Clinical trial NCT04335669: NordicTrip, a Translational Study of Preoperative Chemotherapy in TNBC
Official title: A Translational Randomized Phase III Study Exploring the Effect of the Addition of Capecitabine to Carboplatine Based Chemotherapy in Early "Triple Negative" Breast Cancer
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Breast Cancer
Triple Negative Breast Neoplasms
Keywords: Breast neoplasms
Triple negative breast neoplasms
Neoadjuvant treatment
Translational research
Pathologic response
Pathologic complete response
epirubicin
cyclophosphamide
paclitaxel
carboplatin
capecitabine
Survival outcomes
Homologous repair deficiency
pembrolizumab
Lead sponsor: Lund University Hospital
Sponsor class: OTHER
Collaborators: name: Swedish Breast Cancer Group
name: Danish Breast Cancer Cooperative Group
First posted: 2020-04-06
Enrollment: 325
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Primary aim: 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. Pembrolizumab is allowed in both arms after approval for TNBC 2022.

Detailed description: Primary aim: Pathological complete response rate after preoperative chemotherapy is the primary end-point of the study, which will be evaluated by comparing the effects of neoadjuvant administration of a carboplatin-based treatment and treatment adding capecitabine on pCR. After the approval of pembrolizumab in the preoperative treatment of early TNBC in 2022 the study will consist of two cohorts, one (cohort 1) without the addition of pembrolizumab, and one (cohort 2) with the addition of pembrolizumab to both study arms. The primary evaluation will be performed on the entire study population including both cohorts.

Primary translational aim: To investigate if the effects of the treatments depend on homologous repair deficiency (HRD)-status. More specifically, the aim is to test for differential effect of the two treatments on pCR for HRD-negative (HRD low and intermediate by oncoscan) and HRD-positive (HRD high by oncoscan) patients.

Eligibility criteria: Inclusion Criteria:

1. Signed written informed consent approved by the Ethical Review Board (IRB).
2. Age ≥ 18 to \< 76 years.
3. Histologically confirmed unilateral adenocarcinoma of the breast where neoadjuvant chemotherapy followed by definitive surgery is planned.
4. Node positive disease (N1-3) or if clinically N0 Tumor size \>20 mm. When deciding T-stage the following hierarchy applies,

   1. MRI
   2. Ultrasound
   3. Mammography
   4. Clinical examination
5. ER negative tumor defined by at least one the following:

   1. ER \< 1% cells positive by immunohistochemistry (IHC) or ER ≤ 10% cells positive by IHC and basal-like subtype using gene expression analysis
   2. ER \< 10% cells positive by IHC and PgR \< 10% cells positive by IHC
6. HER2-normal tumor defined according to applicable national guidelines
7. Consent for germline mutation screening for BRCA1, BRCA2 and other inherited breast cancer associated genes.
8. WHO performance status 0 or 1.
9. Negative pregnancy test in women of childbearing potential (premenopausal or \<12 months of amenorrhea post-menopause and who have not undergone surgical sterilization).
10. 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.
11. Willingness by the patient to undergo treatment and study related procedures according to the protocol.

Exclusion Criteria:

1. Clinical or radiological signs of metastatic disease.
2. History of other malignancy within the last 5 years, except for carcinoma in situ of the cervix or non-melanoma skin cancer.
3. Previous chemotherapy for cancer or other malignant disease.
4. Charlson comorbidity index, excluding score for malignancy: (CCI) \> 2, Comment: In patients 70-75 a CCI = 3 is allowed, see appendix B.
5. 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 Hemoglobin \< 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
6. Concurrent peripheral neuropathy of grade 3 or greater (NCI-CTCAE, Version 5.0).
7. Patient who is actively breast feeding.
8. Assessed by the Investigator to be unable or unwilling to comply with the requirements of the protocol.
9. Patients with known deficiency of the DPD-enzyme who completely lack DPD.

Primary outcomes:
measure: Pathological complete response rate.
timeFrame: Immediately after surgery
measure: Primary translational outcome.
timeFrame: Immediately after surgery
Secondary outcomes:
measure: Invasive Disease Free Survival (IDFS)
timeFrame: Throughout the study, an average of 3 years
measure: Overall Survival (OS)
timeFrame: Throughout the study, an average of 5 years
measure: Breast Cancer Specific Survival (BCSS)
timeFrame: Throughout the study, an average of 3 years
measure: Distant Recurrence Free Survival (DRFS)
timeFrame: Throughout the study, an average of 3 years
measure: Dose intensity
timeFrame: Immediately after surgery
measure: Toxicity according to CTCAE version 5.0
timeFrame: Immediately after surgery
Other outcomes:
measure: Subset characterization (histological subtypes)
timeFrame: Immediately after surgery
measure: Subset characterization (germline mutations)
timeFrame: Immediately after surgery
measure: Subset characterization (somatic mutations)
timeFrame: Immediately after surgery
measure: Subset characterization (epigenetic alterations)
timeFrame: Immediately after surgery
measure: pCR and long term outcome in histologic subsets of TNBC
timeFrame: Immediately after surgery
measure: pCR and long term outcome in subsets of TNBC defined based on occurrence of germline genetic alterations
timeFrame: Immediately after surgery
measure: pCR and long term outcome in subsets of TNBC defined based on occurrence of somatic genetic alterations
timeFrame: Immediately after surgery
measure: pCR and long term outcome in subsets of TNBC defined on epigenetic alterations
timeFrame: Immediately after surgery
measure: pCR and long term outcome in immun marker defined subsets of TNBC
timeFrame: Immediately after surgery
Locations:
city: Vejle
country: Denmark
facility: Vejle Hospital
state: Region Syd
city: Aalborg
country: Denmark
facility: Aalborg Universitetshospita
city: Copenhagen
country: Denmark
facility: Rigshospitalet
city: Esbjerg
country: Denmark
facility: Sydvestjysk Sygehus
city: Hillerød
country: Denmark
facility: Nordsjællands Hospital
city: Næstved
country: Denmark
facility: Regionsjælland Næstved Sygehus
city: Sønderborg
country: Denmark
facility: Sønderborg sygehus
city: Vejle
country: Denmark
facility: Vejle syghus
city: Kristianstad
country: Sweden
facility: Centralsjukhuset i Kristianstad
state: Skåne
city: Borås
country: Sweden
facility: Södra Älvsborgs Hospital
city: Gävle
country: Sweden
facility: Gävle hospital, Department of Oncology
city: Göteborg
country: Sweden
facility: Sahlgrenska University Hospital, Department of Oncology
city: Halmstad
country: Sweden
facility: Halmstad Hospital, Department of Surgery
city: Jönköping
country: Sweden
facility: Ryhov Hospital
city: Karlstad
country: Sweden
facility: Karlstad Hospital
city: Malmö
country: Sweden
facility: Skåne University Hospital, Department of Oncology
city: Stockholm
country: Sweden
facility: Capio S:t Göran Hospital, Department of Oncology
city: Stockholm
country: Sweden
facility: Södersjukhuset, Department of Oncology
city: Sundsvall
country: Sweden
facility: Sundsvall hospital
city: Umeå
country: Sweden
facility: Norrland University Hospital, Department of Oncology
city: Uppsala
country: Sweden
facility: Academical Hospital, Department of Oncology
city: Västerås
country: Sweden
facility: Västmanlands Hopsital Västerås
city: Växjö
country: Sweden
facility: Växjö Hospital, Department of Oncology
city: Örebro
country: Sweden
facility: Örebro University Hospital, Department of Oncology
Study officials:
affiliation: Lund University Hospital
name: Niklas Loman, MD, PhD
role: STUDY_DIRECTOR
References: