Chemotherapy-Free pCR-Guided Strategy with subcutaneous trastuzumabpertuzumab and T-DM1 in HER2-positive early breast cancer (PHERGAIN-2)

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

16 Jun 2021 → ongoing

Decision date (initial)

2024-09-18

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

F. Hoffmann - La Roche, Ltd.

External identifiers

EU CT number

2023-508738-32-00

EudraCT number

2020-003205-66

ClinicalTrials.gov

NCT04733118

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Efficacy

Primary efficacy objective
To assess 3-year recurrence-free interval (3y-RFI) in all patients with previously
untreated HER2[+] (IHC score 3+) node-negative early-stage breast cancer.

Primary safety objective
To assess global health status decline rate at 1 year from start of neoadjuvant treatment.

Secondary objectives 18

1. To assess pathological complete response (pCR).
2. To compare the rate of pCR by hormone receptor (HR) status and tumor stage
3. To evaluate residual cancer burden (RCB).
4. To evaluate rate of breast-conserving surgery (BCS)
5. To evaluate objective response rate.
6. To evaluate the correlation between final MRI results and breast conserving surgery (BCS), pCR, and RCB at surgery.
7. To analyze the rate of RFI at 5 years.
8. To analyze the rate of event-free survival (EFS) at 3 and 5 years
9. To analyze the rate of relapse-free survival (RFS) at 3 and 5 years.
10. To analyze the rate of distant relapse-free survival (DRFS) at 3 and 5 years.
11. To analyze the rate of disease-free survival (DFS) at 3 and 5 years
12. To analyze the rate of invasive disease-free survival (iDFS) at 3 and 5 years.
13. To analyze overall survival (OS) at 3 and 5 years
14. To analyze the rate of breast cancer-specific survival (BCSS) at 3 years and 5 years
15. To assess the cardiac toxicity profile after 1 year of adjuvant treatment according to the NCI-CTCAE v.5.0.
16. To assess the general toxicity profile according to CTCAE v.5.0.
17. To evaluate health-related quality of life (HRQoL) as assessed by the European Organisation for Research and Treatment of Cancer (EORTC)-QLC-C30 and QLQBR23 questionnaires
18. To evaluate the ratio of patients who have needed chemotherapy.

Conditions and MedDRA coding

Previously untreated and histologically confirmed HER2-Positive (HER2[+]) early- stage breast cancer

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 16

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 or 1.
4. Histologically proven invasive carcinoma of the breast.
5. Tumor size must be ≥5mm and ≤25mm using ultrasound and mammography (tumor size between ≥5mm and ≤30mm by MRI is also accepted given the precision of the technique). Note: Although tumors between ≥ 5mm and ≤ 10mm are not considered target lesions by RECIST v1.1, we will consider these lesions as targets to follow-up.
6. Patients must have node-negative breast cancer by clinical exam, MRI and ultrasound according to the American Joint Committee on Cancer (AJCC) 8th edition.
7. Centrally confirmed HER2[+] status with IHC score 3+.
8. Known estrogen receptor (ER) and progesterone receptor (PgR) status prior to study entry that should be performed by immunohistochemical methods according to the local institution standard protoco
9. Patients with multifocal or multicentric breast cancer are eligible; only patients with a total number of lesions ≤ 2 are eligible and if all lesions sampled meet the inclusion criteria #5, #6, and #7. Note: If two lesions are in such proximity that it is suspected to be the same lesion, it would not be necessary to biopsy both.
10. Normal left ventricular function and diastolic function (left ventricular ejection fraction [LVEF] ≥55%) as assessed by echocardiogram or multiple-gated acquisition scan (MUGA) documented within ≤28 days prior to first dose of study treatment.
11. Adequate bone marrow, liver, and renal function: a. Hematological: White blood cell (WBC) count > 3.0 × 109/L, absolute neutrophil count (ANC) ≥ 1.5 × 109/L, platelet count ≥ 100.0 × 109/L, and hemoglobin ≥ 10.0 g/dL (≥ 6.2 mmol/L). b. 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. c. Renal: serum creatinine ≤ 1.5 × ULN or creatinine clearance ≥ 50 mL/min/1.73 m2 for patients with creatinine levels above institutional normal. d. International normalized ratio (INR) and activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN
12. Patient must be accessible for treatment and follow-up.
13. Willingness and ability to provide blood samples at baseline, C3D1 before treatment infusion, pre-surgery and then after surgery: every 6 months for the first 5 years, and every year thereafter until the EoS
14. Willingness and ability to provide tumor tissue samples at baseline and at surgery.
15. Women of childbearing potential and men with partners of childbearing potential must be willing to use one highly effective form of nonhormonal contraception or two effective forms of nonhormonal contraception by the patient and/or partner and to continue its use for the duration of study treatment and for seven months after the last dose of study treatment. Note: Acceptable forms of effective contraception should include two of the following: i. Placement of non-hormonal intrauterine device (IUD) ii. Condom with spermicidal foam/gel/film/cream/suppository iii. Diaphragm or cervical/vault caps with spermicidal foam/film/cream/suppository The above contraception is not a requirement in the case the male patient, or male partner of a female patient, is surgically sterilized, the female patient is postmenopausal or the patient remains abstinent and truly abstains from sexual activity (refrains from heterosexual intercourse).
16. Negative serum pregnancy test for premenopausal women including women who have had a tubal ligation and for women less than 12 months after the onset of menopause.

Exclusion criteria 19

1. Any previous treatment, including chemotherapy, anti-HER2 therapy, radiation therapy, or ET for invasive breast cancer (except for breast carcinoma in situ of the contralateral breast cancer, in the last five years before treatment initiation in this study)
2. HER2 disease with IHC score 0, 1+ or 2+ and in situ hybridization (ISH) positive result.
3. Evidence of metastatic disease. Note: All patients must be willing to undergo chest and pelvis computed tomography (CT)/MRI scan before enrolment to prove no evidence of metastatic disease. Bone scan will be performed at screening only if there is suspicion of bone metastases. If a bone scan cannot be performed at screening, an alternative is PET/CT using 18F-labeled sodium fluoride (18F-fluoride PET/CT).
4. Patients with bilateral breast cancer.
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. Uncontrolled hypertension (systolic > 150 mm Hg and/or diastolic > 100 mm Hg) despite adequate antihypertensive treatment.
8. Serious cardiac illness or medical conditions including, but not confined to, the following: − History of NCI CTCAE v5.0 Grade ≥ 3 symptomatic congestive heart failure (CHF) or New York Heart Association (NYHA) Class ≥ II. − High-risk uncontrolled arrhythmias (i.e., atrial tachycardia with a heart rate ≥ 100/min at rest, significant ventricular arrhythmia [ventricular tachycardia], or highergrade atrioventricular [AV]-block, such as second-degree AV-block Type 2 [Mobitz II] or third-degree AV-block). − Serious cardiac arrhythmia or severe conduction abnormality not controlled by adequate medication. − Angina pectoris requiring anti-angina medication. − Clinically significant valvular heart disease. − Evidence of transmural infarction on electrocardiogram (ECG). − Evidence of myocardial infarction within the last 12 months prior to study entry.
9. History of ventricular dysrhythmias or risk factors for ventricular dysrhythmias, such as structural heart disease (e.g., severe left ventricular systolic dysfunction [LVSD], left ventricular hypertrophy), coronary heart disease (symptomatic or with ischemia demonstrated by diagnostic testing), clinically significant electrolyte abnormalities (e.g., hypokalemia, hypomagnesemia, hypocalcemia), or family history of sudden unexplained death or long QT syndrome.
10. Active uncontrolled infection at the time of enrollment.
11. Current known infection with human immunodeficiency virus (HIV), hepatitis B virus, or hepatitis C virus.
12. Patients with pulmonary disease requiring continuous oxygen therapy.
13. Grade ≥2 neuropathy as per National Cancer Institute – Common Terminology Criteria for Adverse Events (NCI–CTCAE) version (v)5.0.
14. Previous history of bleeding diathesis.
15. Patient is currently receiving chronic treatment with corticosteroids, or another immunosuppressive agent (standard premedication for chemotherapy and local applications are allowed).
16. Major surgical procedure or significant traumatic injury within 14 days prior to study entry or anticipation of need for major surgery within the course of the study treatment
17. Any other concurrent severe and/or uncontrolled medical condition that would contraindicate patient participation in the clinical study.
18. History of having received any investigational treatment within 28 days prior to study entry.
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. Primary efficacy endpoint: 3y-RFI defined as time from start of treatment in adjuvant setting until recurrence, new invasive disease, or death from breast cancer in the overall population. Recurrence will be defined in accordance with the standardized efficacy endpoints (STEEP) criteria.
2. Primary safety endpoint Global health status decline rate at 1 year from start of neoadjuvant treatment, defined as the rate of patients with a ≥10% global health status decline at 1 year from start of neoadjuvant treatment as assessed by the Global Health Status/QoL EORTC-QLC-C30 scale and its breast cancer module QLQ-BR23.

Secondary endpoints 18

1. pCR rates (pCRBREAST+LYMPH NODES -ypT0/Tis ypN0- and pCRBREAST -ypT0/Tis-) in the overall study population.
2. pCR rates (pCRBREAST+LYMPH NODES -ypT0/Tis ypN0- and pCRBREAST -ypT0/Tis-) according to HR status (positive, negative), and tumor stage (T1, T2).
3. RCB score in the overall study population and according to HR status (positive, negative), and tumor stage (T1, T2).
4. Rate of BCS in the overall study population and according to HR status (positive, negative), and tumor stage (T1, T2)
5. MRI-guided objective response rate by Response Evaluation Criteria in Solid Tumors (RECIST) version (v.)1.1 in the overall study population and according to HR status (positive, negative), and tumor stage (T1, T2)
6. Correlation of MRI-guided objective response rate by RECIST v.1.1 with BCS, pCR, and RCB in the overall study population and according to HR status (positive, negative), and tumor stage (T1, T2).
7. 5-year RFI in the overall study population and according to study arm (A, B, C), HR status (positive, negative), and tumor stage (T1, T2).
8. 3-year and 5-year EFS in the overall study population and according to study arm (A, B, C), HR status (positive, negative), and tumor stage (T1, T2).
9. 3-year and 5-year RFS in the overall study population and according to study arm (A, B, C), HR status (positive, negative), and tumor stage (T1, T2)
10. 3-year and 5-year DRFS in the overall study population and according to study arm (A, B, C), HR status (positive, negative), and tumor stage (T1, T2)
11. 3-year and 5-year DFS in the overall study population and according to study arm (A, B, C), HR status (positive, negative), and tumor stage (T1, T2).
12. 3-year and 5-year iDFS in the overall study population and according to study arm (A, B, C), HR status (positive, negative), and tumor stage (T1, T2).
13. 3-year and 5-year OS in the overall study population and according to study arm (A, B, C), HR status (positive, negative), and tumor stage (T1, T2).
14. 3-year and 5-year BCSS in the overall study population and according to study arm (A, B, C), HR status (positive, negative), and tumor stage (T1, T2).
15. Adverse events of cardiotoxicity after 1 year of adjuvant treatment according to the NCI-CTCAE v.5.0.
16. Toxicity and safety profile at 3 and 5 years as per NCI-CTCAE v.5.0 in the overall study population and in each study arm (A, B, C).
17. Patient Reported Outcomes (PROs) HRQoL assessment as per EORTC-QLC-C30 and QLQ-BR23 questionnaires in the overall study population and in each study arm (A, B, C)
18. Ratio of patients of cohort C who will receive adjuvant chemotherapy before T-DM1.

Investigational products

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

Test 3

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

Emilia Szostak

Third parties 1

Locations

4 EU/EEA countries · 38 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 21 files

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

Application history

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