NordicTrip, a Translational Study of Preoperative Chemotherapy in TNBC

Breast Cancer Clinical Trial

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04335669
• Other study ID #: NBG-19-01; SWEBCG 19-01
• Status: Recruiting
• Phase: Phase 3
• Start date: December 20, 2019
• Est. completion date: June 30, 2035

Study information

• Verified date: November 2022
• Source: Lund University Hospital
• Contact: Niklas Loman, MD, PhD
• Phone: +46 46 17 75 20
• Email: niklas.loman[@]med.lu.se
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 920
• Est. completion date: June 30, 2035
• Est. primary completion date: June 25, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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.

Related Conditions & MeSH terms

• Breast Cancer
• Breast Neoplasms
• Neoplasms
• Triple Negative Breast Neoplasms

Intervention

Drug:
• epirubicin, cyclophosphamide, paclitaxel, carboplatin, pembrolizumab
Cytotoxic agents.
• epirubicin, cyclophosphamide, capecitabine, paclitaxel, carboplatin, pembrolizumab
Cytotoxic agents.

Locations

Country	Name	City	State
Denmark	Aalborg Universitetshospita	Aalborg
Denmark	Rigshospitalet	Copenhagen
Denmark	Sydvestjysk Sygehus	Esbjerg
Denmark	Nordsjællands Hospital	Hillerød
Denmark	Regionsjælland Næstved Sygehus	Næstved
Denmark	Odense University Hospital	Odense	Region Syd
Denmark	Sønderborg sygehus	Sønderborg
Denmark	Vejle Hospital	Vejle	Region Syd
Denmark	Vejle syghus	Vejle
Sweden	Södra Älvsborgs Hospital	Borås
Sweden	Gävle hospital, Department of Oncology	Gävle
Sweden	Sahlgrenska University Hospital, Department of Oncology	Göteborg
Sweden	Halmstad Hospital, Department of Surgery	Halmstad
Sweden	Ryhov Hospital	Jönköping
Sweden	Karlstad Hospital	Karlstad
Sweden	Centralsjukhuset i Kristianstad	Kristianstad	Skåne
Sweden	Skåne University Hospital, Department of Oncology	Malmö
Sweden	Örebro University Hospital, Department of Oncology	Örebro
Sweden	Capio S:t Göran Hospital, Department of Oncology	Stockholm
Sweden	Södersjukhuset, Department of Oncology	Stockholm
Sweden	Sundsvall hospital	Sundsvall
Sweden	Norrland University Hospital, Department of Oncology	Umeå
Sweden	Academical Hospital, Department of Oncology	Uppsala
Sweden	Västmanlands Hopsital Västerås	Västerås
Sweden	Växjö Hospital, Department of Oncology	Växjö

Sponsors (5)

Lead Sponsor	Collaborator
Lund University Hospital	Danish Breast Cancer Cooperative Group, Finnish Breast Cancer Group, Icelandic Breast Cancer Group, Swedish Breast Cancer Group

Countries where clinical trial is conducted

Denmark,  Sweden, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Subset characterization (histological subtypes)	Distribution of different histopathological subsets of Triple Negative Breast Cancer (TNBC).	Immediately after surgery
Other	Subset characterization (germline mutations)	Distribution of subsets of Triple Negative Breast Cancer (TNBC) associated with different inherited breast cancer genes (BRCA1, BRCA2, PALB2, TP53, CHEK2, ATM, RAD51 C and RAD51D).	Immediately after surgery
Other	Subset characterization (somatic mutations)	Distribution of subsets of Triple Negative Breast Cancer (TNBC) associated with somatic mutations, (Eg BRCA1, BRCA2, PALB2, TP53, and other).	Immediately after surgery
Other	Subset characterization (epigenetic alterations)	Distribution of different subsets of Triple Negative Breast Cancer (TNBC) defined based on epigenetic alterations associated with silencing of BRCA1, RAD51 and related HRD-associated genes.	Immediately after surgery
Other	pCR and long term outcome in histologic subsets of TNBC	pCR rate in different histopathological subsets of Triple Negative Breast Cancer (TNBC).	Immediately after surgery
Other	pCR and long term outcome in subsets of TNBC defined based on occurrence of germline genetic alterations	pCR rate in subsets of Triple Negative Breast Cancer (TNBC) associated with different inherited breast cancer genes (BRCA1, BRCA2, PALB2, TP53, CHEK2, ATM, RAD51 C and RAD51D).	Immediately after surgery
Other	pCR and long term outcome in subsets of TNBC defined based on occurrence of somatic genetic alterations	pCR rate in subsets of Triple Negative Breast Cancer (TNBC) associated with somatic mutations, (Eg BRCA1, BRCA2, PALB2, TP53, and other).	Immediately after surgery
Other	pCR and long term outcome in subsets of TNBC defined on epigenetic alterations	pCR rate in different subsets of Triple Negative Breast Cancer (TNBC) based on epigenetic alterations associated with silencing of BRCA1, RAD51 and related HRD-associated genes.	Immediately after surgery
Other	pCR and long term outcome in immun marker defined subsets of TNBC	pCR rate in subsets of Triple Negative Breast Cancer (TNBC) associated with the expression of PDL1.	Immediately after surgery
Primary	Pathological complete response rate.	Rate of pathological complete response, allowing residual dcis, at surgery after preoperative chemotherapy.	Immediately after surgery
Primary	Primary translational outcome.	Pathological complete response rate, allowing residual dcis, stratified for homologous repair deficiency.	Immediately after surgery
Secondary	Invasive Disease Free Survival (IDFS)	Invasive disease-free survival	Throughout the study, an average of 3 years
Secondary	Overall Survival (OS)	Overall survival	Throughout the study, an average of 5 years
Secondary	Breast Cancer Specific Survival (BCSS)	Breast cancer specific survival	Throughout the study, an average of 3 years
Secondary	Distant Recurrence Free Survival (DRFS)	Distant recurrence free survival.	Throughout the study, an average of 3 years
Secondary	Dose intensity	Actual dosis/dosis per protocol	Immediately after surgery
Secondary	Toxicity according to CTCAE version 5.0	Rate of included patients with toxicity grade 3 or greater during study treatment	Immediately after surgery