Chemotherapy-free trastuzumab and pertuzumab in HER2-positive breast cancer after FDG-PET response-adapted strategy. The PHERGain study

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Medica Scientia Innovation Research S.L.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

6 Jul 2017 → ongoing

Decision date (initial)

2024-07-24

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

F. Hoffmann - La Roche, Ltd.

External identifiers

EU CT number

2023-509923-42-00

EudraCT number

2016-002676-27

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Efficacy

• To 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.
• To assess 3-year invasive disease-free survival (iDFS) in patients with HER2-positive breast cancer treated with neoadjuvant trastuzumab and pertuzumab (± endocrine therapy) using a FDG-PET response-adapted strategy.

Secondary objectives 18

1. To assess 3, 5, and 7-year invasive breast cancer free survival (iBCFS) in patients with HER2-positive breast cancer treated with neoadjuvant trastuzumab and pertuzumab (± endocrine therapy) using a FDG-PET response-adapted strategy.
2. To assess efficacy by other pCR definitions [pCR in the breast only and Residual Cancer Burden (RCB) score].
3. To compare the rate of pCR between the treatment groups by 18F-FDG PET/CT response, hormone receptor (HR) status, HER2 status, and tumor stage.
4. To compare the rate of conversion to breast conserving surgery between the treatment groups.
5. To compare the overall response rate (ORR) by 18F-FDG PET/CT between the treatment groups.
6. To analyze optimal 18F-FDG PET/CT cut-off for pCR.
7. To analyze other 18F-FDG PET quantification parameters beside SUVmax for pCR.
8. To compare the ORR by MRI between the treatment groups.
9. To evaluate changes in health-related quality of life assessments from baseline using the EORTC QLQ-C30 and QLQ-BR23 questionnaires.
10. To assess 3, 5, and 7-year iDFS between the treatment groups by 18F-FDG PET/CT response, pCR, HR status, HER2 status, and in patients who did not receive chemotherapy (group B/18F-FDG-PET-responders who achieved a pCR).
11. To assess 3, 5, and 7-year iBCFS between the treatment groups by 18F-FDG PET/CT response, pCR, HR status, HER2 status, and in patients who did not receive chemotherapy (group B/18F-FDG-PET-responders who achieved a pCR).
12. To assess 3, 5, and 7-year distant disease-free survival (DDFS) between the treatment groups by 18F-FDG PET/CT response, pCR, HR status, HER2 status, and in patients who did not receive chemotherapy (group B/18FFDG-PET-responders who achieved a pCR).
13. To assess 3, 5, and 7-year disease-free survival (DFS) between the treatment groups by 18F-FDG PET/CT response, pCR, HR status, HER2 status, and in patients who did not receive chemotherapy (group B/18F-FDGPET-responders who achieved a pCR).
14. To assess 3, 5, and 7-year adapted iDFS, iBCR, DDFS, and DFS on patients with subclinical M1 at baseline by 18F-FDG PET/CT – cohort C.
15. To assess 3, 5, and 7-year event-free survival (EFS) between the treatment groups by 18F-FDG PET/CT response, pCR, HR status, HER2 status, and in patients who did not receive chemotherapy (group B/18F-FDGPET-responders who achieved a pCR).
16. To assess 3, 5, and 7-year overall survival (OS) between the treatment groups by 18F-FDG PET/CT response, pCR, HR status, HER2 status, and in patients who did not receive chemotherapy (group B/18F-FDG-PETresponders who achieved a pCR).
17. To assess progression-free survival (PFS) in patients with subclinical M1 at baseline by 18F-FDG PET/CT – cohort C.
18. To assess safety outcomes between the treatment groups by 18F-FDG PET/CT response, pCR, HR status, HER2 status, and in patients who did not receive chemotherapy (group B/18F-FDG-PET-responders who achieved a pCR).

Conditions and MedDRA coding

HER2- positive breast cancer

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

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).
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 standardized uptake value (SUVmax) ≥1.5 x SUVmean liver + 2 SD. 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.
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 19

1. Previous treatment with chemotherapy, anti-HER2 therapy, radiation therapy, or endocrine therapy for invasive breast cancer.
2. cT4 and/or cN3 tumors.
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 and abdomen and bone scan], except patients with subclinical M1 at baseline only according to 18Ffluorodeoxyglucose (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 arrytmhias 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 condition 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. The first co-primary endpoint is to 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].
2. The second co-primary endpoint is to evaluate 3-year iDFS rate defined as 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.

Secondary endpoints 20

1. 3, 5, and 7-year iBCFS defined as time from the first date of no disease (i.e., date of surgery) to invasive breast cancer recurrence, or death by any cause. Recurrence Will be defined in accordance with the standardized efficacy endpoints (STEEP) criteria.
2. pCR rates in the breast and axilla (ypT0/isN0) (cohort A; cohort B; cohorts A/B by PET responder status).
3. pCR rates in the breast (ypT0/is) (cohort A; cohort B; cohorts A/B by PET responder status).
4. RCB score (cohort A; cohort B; cohorts A/B by PET responder status).
5. pCR rates in the breast and axilla (ypT0/isN0) (cohort A; cohort B; cohorts A/B by PET responder status; HR status, HER2 status and tumor stage).
6. Rate of breast conserving surgery (cohort A; cohort B; cohorts A/B by PET responder status).
7. 18F-FDG PET/CT response rate (according to the adapted EORTC criteria) (cohort A; cohort B).
8. Optimal 18F-FDG PET/CT cut-off for pCR (cohort A; cohort B).
9. Other 18F-FDG PET quantification parameters beside SUVmax for pCR (cohort A; cohort B).
10. MRI response rate (according to the RECIST criteria version 1.1) (cohort A; cohort B; cohorts A/B by PET responder status).
11. Health-related quality of life (EORTC QLQ-C30 and QLQBR23 questionnaires) (cohort A; cohort B; cohort C; cohorts A/B by PET responder status).
12. 3, 5, and 7-year iDFS (cohort A; cohort B [with the exception of 3-year iDFS]; cohorts A/B by PET responder status, pCR status, HR status, HER2 status, and in patients who did not receive chemotherapy (group B/18FFDG- PET-responders who achieved a pCR)).
13. 3, 5, and 7-year iBCR (cohort A; cohort B; cohorts A/B by PET responder status, pCR status, HR status, HER2 status, and in patients who did not receive chemotherapy (group B/18F-FDG-PET-responders who achieved a pCR)).
14. 3, 5, and 7-year DDFS (cohort A; cohort B; cohorts A/B by PET responder status, pCR status, HR status, HER2 status, and in patients who did not receive chemotherapy (group B/18F-FDG-PET-responders who achieved a pCR)).
15. 3, 5, and 7-year DFS (cohort A; cohort B; cohorts A/B by PET responder status, pCR status, HR status, HER2 status, and in patients who did not receive chemotherapy (group B/18F-FDG-PET-responders who achieved a pCR)).
16. 3, 5, and 7-year adapted iDFS, DDFS, and DFS (patients with subclinical M1 at baseline by 18F-FDG PET/CT – cohort C).
17. 3, 5, and 7-year EFS (cohort A; cohort B; cohorts A/B by PET responder status, pCR status, HR status, HER2 status, and in patients who did not receive chemotherapy (group B/18F-FDG-PET-responders who achieved a pCR).
18. 3, 5, and 7-year OS (cohort A; cohort B; cohorts A/B by PET responder status, pCR status, HR status, HER2 status, and in patients who did not receive chemotherapy (group B/18F-FDG-PET-responders who achieved a pCR)).
19. PFS (patients with subclinical M1 at baseline by 18F-FDG PET/CT – cohort C).
20. Adverse events, grade 3-4 adverse events, related adverse events, serious adverse events, related serious adverse events, and adverse events leading to discontinuation (cohort A; cohort B; cohorts A/B by PET responder status, pCR status, HR status, HER2 status, and in patients who did not receive chemotherapy (group B/18F-FDG-PET-responders who achieved a pCR)).

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 6

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Medica Scientia Innovation Research S.L.

Sponsor organisation

Medica Scientia Innovation Research S.L.

Address

Carrer De Pere IV 128 3rd Floor

City

Barcelona

Postcode

08005

Country

Spain

Scientific contact point

Organisation

Medica Scientia Innovation Research S.L.

Contact name

Alicia García

Public contact point

Organisation

Medica Scientia Innovation Research S.L.

Contact name

Alicia García

Locations

5 EU/EEA countries · 40 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 41 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

7 submissions — initial application plus substantial / non-substantial modifications