Chemotherapy-free Trastuzumab and Pertuzumab in HER2-positive Breast Cancer: FDG-PET Response-adapted Strategy.

NCT03161353 | Active Not Recruiting Phase 2 DMC

• 2 other identifiers: MedOPP0962016-002676-27
• Study Type: interventional
• Target: 377
• Locations: 7 countries
• Sites: 56

Brief Summary

The study assess the early metabolic effects of neoadjuvant treatment with trastuzumab and pertuzumab (± endocrine therapy) on the primary tumor and axillary lymph nodes and their predictive value for pathologic complete response (pCR) in the breast and axilla. And also assess 3-year invasive disease-free survival (iDFS) in patients with HER2-positive (HER: human epidermal receptor) breast cancer treated with neoadjuvant trastuzumab and pertuzumab (± endocrine therapy) using a FDG-PET response-adapted strategy.

Conditions

Breast Cancer

Outcome Measures

Primary Outcomes (2)

• Evaluate the rate of pCR

  evaluate the rate of pCR as defined by the absence of invasive disease in the breast and axilla (ypT0/isN0) at the time of surgery achieved with the combination of trastuzumab and pertuzumab (± endocrine therapy) as exclusive neoadjuvant treatment in PET responders patients (cohort B/PET responders) \[PET/CT positive predictive value (PPV) for a pCR among patients who are PET responders\].

  After Cycle 6 or 8 (each cycle 21 days- After 4.2 or 5.6 months)

• 3-year iDFS rate

  time from the first date of no disease (i.e., date of surgery) to invasive recurrence, new invasive disease, or death by any cause. Recurrence will be defined in accordance with the standardized efficacy endpoints (STEEP) criteria. The primary analysis will be to estimate 3-year iDFS rate in cohort B.

  After 3 years (36 months)

Secondary Outcomes (18)

• pCR rates in the breast and axilla (ypTO/isN0)

  After Cycle 6 or 8 (each cycle 21 days- After 4.2 or 5.6 months)

• pCR rates in the breast (ypT0/is)

  After Cycle 6 or 8 (each cycle 21 days- After 4.2 or 5.6 months)

• RCB score (residual cancer burden)

  After Cycle 6 or 8 (each cycle 21 days- After 4.2 or 5.6 months)

• pCR rates in the breast and axilla

  After Cycle 6 or 8 (each cycle 21 days- After 4.2 or 5.6 months)

• Rate of breast conserving surgery

  After Cycle 6 or 8 (each cycle 21 days- After 4.2 or 5.6 months)

Other Outcomes (1)

• LINGain sub-study: analyze the variation of peripheral γδ T cells in blood samples

  Screening, end of cycle 1 and end of cycle 2 (each cycle is 21 days)

Study Arms (3)

Cohort A

EXPERIMENTAL

Cohorts A/B if there is no evidence of subclinic M1 assessed by 18F-FDG PET/CT at screening. Interventional: Perjeta+Herceptin+Carboplatin+Docetaxel (during 4 cycles): PET responders or not responders after surgery: Continue with Perjeta+Herceptin+ Endocrine therapy (tamoxifen or letrozole) during 12 cycles A sub-set of 42 patients (35 patients from cohort A and 7 patients from cohort B) from 5 sites in Spain are participating in the LINGain sub-study "Prospective evaluation of predictive/prognostic immunogenicity biomarkers for target therapy in HER2-positive early breast cancer within the PHERGain study".

Drug: Perjeta; Drug: Herceptin; Drug: Docetaxel; Drug: Carboplatin; Drug: Letrozole; Drug: Tamoxifen

Cohort B

EXPERIMENTAL

Cohorts A/B if there is no evidence of subclinic M1 assessed by 18F-FDG PET/CT at screening. Interventional: Perjeta+Herceptin+Endocrine therapy (tamoxifen or letrozole) during 2 cycles. * PET responders: Perjeta+Herceptin+Endocrine therapy during 6 cycles. -Complete response: continue with Perjeta+Herceptin+ Endocrine therapy during 10 cycles -Non-complete response: Perjeta+Herceptin+ Carboplatin+ Docetaxel during 6 cycles and Perjeta+Herceptin+Endocrine therapy during 4 cycles. * PET non-responders: Perjeta+Herceptin+Carboplatin+Docetaxel during 6 cycles. Patients with or without complete response will continue with Perjeta+Herceptin+Endocrine therapy during 10 cycles. A sub-set of 42 patients (35 patients from cohort A and 7 patients from cohort B) from 5 sites in Spain are participating in the LINGain sub-study "Prospective evaluation of predictive/prognostic immunogenicity biomarkers for target therapy in HER2-positive early breast cancer within the PHERGain study".

Drug: Perjeta; Drug: Herceptin; Drug: Docetaxel; Drug: Carboplatin; Drug: Letrozole; Drug: Tamoxifen

Cohort C

EXPERIMENTAL

cohorts C if there is evidence of subclinic M1 assessed by 18F-FDG PET/CT at screening Interventional: Perjeta+Herceptin+Carboplatin+Docetaxel during 6 cycles. Patients will continue with Perjeta+Herceptin+Endocrine therapy (tamoxifen or letrozole) after surgery or no surgery.

Drug: Perjeta; Drug: Herceptin; Drug: Docetaxel; Drug: Carboplatin; Drug: Letrozole; Drug: Tamoxifen

Interventions

Perjeta DRUG

All patients will receive Perjeta® as an IV infusion on Day 1 of the first treatment cycle as a loading dose of 840 mg, followed by 420 mg on Day 1 of each subsequent 3-week cycle. Perjeta® IV should be administered 60 minutes after the end of Herceptin® SC (subcutaneous) administration. An observation period of 30-60 minutes is recommended after each Perjeta® infusion.

Also known as: Pertuzumab

Cohort A; Cohort B; Cohort C

Herceptin DRUG

All patients will receive a fixed dose of 600 mg, irrespective of the patient's weight, will be administered throughout the treatment phase. All doses of Herceptin® SC will be administered as an SC injection into the thigh by a trained health care professional over a period of 2-5 minutes. No loading dose is required with Herceptin® SC.

Also known as: Trastuzumab

Cohort A; Cohort B; Cohort C

Docetaxel DRUG

Docetaxel will be administered in line with the respective product information and/or recognized clinical practice guidelines. It will be administered after Herceptin® SC, Perjeta® IV, and carboplatin

Cohort A; Cohort B; Cohort C

Carboplatin DRUG

Carboplatin will be administered in line with the respective product information and/or recognized clinical practice guidelines. It will be administered after Herceptin® SC and Perjeta® IV.

Cohort A; Cohort B; Cohort C

Letrozole DRUG

Postmenopausal women will receive letrozole 2.5 mg tablet orally once daily beginning on Day 1 and continuing through Day 21 of a 21-day cycle as neoadjuvant therapy.

Cohort A; Cohort B; Cohort C

Tamoxifen DRUG

Premenopausal women will receive tamoxifen 20 mg tablet orally once daily beginning on Day 1 and continuing through Day 21 of a 21-day cycle as neoadjuvant therapy. Male patients will receive tamoxifen 20 mg tablet orally once daily beginning on Day 1 and continuing through Day 21 of a 21-day cycle as neoadjuvant therapy.

Cohort A; Cohort B; Cohort C

Eligibility Criteria

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

You may qualify if:

• Written informed consent prior to beginning specific protocol procedures.
• Female or male patients ≥ 18 years of age.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
• Histologically proven invasive breast cancer.
• Operable breast cancer (cT1-3 and/or cN0-2 tumors) (breast cancer TNM classification)
• Tumor size larger than or equal to 1.5 centimeter (cm) in diameter by magnetic resonance imaging (MRI) or ultrasound with a significant 18F-FDG uptake defined as maximum standarized uptake value (SUVmax: maximum standarized uptake value) ≥1.5 x SUVmean (mean standarized uptake value) liver + 2 SD (standard deviation.
• Multicentric/multifocal tumors will be allowed only if:
• Histological confirmation of at least two lesions.
• All tumors must be HER2-positive.
• Largest lesion must be larger than or equal to 1.5 cm in diameter by MRI or ultrasound.
• )Centrally confirmed HER2-positive disease according to the 2018 American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) criteria.
• )Patient must have known estrogen receptor (ER) and progesterone receptor (PR) status locally determined prior to study entry.
• Patient has adequate bone marrow, liver, and renal function:
• )Hematological: White blood cell (WBC) count \> 3.0 x 109/L, absolute neutrophil count (ANC) ≥ 1.5 x 109/L, platelet count ≥ 100.0 x109/L, and hemoglobin ≥ 10.0 g/dL (≥ 6.2 mmol/L).
• )Hepatic: total bilirubin ≤ institutional upper limit of normal (ULN) (except for Gilbert's syndrome); alkaline phosphatase (ALP) ≤ 2.5 times ULN; aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 1.5 times ULN.

You may not qualify if:

• Previous treatment with chemotherapy, anti-HER2 therapy, radiation therapy, or endocrine therapy for invasive breast cancer.
• cT4 and/or cN3 tumors (TNM breast cancer classification)
• Bilateral breast cancer.
• Evidence of metastatic disease by routine clinical assessment chest x-ray, liver ultrasound, and bone scan; or computed tomography (CT) scan of thorax and abdomen and bone scan, except patients with subclinic M1 (metastases) at baseline only according to 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) that will be allowed to be included into cohort C.
• Known hypersensitivity reaction to any investigational or therapeutic compound or their incorporated substances.
• History of other malignancy within the last five years prior to first dose of study drug administration, except for curatively treated basal and squamous cell carcinoma of the skin and/or in situ cervical carcinoma.
• Left ventricular ejection fraction (LVEF) below 55% as determined by multiple-gated acquisition (MUGA) scan or echocardiography (ECHO).
• Uncontrolled hypertension (systolic \> 150 mm Hg and/or diastolic \> 100 mm Hg) despite adequate antihypertensive treatment.
• Clinically significant cardiovascular disease \[stroke, unstable angina pectoris, or documented myocardial infarction within six months prior to study entry; history of documented congestive heart failure (CHF) (New York Heart Association II-III-IV); symptomatic pericarditis; documented cardiomyopathy; ventricular arrythmias with the exception of benign premature ventricular contractions; conduction abnormality requiring a pacemaker; other arrhythmias not controlled with medication\].
• Active uncontrolled infection at the time of enrollment.
• Current known infection with HIV, hepatitis B virus, or hepatitis C virus.
• Patients with pulmonary disease requiring continuous oxygen therapy.
• Previous history of bleeding diathesis.
• Patient is currently receiving anti-coagulant therapy, chronic treatment with corticosteroids, or another immunosuppressive agent (standard premedication for chemotherapy and local applications are allowed).
• Major surgical procedure or significant traumatic injury within 14 days prior to randomization or anticipation of need for major surgery within the course of the study treatment.

Sponsors & Collaborators

• MedSIR: lead

Study Sites (56)

Institute Jules Bordet

Brussels, Belgium

Location

CLCC d'Auvergne. Centre Jean Perrin.

Clermont-Ferrand, France

Location

Institute de Cancerologie de Laurraine

Nancy, France

Location

Groupe Hospitalier Diaconesses

Paris, France

Location

Hopital Tenon

Paris, France

Location

Hospital Georges Pompidou

Paris, France

Location

Centre Paul Strauss

Strasbourg, France

Location

Institut Claudius Régaud

Toulouse, France

Location

Kliniken Essen Mitte

Essen, Germany

Location

Klinikum der Med. Fakultät Halle

Halle, Germany

Location

National center for tumor disease NCT

Heidelberg, Germany

Location

Städtisches Klinikum "St. Georg" Leipzig

Leipzig, Germany

Location

Clinical of Nuclear Medicine Technical University Munich

Munich, Germany

Location

Hämatologisch-Onkologische Schwerpunktpraxis

München, Germany

Location

Ospedale Maggiore Bologna

Bologna, Italy

Location

Ospedale Antonio Perrino

Brindisi, Italy

Location

Istituto Ospedalieri di Cremona

Cremona, Italy

Location

Ospedale Mantova

Mantova, Italy

Location

Istituto Europeo di Oncologia

Milan, Italy

Location

Ospedale San Gerardo

Monza, Italy

Location

Ospedale Guglielmo de Saliceto

Piacenza, Italy

Location

Hospital Senhora da Oliveira

Guimarães, Portugal

Location

Hospital Beatriz Angelo

Lisbon, Portugal

Location

Hospital da Luz

Lisbon, Portugal

Location

Hospital Fernando Fonseca

Lisbon, Portugal

Location

Centro Hospitalar Sao Joao

Porto, Portugal

Location

Hospital do Santo Antonio

Porto, Portugal

Location

Centro Hospitalaer de Tras-os-Montes e Alto Douro

Vila Real, Portugal

Location

ICO Badalona

Badalona, Barcelona, Spain

Location

ICO l'Hospitalet

L'Hospitalet de Llobregat, Barcelona, 08007, Spain

Location

Hospital Provincial de Castellón

Castelló, Castelló, Spain

Location

Hospital de Jaén

Jaén, Jaén, Spain

Location

Hospital Universitario Virgen de la Victoria

Málaga, Málaga, Spain

Location

Hospital San Joan de Reus

Reus, Tarragona, Spain

Location

Hospital Universitario A Coruña

A Coruña, Spain

Location

Hospital Vall D'Hebrón

Barcelona, 08035, Spain

Location

Hospital Clínic i Provincial de Barcelona

Barcelona, Spain

Location

Hospital Universitario de Burgos

Burgos, Spain

Location

Hospital Reina Sofía

Córdoba, Spain

Location

ICO Girona

Girona, Spain

Location

Hospital Arnau de Vilanova

Lleida, Spain

Location

Hospital La Paz

Madrid, Spain

Location

Hospital Ramón y Cajal

Madrid, Spain

Location

CHUS Santiago de Compostela

Santiago de Compostela, Spain

Location

Hospital Universitario Virgen del Rocío

Seville, Spain

Location

Hospital Arnau de Vilanova

Valencia, Spain

Location

Hospital Clínic Universitari de Valencia

Valencia, Spain

Location

Hospital Dr Peset

Valencia, Spain

Location

Hospital General Universitari de Valencia

Valencia, Spain

Location

Hospital Universitari i Politecnic La Fe

Valencia, Spain

Location

Instituto Valenciano de Oncologia

Valencia, Spain

Location

Hospital Lozano Blesa

Zaragoza, 50009, Spain

Location

Hospital Universitario Miquel Servet

Zaragoza, Spain

Location

Barts Cancer Institute

London, United Kingdom

Location

The Christie NHS Foundation Trust

Manchester, United Kingdom

Location

Royal Cornwall Hospital

Truro, United Kingdom

Location

Related Publications (4)

• Llombart-Cussac A, Prat A, Perez-Garcia JM, Mateos J, Pascual T, Escriva-de-Romani S, Stradella A, Ruiz-Borrego M, de Las Heras BB, Keyaerts M, Galvan P, Braso-Maristany F, Garcia-Mosquera JJ, Guiot T, Gion M, Sampayo-Cordero M, Di Cosimo S, Perez-Escuredo J, de Frutos MA, Cortes J, Gebhart G. Clinicopathological and molecular predictors of [18F]FDG-PET disease detection in HER2-positive early breast cancer: RESPONSE, a substudy of the randomized PHERGain trial. Eur J Nucl Med Mol Imaging. 2024 Jul;51(9):2733-2743. doi: 10.1007/s00259-024-06683-0. Epub 2024 Apr 8.

  PMID: 38587643 DERIVED

• Perez-Garcia JM, Cortes J, Ruiz-Borrego M, Colleoni M, Stradella A, Bermejo B, Dalenc F, Escriva-de-Romani S, Calvo Martinez L, Ribelles N, Marme F, Cortes A, Albacar C, Gebhart G, Prat A, Kerrou K, Schmid P, Braga S, Di Cosimo S, Gion M, Antonarelli G, Popa C, Szostak E, Alcala-Lopez D, Gener P, Rodriguez-Morato J, Mina L, Sampayo-Cordero M, Llombart-Cussac A; PHERGain Trial Investigators. 3-year invasive disease-free survival with chemotherapy de-escalation using an 18F-FDG-PET-based, pathological complete response-adapted strategy in HER2-positive early breast cancer (PHERGain): a randomised, open-label, phase 2 trial. Lancet. 2024 Apr 27;403(10437):1649-1659. doi: 10.1016/S0140-6736(24)00054-0. Epub 2024 Apr 3.

  PMID: 38582092 DERIVED

• Perez-Garcia JM, Gebhart G, Borrego MR, Schmid P, Marme F, Prat A, Dalenc F, Kerrou K, Colleoni M, Braga S, Malfettone A, Sampayo-Cordero M, Cortes J, Llombart-Cussac A. Trastuzumab and pertuzumab without chemotherapy in early-stage HER2+ breast cancer: a plain language summary of the PHERGain study. Future Oncol. 2022 Oct;18(33):3677-3688. doi: 10.2217/fon-2022-0663. Epub 2022 Oct 27.

  PMID: 36300423 DERIVED

• Perez-Garcia JM, Gebhart G, Ruiz Borrego M, Stradella A, Bermejo B, Schmid P, Marme F, Escriva-de-Romani S, Calvo L, Ribelles N, Martinez N, Albacar C, Prat A, Dalenc F, Kerrou K, Colleoni M, Afonso N, Di Cosimo S, Sampayo-Cordero M, Malfettone A, Cortes J, Llombart-Cussac A; PHERGain steering committee and trial investigators. Chemotherapy de-escalation using an 18F-FDG-PET-based pathological response-adapted strategy in patients with HER2-positive early breast cancer (PHERGain): a multicentre, randomised, open-label, non-comparative, phase 2 trial. Lancet Oncol. 2021 Jun;22(6):858-871. doi: 10.1016/S1470-2045(21)00122-4. Epub 2021 May 18.

  PMID: 34019819 DERIVED

MeSH Terms

Conditions

Breast Neoplasms

Interventions

pertuzumab; Trastuzumab; Docetaxel; Carboplatin; Letrozole; Tamoxifen

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Diterpenes; Terpenes; Coordination Complexes; Nitriles; Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Stilbenes; Benzylidene Compounds; Benzene Derivatives; Hydrocarbons, Aromatic

Study Officials

• Antonio Llombart, MD

  Hospital Arnau de Vilanova

  PRINCIPAL INVESTIGATOR

Study Design

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

Model Details: This randomized, open-label phase II study will assess the efficacy of the combination of trastuzumab and pertuzumab, ± endocrine therapy according to HR (hormone receptor) status, as exclusive neoadjuvant and adjuvant treatment in patients with HER2-positive breast cancer through a FDG-PET response-adapted strategy.

Study Record Dates

• First Submitted: May 15, 2017
• First Posted: May 19, 2017
• Study Start: June 26, 2017
• Primary Completion: November 1, 2023
• Study Completion (Estimated): November 1, 2026
• Last Updated: April 23, 2025

Record last verified: 2025-04

Data Sharing

• IPD Sharing: Will not share

Locations

BE (1); PT (7); DE (6); FR (7); ES (25); IT (7); GB (3)