Overview
Sponsor-declared trial summary
Phase
Therapeutic confirmatory (Phase III)
Status
Ongoing, recruitment ended
Participants planned
325
Countries
2
Sites
21
Early triple negative breast cancer
To compare the effect on pathologic complete response (pCR) rate of adding capecitabine to carboplatin based preoperative chemotherapy in early ER-negative and HER2-negative breast cancer.
Key facts
- Sponsor
- Region Skåne
- Participant type
- Patients
- Age range
- 18-64 years, 65+ years
- Gender
- Male and Female
- Therapeutic area
- Diseases [C] - Neoplasms [C04]
- Trial duration
- 2 Dec 2019 → ongoing
- Decision date (initial)
- 2024-06-06
- Transition trial
- Yes
- Low-intervention
- No
- Rare-disease indication
- No
- Vulnerable population
- Yes
- Funding sources
- Department of Hematology, Oncology and Radiation Physics, Skåne University Hospital, Sweden · Vetenskapsrådet, Sweden
External identifiers
- EU CT number
- 2022-501102-35-00
- EudraCT number
- 2018-002080-25
- ClinicalTrials.gov
- NCT04335669
Trial design
CTIS Part I — objectives, methods, condition coding
Main objective
Scope: Therapy, Efficacy, Safety
To compare the effect on pathologic complete response (pCR) rate of adding capecitabine to carboplatin based preoperative chemotherapy in early ER-negative and HER2-negative breast cancer.
Secondary objectives 5
- To compare invasive disease free (IDFS), breast cancer specific survival (BCSS), distant recurrence free survival (DRFS), and overall survival (OS).
- To evaluate the tolerability defined by toxicity and dose intensity.
- To determine the pCR rates in different treatment arms stratified for Homologous Repair Deficiency (HRD) positive vs. HRD-negative/HRDintermediate.
- To characterize different subsets of TNBC in terms of morphology, epigenetic alterations as well as somatic and inherited genetic alterations.
- To determine the pCR rate and long-term outcome in subsets of TNBC with defined molecular genetic alterations including BRCA1, BRCA2 and PALB2 germline mutations and others, BRCA1, BRCA2 and PALB2 somatic mutations and others and BRCA1 or RAD51 promoter metylation.
Conditions and MedDRA coding
Early triple negative breast cancer
| Version | Level | Code | Term | System organ class |
|---|---|---|---|---|
| 20.0 | LLT | 10006192 | Breast cancer NOS | 10029104 |
Study design 1 period
| # | Title | Allocation | Blinding | Roles blinded | Arms |
|---|---|---|---|---|---|
| 1 | Clinical Trial This clinical trial consists of one single period
|
Randomised Controlled | None | Arm A: ddEC x 4 + pembrolizumab→ PK x 4 + pembrolizumab Arm B: CEX x 4 + pembrolizumab → PK x 4 + pembrolizumab |
Eligibility criteria
Principal inclusion / exclusion criteria as submitted by sponsor
Inclusion criteria 11
- Signed written informed consent approved by the Ethical Review Board (IRB).
- Age ≥ 18 to < 76 years.
- Histologically confirmed unilateral adenocarcinoma of the breast where neoadjuvant chemotherapy followed by definitive surgery is planned.
- Node positive disease (N1-3) or if clinically N0 Tumor over 20 mm.
- ER negative tumor defined by at least one the following: a. ER < 1% cells positive by immunohistochemistry (IH.C) or ER < 10% cells positive by IHC and basal-like subtype using gene expression analysis b. ER < 10% cells positive by IHC and < 10% cells positive by IHC.
- HER2-normal tumor defined according to applicable national guidelines.
- Consent for germline mutation screening for BRCA1, BRCA2 and other inherited breast cancer associated genes.
- WHO performance status 0 or 1.
- Negative pregnancy test in women of childbearing potential (premenopausal or <12 months of amenorrhea post-menopause and who have not undergone surgical sterilization).
- Willingness of female patients of childbearing potential, male patients and their sexual partners to use an effective means of contraception during the treatment period and at least 6 months thereafter.
- Willingness by the patient to undergo treatment and study related procedures according to the protocol.
Exclusion criteria 9
- Clinical or radiological signs of metastatic disease.
- History of other malignancy within the last 5 years, except for carcinoma in situ of the cervix or non-melanoma skin cancer.
- Previous chemotherapy for cancer or other malignant disease.
- Charlson comorbidity index, excluding score for malignancy: (CCI) > 2, Comment: In patients 70-75 a CCI = 3 is allowed, see appendix B.
- Inadequate organ function, suggested by the following laboratory results: a Absolute neutrophil count < 1,5 x 109/L b Platelet count < 100 x 109/L c Haemoglobin < 90 g/L d Total bilirubin greater than the upper limit of normal (ULN) unless the patient has documented Gilbert´s syndrome e ASAT (SGOT) and/or ALAT (SGPT) > 2,5 x ULN f ASAT (SGOT) and/or ALAT (SGPT) > 1,5 x ULN with concurrent serum alkaline phosphatase (ALP) > 2,5 x ULN g Serum creatinine clearance < 50 ml/min
- Concurrent peripheral neuropathy of grade 3 or greater (NCI-CTCAE, Version 5.0)
- Patient who is actively breast feeding.
- Assessed by the Investigator to be unable or unwilling to comply with the requirements of the protocol.
- Patients with known deficiency of the DPD-enzyme who completely lack DPD.
Endpoints
Primary and secondary outcome measures (English text)
Primary endpoints 1
- pCR with the addition of capecitabine compared with carboplatin-based chemotherapy alone.
Secondary endpoints 3
- Invasive Disease Survival (IDFS) with the addition of capecitabine compared with carboplatin-based chemotherapy alone.
- Breast Cancer Specific Survival (BCSS) with the addition of capecitabine compared with carboplatin-based chemotherapy alone.
- Overall Survival (OS) with the addition of capecitabine compared with carboplatin-based chemotherapy alone.
Investigational products
Investigational medicinal products (IMPs), comparators, placebo, auxiliary
Test 6
SUB12474MIG · Substance
- Active substance
- Capecitabine
- Pharmaceutical form
- FILM-COATED TABLET
- Route of administration
- ORAL USE
- Max daily dose
- 1800 mg/m2 milligram(s)/sq. meter
- Max total dose
- 100800 mg/m2 milligram(s)/sq. meter
- Max treatment duration
- 23 Week(s)
- Authorisation status
- Authorised
- ATC code
- - — -
- Marketing authorisation
- -
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
SUB06859MIG · Substance
- Active substance
- Cyclophosphamide
- Pharmaceutical form
- POWDER FOR SOLUTION FOR INFUSION
- Route of administration
- INTRAVENOUS USE
- Max daily dose
- 600 mg/m2 milligram(s)/sq. meter
- Max total dose
- 1800 mg/m2 milligram(s)/sq. meter
- Max treatment duration
- 23 Week(s)
- Authorisation status
- Authorised
- ATC code
- - — -
- Marketing authorisation
- -
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
SUB06571MIG · Substance
- Active substance
- Epirubicin
- Pharmaceutical form
- CONCENTRATE FOR SOLUTION FOR INFUSION
- Route of administration
- INTRAVENOUS USE
- Max daily dose
- 90 mg/m2 milligram(s)/sq. meter
- Max total dose
- 360 mg/m2 milligram(s)/sq. meter
- Max treatment duration
- 23 Week(s)
- Authorisation status
- Authorised
- ATC code
- - — -
- Marketing authorisation
- -
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
SUB06614MIG · Substance
- Active substance
- Carboplatin
- Pharmaceutical form
- CONCENTRATE FOR SOLUTION FOR INFUSION
- Route of administration
- INTRAVENOUS USE
- Max daily dose
- 5 Other
- Max total dose
- 20 Other
- Max treatment duration
- 23 Week(s)
- Authorisation status
- Authorised
- ATC code
- - — -
- Marketing authorisation
- -
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
SUB09583MIG · Substance
- Active substance
- Paclitaxel
- Pharmaceutical form
- CONCENTRATE FOR SOLUTION FOR INFUSION
- Route of administration
- INTRAVENOUS USE
- Max daily dose
- 80 mg/m2 milligram(s)/sq. meter
- Max total dose
- 960 mg/m2 milligram(s)/sq. meter
- Max treatment duration
- 23 Week(s)
- Authorisation status
- Authorised
- ATC code
- - — -
- Marketing authorisation
- -
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
KEYTRUDA 25 mg/mL concentrate for solution for infusion
PRD4323105 · Product
- Active substance
- Pembrolizumab
- Substance synonyms
- LAMBROLIZUMAB, MK-3475, SCH-900475, ABP 234
- Pharmaceutical form
- SOLUTION FOR INFUSION
- Route of administration
- INTRAVENOUS USE
- Max daily dose
- 400 mg milligram(s)
- Max total dose
- 1600 mg milligram(s)
- Max treatment duration
- 23 Week(s)
- Authorisation status
- Authorised
- ATC code
- L01FF02 — -
- Marketing authorisation
- EU/1/15/1024/002
- MA holder
- MERCK SHARP & DOHME B.V.
- MA country
- EU
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
Sponsors and contacts
Sponsor organisations, regulatory contacts, third parties
Region Skåne
- Sponsor organisation
- Region Skåne
- Address
- Dockplatsen 26, Malmo S:t Petri Malmo S:t Petri
- City
- Malmo
- Postcode
- 211 74
- Country
- Sweden
Scientific contact point
- Organisation
- Region Skåne
- Contact name
- Niklas Loman
Public contact point
- Organisation
- Region Skåne
- Contact name
- Niklas Loman
Locations
2 EU/EEA countries · 21 investigational sites
By country
| Country | MS status | Planned subjects | Sites |
|---|---|---|---|
| Denmark | Ongoing, recruitment ended | 80 | 6 |
| Sweden | Ongoing, recruitment ended | 245 | 15 |
| Rest of world | — | 0 | — |
Investigational sites
Aalborg University Hospital
Ankologisk Afdelning, Hobrovej 18/22, 9000, Aalborg
Næstved Hospital
Onkologisk ambulatorium, Ringstedgade 61, 4700, Næstved
Sygehus Lillebaelt Vejle Sygehus
Onkologisk Afdelning, Kabbeltoft 25, 7100, Vejle
Sygehus Soenderjylland Soenderborg
Onkologisk Ambulatorium, Sydvang 1, 6400, Soenderborg
Rigshospitalet
Department of Oncology, Blegdamsvej 9, 2100, Copenhagen Oe
Nordsjaellands Hospital
Onkologisk Afdelning, Dyrehavevej 29, 3400, Hilleroed
Region Gaevleborg
Department of Oncology, Rektorsgatan 1, 802 50, Gavle
Region Vaestmanland
Department of Oncology, Sigtunagatan, 721 89, Vasteras
Region Vaesterbotten
Department of Oncology, Koksvagen 11, Alidhem, Umea
Region Joenkoepings Laen
Department of Oncology, Lanssjukhuset Ryhov, Sjukhusgatan, Jonkoping
Region Kronoberg
Department of Oncology, Nygatan 20, Vaxjo Stads- Och Domkyrkofors., Vaxjo
Region Skane Kristianstad Central Hospital
Onkologimottagningen, J A Hedlunds Vag 5, Kristianstads Heliga Trefaldighet, Kristianstad
Sodra Alvsborg Hospital-Vastra Gotalandsregionen
Department of Oncology, Bramhultsvagen 53, Boras Gustav Adolf, Boras
Sahlgrenska University Hospital-Vastra Gotalandsregionen
Department of Oncology, Bla Straket 5, 413 46, Goteborg
Soedersjukhuset AB
Department of Oncology, Sjukhusbacken 10, Hogalid, Stockholm
Region Vaesternorrland
Department of Oncology, Lasarettsvagen 21, 856 43, Sundsvall
Uppsala University Hospital
Department of Oncology, Akademiska Sjukhuset, 751 85, Uppsala
Region Skane Skanes Universitetssjukhus
Department of Oncology, Entregatan 7, 222 42, Lund
Capio S:t Goerans Sjukhus AB
Department of Oncology, Sankt Goransplan 1, Vastermalm, Stockholm
Region Vaermland
Department of Oncology, Rosenborgsgatan 50, 652 33, Karlstad
Region Oerebro Laen
Department of Oncology, Sodra Grev Rosengatan, 701 85, Orebro
Country notifications
Trial-start, recruitment-start, end and early-termination notifications submitted per Member State
| Country | Trial start | Trial end | Recruitment start | Recruitment end | Early termination |
|---|---|---|---|---|---|
| Denmark | 2021-06-03 | 2021-06-07 | 2025-01-25 | ||
| Sweden | 2019-12-02 | 2020-01-02 | 2025-01-29 |
Oversight and notifications
Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77
Serious breaches 1 · Art. 52 CTR
Serious breach SB-70175
- Sponsor became aware
- 2025-02-06
- Date of breach
- 2024-11-18
- Submission date
- 2025-02-11
- Member states concerned
- Sweden, Denmark
- Categories
- Protocol
- Areas impacted
- Subject safety, Data reliability or robustness
- Benefit-risk balance changed
- No
- Description
- At the time of diagnosis, the patient was reported (2024-11-13 MRI and 2024-10-24 Pathology results for needle biopsy) with an invasive ductal carcinoma in ectopic mammary tissue, with IHC positive for high molecular weight cytokeratin (CK5/6), GATA3 and TRPS1. ER and HER2 both were negative. Based on this information the patient was offered participation on the NordicTrip protocol following discussion with the sponsor regarding localization of the cancer in ectopic mammary tissue.
Patients signed Informed consent on 18-Nov-2024 and was randomized to control arm A (ddEC) on 25-Nov-2024 and received 2 Cycles of dose dense EC along with 2 Cycles of immunotherapy, pembrolizumab.
Response evaluation after 2 cycles of ddEC chemotherapy showed no response, rather progression with two new satellite tumors. New tumor lesions were biopsied (20-Dec-2024) showing no signs of malignancy but whether collected material was representative of the tumor was unclear. The material was fragmented consisting of fibroadipose tissue containing individual vessels. In addition, loose secretions were seen. Immunohistochemical staining for CKPAN is without infiltration of epithelial cells.
Patient treatment plan was discussed during the Multidisciplinary team meeting on 09-Jan-2025 and booked for surgery on 13-Jan-2025 where tumor under breast and lymph node were removed.
The Pathology report showed microscopically, a well-defined partially cystic, partially lobulated tumor located in the dermis without connection to the epidermis is seen. The tumor cells are closely spaced in solid formations separated by hyalinized connective tissue stroma, while the cyst lumen is toroidal. A fibrous pseudocapsule is seen around the lesion. The tumor cells have small uniform nuclei and very few mitoses. No necrosis. Immunohistochemically, there is a reaction for EMA in the cells against the cyst lumen. CEA has the same reaction pattern, although in fewer numbers. Of other immune systems, a positive reaction is seen for CK7, P63, Gata3, TRPS1. Mammoglobin, GCDFP, SOX10, ER and HER2 are negative. It was identified as a hidradenoma, a benign adnexal tumor.
As the diagnosis differed from the primary needle biopsy from 24-Oct-2025, primary biopsy was re-evaluated. It was concluded that even primary biopsy is hidradenoma ant is not malignant. Immunohistochemically and with scant biopsy material, hidradenoma can be difficult to distinguish from an ER-negative breast carcinoma, as both show reaction for mammary markers. The case is reported as an accidental incident.
In light of the new information regarding pathology report and patients hidradenoma diagnosis, it can be concluded that the patient has been incorrectly enrolled in the NordicTrip trial and received chemotherapy and immune therapy without having a breast cancer. - Sponsor actions
- Site and Investigator will provide all support necessary if so desired by the patient. The patient was informed of above results by the surgeon on 03-Feb-2025. Oncology ward was informed on 05-Feb-2025 and Sponsor notified on 6-Feb-2025. Patient was also advised to apply for compensation. Patient will be seen by PI Vesna Glavicic on 11-Feb-2025. Patient hasn’t had any SAEs. She will be followed as oncology outpatient in case she will get side effect to the given treatment.
Current breach will be documented in the Trial Master File and data from this patient will be excluded from the trial analysis.
The current case is a single accidental incident and has not affected any other patient being included in the Nordic Trip trial at the same site.
| Organisation | City | Country | Type |
|---|---|---|---|
| Næstved Hospital | Næstved | Denmark | Clinical facility BE/BA |
Results and documents
Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial
Documents 6 files
Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.
| Type | Title | Version |
|---|---|---|
| Recruitment arrangements (for publication) | Not part of CTD_placeholder | 1 |
| Recruitment arrangements (for publication) | O_Danish addendum to protocol | 2.4 |
| Subject information and informed consent form (for publication) | L1_SIS and ICF | 4.1 |
| Subject information and informed consent form (for publication) | L1_SIS and ICF | 5.0 |
| Subject information and informed consent form (for publication) | L1_SIS and ICF_extra provtagning A | 2.1a |
| Subject information and informed consent form (for publication) | L1_SIS and ICF_extra provtagning B | 2.1b |
Application history
3 submissions — initial application plus substantial / non-substantial modifications
| # | Type | Code | Submitted | Reference MS | Conclusion | Decision date |
|---|---|---|---|---|---|---|
| 1 | INITIAL | IN | 2024-04-30 | Sweden | Acceptable 2024-06-04
|
2024-06-05 |
| 2 | NON SUBSTANTIAL MODIFICATION | NSM-1 | 2024-10-07 | Sweden | Acceptable 2024-06-04
|
2024-10-07 |
| 3 | SUBSTANTIAL MODIFICATION | SM-1 | 2025-05-07 | Acceptable | 2025-07-08 |