 2013
• First Posted: October 31, 2013
• Study Start: October 1, 2013
• Primary Completion: June 1, 2016
• Study Completion: December 1, 2017
• Last Updated: September 19, 2018

Record last verified: 2018-09

Locations

ES (22)