Image‐guided de‐escalation of neoadjuvant chemotherapy in HER2‐positive breast cancer: the TRAIN‐3 study

Overview

Sponsor-declared trial summary

Key facts

Sponsor

BOOG Study Center B.V.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

9 Apr 2019 → ongoing

Decision date (initial)

2024-11-12

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2024-516205-23-00

EudraCT number

2018-003275-35

ClinicalTrials.gov

NCT03820063

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Pharmacogenomic, Therapy, Efficacy

To evaluate efficacy of image‐guided de‐escalating chemotherapy in the presence of dual HER2‐blockade with Herceptin® and pertuzumab in HER2‐positive breast cancer, as measured by three‐year event‐free survival

Secondary objectives 12

1. To evaluate 3‐year overall survival
2. To evaluate pCR rate in breast and axilla
3. To evaluate 5‐year, and 10‐year overall and event‐free survival rate
4. To evaluate the association between pCR and long‐term outcome
5. To evaluate the association between radiologic complete response (rCR) and pCR
6. To evaluate the association between on‐treatment VACBs and pCR
7. To compare short‐term and long‐term efficacy by number of chemotherapy cycles received
8. To compare non‐radical resection percentages between rCR and no rCR
9. To compare quality of life after receiving 3, 6 or 9 cycles of chemotherapy using the EORTC QLQ‐30 and QLQ‐BR45 questionnaires
10. Incidence and severity of adverse events grade ≥3 (CTCAE v5.0)
11. Incidence and severity of cardiotoxicity and neuropathy grade ≥2
12. Incidence of symptomatic LVSD (heart failure), and incidence of asymptomatic decrease in LVEF, defined as an asymptomatic decline in LVEF requiring treatment or leading to discontinuation of pertuzumab and Herceptin® or T‐DM1, or a decrease ≥10 percentage points from baseline to a LVEF <50%

Conditions and MedDRA coding

Breast cancer

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. Histologically confirmed primary infiltrating breast cancer
2. Stage II or III disease according to TNM‐staging (8th edition, AJCC). Nodal status must be examined by ultrasound and fine‐needle aspiration or core biopsy in case of suspicious lymph nodes.
3. Overexpression and/or amplification of HER2 in an invasive component of the core biopsy, according to ASCO/CAP 2013 guideline (locally assessed)
4. Known estrogen‐ and progesteron‐receptor expression of the invasive tumor
5. Age ≥18
6. WHO performance status ≤1
7. Visible breast tumor on contrast enhanced MRI and/or the presence of malignant lymph node(s)
8. Laboratory requirements – within 21 days prior to enrolment: 1) Adequate bone marrow function (ANC ≥1.5 x 109/l, platelets ≥100 x 109/l); 2) Adequate hepatic function (ALAT, ASAT and bilirubin ≤2.5 times upper limit of normal); 3) Subjects with Gilbert's syndrome may have a total bilirubin ≥2.5 × the ULN range, if no evidence of biliary obstruction exists; 4) Adequate renal function: creatinine clearance >50 ml/min estimated using the Cockcroft‐Gault equation, or based on a 24‐hour urine collection measurement
9. LVEF ≥50% measured by echocardiography, MUGA, or MRI
10. Women of childbearing potential and men must agree to remain abstinent (refrain from heterosexual intercourse) or use adequate contraceptive methods (failure rate of <1% per year,) during treatment and for at least seven months after the last dose of pertuzumab/Herceptin®. A woman is considered to be of childbearing potential if she is post‐menarcheal, has not reached a postmenopausal state (≥12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus).
11. Women who are not postmenopausal (≥12 months of non−therapy‐induced amenorrhea) or surgically sterile must have a negative β‐HCG serum or urine pregnancy test result.

Exclusion criteria 7

1. Concurrent breastfeeding
2. Evidence of distant metastases on FDG‐PET
3. Concurrent contralateral or ipsilateral second primary infiltrating breast cancer
4. Concurrent anti‐cancer treatment or another investigational drug
5. Contra‐indication for neoadjuvant chemotherapy
6. Other invasive malignancy unless treated without chemotherapy more than five years ago and without evidence of recurrence. Patients with prior adequately treated basal cell or squamous cell skin cancer are also eligible.
7. Peripheral neuropathy ≥ grade 2 CTCAE v5.0

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Three-year event-free survival

Secondary endpoints 7

1. Overall survival (OS), defined as the time from registration to death from any cause.
2. Pathologic complete response in breast and axilla, defined as the absence of invasive tumor cells, irrespective of the presence of in-situ lesions
3. Radiologic complete response, defined as the absence of pathologic enhancement on MRI and normalization of possible lymph node involvement at ultrasound and FNA examination
4. Concordance between radiologic response and pathologic response: difference in EFS and OS between patient with rCR after 3, 6, and 9 cycles
5. Difference in EFS and OS between patient with pCR after 3, 6, and 9 cycles
6. Difference in radical resections in rCR and no‐rCR
7. Health‐related quality of life

Investigational products

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

Test 5

Comparator 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

BOOG Study Center B.V.

Sponsor organisation

BOOG Study Center B.V.

Address

Moreelsepark 1

City

Utrecht

Postcode

3511 EP

Country

Netherlands

Scientific contact point

Organisation

BOOG Study Center B.V.

Contact name

BOOG Study Center

Public contact point

Organisation

BOOG Study Center B.V.

Contact name

BOOG Study Center

Third parties 2

Locations

1 EU/EEA country · 43 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 11 files

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

Application history

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