Clinical trial NCT03161353: Chemotherapy-free Trastuzumab and Pertuzumab in HER2-positive Breast Cancer: FDG-PET Response-adapted Strategy.
Official title: Chemotherapy-free Trastuzumab and Pertuzumab in HER2-positive (Human Epidermal Receptor) Breast Cancer: FDG-PET Response-adapted Strategy. The PHERGain Study
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Breast Cancer
Lead sponsor: MedSIR
Sponsor class: OTHER
First posted: 2017-05-19
Enrollment: 377
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: 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.
Primary purpose: TREATMENT

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.

Detailed description: Investigational Medicinal Products (IMPs) will be trastuzumab and pertuzumab, carboplatin, and docetaxel, as well as all endocrine therapy drugs to be administered according to HR status (hormone receptor). For cohort C, trastuzumab SC (subcutaneous) and pertuzumab IV will be IMPs until a maximum of 18 cycles.

Patients will be randomly assigned in a 1:4 ratio, with a randomization stratified by HR status to receive trastuzumab and pertuzumab with docetaxel and carboplatin (cohort A) or trastuzumab and pertuzumab ± endocrine therapy according to HR status (cohort B).

A F-FDG PET/CT will be performed at baseline (total body) and after 2 cycles of neoadjuvant therapy. Central review of F-FDG PET/CT will be mandatory. Patients allocated into cohort A will continue with the same treatment for a total of six cycles regardless of 18F-FDG PET/CT results. Patients enrolled into cohort B showing at least 40% reduction of the SUVmax of F-FDG PET/CT respect to baseline (PET responders) will continue with the same treatment for a total of 8 cycles. PET-non responders patients will also receive neoadjuvant chemotherapy based on six cycles of docetaxel and carboplatin concurrently with trastuzumab and pertuzumab for all cycles.

Following surgery, cohort B/PET responders patients who do not achieve a pCR will additionally receive six cycles of docetaxel and carboplatin concurrently with trastuzumab and pertuzumab for all cycles. Moreover, all patients from cohorts A/B must complete 18 cycles of trastuzumab and pertuzumab, along with adjuvant endocrine therapy and radiotherapy according to HR status (hormone receptor) and institutional practices, respectively.

An additional exploratory cohort (cohort C) will include patients with evidence of subclinic M1 at baseline 18F-FDG PET/CT, but not previously detected by routine clinical assessment. These patients will receive trastuzumab and pertuzumab with docetaxel and carboplatin for a total of six cycles. After first six cycles, these patients will receive trastuzumab and pertuzumab ± endocrine.therapy according to HR status for at least 12 additional cycles after surgery (only if surgery is performed). According to institutional practices, it will be allowed to continue treatment with trastuzumab and pertuzumab, along endocrine therapy on the basis of HR status, as maintenance therapy until disease progression or unacceptable toxicity.

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" : Hospital General de Valencia, Hospital Clínico Universitario de Valencia, IVO, Hospital La Fe and Hospital Arnau de Vilanova.

Eligibility criteria: Inclusion Criteria:

1. Written informed consent prior to beginning specific protocol procedures.
2. Female or male patients ≥ 18 years of age.
3. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
4. Histologically proven invasive breast cancer.
5. Operable breast cancer (cT1-3 and/or cN0-2 tumors) (breast cancer TNM classification)
6. 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:

1. Histological confirmation of at least two lesions.
2. All tumors must be HER2-positive.
3. Largest lesion must be larger than or equal to 1.5 cm in diameter by MRI or ultrasound.

7)Centrally confirmed HER2-positive disease according to the 2018 American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) criteria.

8)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:

9)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).

10)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.

11)Renal: serum creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 50 mL/min/1.73 m2 for patients with creatinine levels above institutional normal.

12)Patient must be accessible for treatment and follow-up.

Exclusion Criteria:

1. Previous treatment with chemotherapy, anti-HER2 therapy, radiation therapy, or endocrine therapy for invasive breast cancer.
2. cT4 and/or cN3 tumors (TNM breast cancer classification)
3. Bilateral breast cancer.
4. 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.
5. Known hypersensitivity reaction to any investigational or therapeutic compound or their incorporated substances.
6. 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.
7. Left ventricular ejection fraction (LVEF) below 55% as determined by multiple-gated acquisition (MUGA) scan or echocardiography (ECHO).
8. Uncontrolled hypertension (systolic \> 150 mm Hg and/or diastolic \> 100 mm Hg) despite adequate antihypertensive treatment.
9. Clinically significant cardiovascular disease \[stroke, unstable angina pectoris, or documented myocardial infarction within six months prior to study entry; history of documented congestive heart failure (CHF) (New York Heart Association II-III-IV); symptomatic pericarditis; documented cardiomyopathy; ventricular arrythmias with the exception of benign premature ventricular contractions; conduction abnormality requiring a pacemaker; other arrhythmias not controlled with medication\].
10. Active uncontrolled infection at the time of enrollment.
11. Current known infection with HIV, hepatitis B virus, or hepatitis C virus.
12. Patients with pulmonary disease requiring continuous oxygen therapy.
13. Previous history of bleeding diathesis.
14. Patient is currently receiving anti-coagulant therapy, chronic treatment with corticosteroids, or another immunosuppressive agent (standard premedication for chemotherapy and local applications are allowed).
15. 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.
16. Patient has other concurrent severe and/or uncontrolled medical conditions that would, in the investigator´s judgment, contraindicate her participation in the clinical study.
17. Concurrent participation in other clinical trial, except other translational studies.
18. History of receiving any investigational treatment within 28 days prior to randomization.
19. Pregnant or breast-feeding women or patients not willing to apply highly effective contraception as defined in the protocol.

LINGain sub-study: The LINGAIN project intends to include a total of 126 blood samples from PHERGain trial, as follows:

105 from patients treated with trastuzumab and pertuzumab ± endocrine therapy (according to HR status); 21 from patients treated with trastuzumab and pertuzumab + carboplatin and docetaxel.

Primary outcomes:
measure: Evaluate the rate of pCR
timeFrame: After Cycle 6 or 8 (each cycle 21 days- After 4.2 or 5.6 months)
measure: 3-year iDFS rate
timeFrame: After 3 years (36 months)
Secondary outcomes:
measure: pCR rates in the breast and axilla (ypTO/isN0)
timeFrame: After Cycle 6 or 8 (each cycle 21 days- After 4.2 or 5.6 months)
measure: pCR rates in the breast (ypT0/is)
timeFrame: After Cycle 6 or 8 (each cycle 21 days- After 4.2 or 5.6 months)
measure: RCB score (residual cancer burden)
timeFrame: After Cycle 6 or 8 (each cycle 21 days- After 4.2 or 5.6 months)
measure: pCR rates in the breast and axilla
timeFrame: After Cycle 6 or 8 (each cycle 21 days- After 4.2 or 5.6 months)
measure: Rate of breast conserving surgery
timeFrame: After Cycle 6 or 8 (each cycle 21 days- After 4.2 or 5.6 months)
measure: 18F-FDG PET/CT response rate (18F-FDG: 18F-fluorodeoxyglucose)
timeFrame: After cycle 2 (each cycle 21 days- After 42 days approximately)
measure: Optimal 18F-FDG PET/CT cut-off for pCR
timeFrame: After cycle 2 (each cycle 21 days-After 42 days approximately)
measure: Other 18FDG PET quantification parameters
timeFrame: After cycle 2 (each cycle 21 days- After 42 days approximately)
measure: MRI response rate
timeFrame: After two cycles of neoadjuvant therapy, and prior to surgery (each cycle 21 days)
measure: Health-related quality of life
timeFrame: Baseline, cycle 3 (after 63 days approximately), before surgery and end of study through study completion (after cycle 18- after 12 months approximately)
measure: 3, 5, and 7-year iDFS
timeFrame: After 3, 5 and 7 years (After 36, 60 and 80 months)
measure: 3,5 and 7-year DDFS (DDFS:Distant disease-free survival)
timeFrame: After 3, 5 and 7 years (After 36, 60 and 80 months)
measure: 3, 5 and 7-year DFS (DFS:Disease-free survival)
timeFrame: After 3, 5 and 7 years (After 36, 60 and 80 months)
measure: 3, 5 and 7-year (OS: overall survival)
timeFrame: After 3, 5 and 7 years (After 36, 60 and 80 months)
measure: PFS (cohort C) (PFS: Progression-free survival)
timeFrame: Until progression or death, assessed up to approximately 84 months
measure: Adverse events
timeFrame: Until progression or death, assessed up to approximately 84 months
measure: 3, 5, and 7-year EFS
timeFrame: After 3, 5 and 7 years (After 36, 60 and 80 months)
measure: To assess 3, 5, and 7-year adapted iDFS, DDFS, and DFS
timeFrame: After 3, 5 and 7 years (After 36, 60 and 80 months)
Other outcomes:
measure: LINGain sub-study: analyze the variation of peripheral γδ T cells in blood samples
timeFrame: Screening, end of cycle 1 and end of cycle 2 (each cycle is 21 days)
Locations:
city: Bruxelles
country: Belgium
facility: Institute Jules Bordet
city: Clermont-Ferrand
country: France
facility: CLCC d'Auvergne. Centre Jean Perrin.
city: Nancy
country: France
facility: Institute de Cancerologie de Laurraine
city: Paris
country: France
facility: Groupe Hospitalier Diaconesses
city: Paris
country: France
facility: Hopital Tenon
city: Paris
country: France
facility: Hospital Georges Pompidou
city: Strasbourg
country: France
facility: Centre Paul Strauss
city: Toulouse
country: France
facility: Institut Claudius Régaud
city: Essen
country: Germany
facility: Kliniken Essen Mitte
city: Halle
country: Germany
facility: Klinikum der Med. Fakultät Halle
city: Heidelberg
country: Germany
facility: National center for tumor disease NCT
city: Leipzig
country: Germany
facility: Städtisches Klinikum "St. Georg" Leipzig
city: Munchen
country: Germany
facility: Hämatologisch-Onkologische Schwerpunktpraxis
city: Munich
country: Germany
facility: Clinical of Nuclear Medicine Technical University Munich
city: Bologna
country: Italy
facility: Ospedale Maggiore Bologna
city: Brindisi
country: Italy
facility: Ospedale Antonio Perrino
city: Cremona
country: Italy
facility: Istituto Ospedalieri di Cremona
city: Mantova
country: Italy
facility: Ospedale Mantova
city: Milan
country: Italy
facility: Istituto Europeo di Oncologia
city: Monza
country: Italy
facility: Ospedale San Gerardo
city: Piacenza
country: Italy
facility: Ospedale Guglielmo de Saliceto
city: Guimarães
country: Portugal
facility: Hospital Senhora da Oliveira
city: Lisboa
country: Portugal
facility: Hospital Beatriz Angelo
city: Lisboa
country: Portugal
facility: Hospital da Luz
city: Lisboa
country: Portugal
facility: Hospital Fernando Fonseca
city: Oporto
country: Portugal
facility: Centro Hospitalar Sao Joao
city: Oporto
country: Portugal
facility: Hospital do Santo Antonio
city: Vila Real
country: Portugal
facility: Centro Hospitalaer de Tras-os-Montes e Alto Douro
city: Badalona
country: Spain
facility: ICO Badalona
state: Barcelona
city: L'Hospitalet de Llobregat
country: Spain
facility: ICO l'Hospitalet
state: Barcelona
city: Castello
country: Spain
facility: Hospital Provincial de Castellón
state: Castelló
city: Jaen
country: Spain
facility: Hospital de Jaén
state: Jaén
city: Malaga
country: Spain
facility: Hospital Universitario Virgen de la Victoria
state: Málaga
city: Reus
country: Spain
facility: Hospital San Joan de Reus
state: Tarragona
city: A Coruna
country: Spain
facility: Hospital Universitario A Coruña
city: Barcelona
country: Spain
facility: Hospital Vall D'Hebrón
city: Barcelona
country: Spain
facility: Hospital Clínic i Provincial de Barcelona
city: Burgos
country: Spain
facility: Hospital Universitario de Burgos
city: Cordoba
country: Spain
facility: Hospital Reina Sofía
city: Girona
country: Spain
facility: ICO Girona
city: Lleida
country: Spain
facility: Hospital Arnau de Vilanova
city: Madrid
country: Spain
facility: Hospital La Paz
city: Madrid
country: Spain
facility: Hospital Ramón y Cajal
city: Santiago de Compostela
country: Spain
facility: CHUS Santiago de Compostela
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocío
city: Valencia
country: Spain
facility: Hospital Arnau de Vilanova
city: Valencia
country: Spain
facility: Hospital Clínic Universitari de Valencia
city: Valencia
country: Spain
facility: Hospital Dr Peset
city: Valencia
country: Spain
facility: Hospital General Universitari de Valencia
city: Valencia
country: Spain
facility: Hospital Universitari i Politecnic La Fe
city: Valencia
country: Spain
facility: Instituto Valenciano de Oncologia
city: Zaragoza
country: Spain
facility: Hospital Lozano Blesa
city: Zaragoza
country: Spain
facility: Hospital Universitario Miquel Servet
city: London
country: United Kingdom
facility: Barts Cancer Institute
city: Manchester
country: United Kingdom
facility: The Christie NHS Foundation Trust
city: Truro
country: United Kingdom
facility: Royal Cornwall Hospital
Study officials:
affiliation: Hospital Arnau de Vilanova
name: Antonio Llombart, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.