NordicTrip, a Translational Study of Preoperative Chemotherapy in TNBC

A Translational Randomized Phase III Study Exploring the Effect of the Addition of Capecitabine to Carboplatine Based Chemotherapy in Early "Triple Negative" Breast Cancer

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.

Study Overview

• Status: Recruiting
• Conditions: Breast Cancer; Triple Negative Breast Neoplasms
• Intervention / Treatment: Drug: epirubicin, cyclophosphamide, paclitaxel, carboplatin, pembrolizumab; Drug: epirubicin, cyclophosphamide, capecitabine, paclitaxel, carboplatin, pembrolizumab

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.

• Study Type: Interventional
• Enrollment (Anticipated): 920
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Niklas Loman, MD, PhD; Phone Number: +46 46 17 75 20; Email: niklas.loman@med.lu.se
• Study Contact Backup: Name: Lina Zander, RN; Phone Number: +46 46 17 78 29; Email: nordictrip.onkologi@skane.se

Study Locations

• Denmark
  • Aalborg, Denmark, 9000
    • Recruiting
    • Aalborg Universitetshospita
    • Contact: Sopie Yammeni, MD; Email: s.yammeni@rn.dk
    • Principal Investigator: Sopie Yammeni, MD
  • Copenhagen, Denmark, 2100
    • Recruiting
    • Rigshospitalet
    • Contact: Ulla Brix Tange, MD; Email: Ulla.Brix.Tange@regionh.dk
    • Principal Investigator: Ulla Brix Tange, MD
  • Esbjerg, Denmark, 6700
    • Recruiting
    • Sydvestjysk Sygehus
    • Contact: Lone Volmer, MD; Email: Lone.Volmer@rsyd.dk
    • Principal Investigator: Lone Volmer, MD
  • Hillerød, Denmark, 3400
    • Recruiting
    • Nordsjællands Hospital
    • Contact: Karin Peschardt, MD; Email: Karin.Peschardt@regionh.dk
    • Principal Investigator: Karin Peschardt, MD
  • Næstved, Denmark, 4700
    • Recruiting
    • Regionsjælland Næstved Sygehus
    • Contact: Vesna Glavicic, MD; Email: vga@regionsjaelland.dk
    • Principal Investigator: Vesna Glavicic, MD
  • Sønderborg, Denmark, 6300
    • Recruiting
    • Sønderborg Sygehus
    • Contact: Erik Hugger Jakobsen, MD; Email: Erik.Hugger.Jakobsen@rsyd.dk
    • Principal Investigator: Erik Hugger Jakobsen, MD
  • Vejle, Denmark, 7100
    • Recruiting
    • Vejle syghus
    • Contact: Lone Volmer, MD; Email: Lone.Volmer@rsyd.dk
    • Principal Investigator: Lone Volmer, MD
  • Region Syd
    • Odense, Region Syd, Denmark, 5000
      • Recruiting
      • Odense University Hospital
      • Contact: Jeanette du Pont Jensen, MD; Email: jeanette.dupont.jensen@rsyd.dk
      • Principal Investigator: Jeanette du Pont Jensen, MD
    • Vejle, Region Syd, Denmark, 7100
      • Not yet recruiting
      • Vejle Hospital
      • Contact: Lone Volmer, MD; Email: Lone.Volmer@rsyd.dk
      • Principal Investigator: Lone Volmer, MD
• Sweden
  • Borås, Sweden, 501 82
    • Recruiting
    • Sodra Alvsborgs Hospital
    • Contact: Zakaria Einbeigi, MD, PhD; Phone Number: +46 33 616 10 00; Email: zakaria.einbeigi@oncology.gu.se
    • Principal Investigator: Zakaria Einbeigi, MD, PhD
  • Gävle, Sweden, 803 24
    • Recruiting
    • Gävle hospital, Department of Oncology
    • Contact: Per Edlund, MD, PhD; Phone Number: +46 26 15 40 00; Email: per.edlund@regiongavleborg.se
    • Principal Investigator: Per Edlund, MD, PhD
  • Göteborg, Sweden, 413 46
    • Recruiting
    • Sahlgrenska University Hospital, Department of Oncology
    • Contact: Barbro Linderholm, MD, PhD; Phone Number: +46 31 342 10 00; Email: barbro.linderholm@ki.se
    • Principal Investigator: Barbro Linderholm, MD, PhD
  • Halmstad, Sweden, 302 33
    • Not yet recruiting
    • Halmstad Hospital, Department of Surgery
    • Contact: Alaa Haidar, MD, PhD; Phone Number: +46 35 13 10 00; Email: alaa.haidar@regionhalland.se
    • Principal Investigator: Alaa Haidar, MD, PhD
  • Jönköping, Sweden, 551 85
    • Recruiting
    • Ryhov Hospital
    • Contact: Ida Spång Rosén, MD; Phone Number: +46 10 241 00 00; Email: ida.spang.rosen@rjl.se
    • Principal Investigator: Ida Spång Rosén, MD
  • Karlstad, Sweden, 652 30
    • Recruiting
    • Karlstad Hospital
    • Contact: Kilian Bachmeier, MD; Phone Number: +46 72 70 39 754; Email: kilian.bachmeier@regionvarmland.se
    • Principal Investigator: Kilian Bachmeier, MD
  • Malmö, Sweden, 20501
    • Recruiting
    • Skåne University Hospital, Department of Oncology
    • Contact: Niklas Loman, MD, PhD; Phone Number: +46 46 17 75 20; Email: niklas.loman@med.lu.se
    • Contact: Rosita Nordkvist, RN; Phone Number: +46 40 33 28 42; Email: rosita.nordkvist@skane.se
    • Principal Investigator: Niklas Loman, MD, PhD
  • Stockholm, Sweden, 112 19
    • Recruiting
    • Capio S:t Göran Hospital, Department of Oncology
    • Contact: Jenny Bergqvist, MD, PhD; Phone Number: +46 8 587 010 00; Email: jenny.bergkvist@capiostgoran.se
    • Principal Investigator: Jenny Bergkvist, MD, PhD
  • Stockholm, Sweden, 118 61
    • Recruiting
    • Södersjukhuset, Department of Oncology
    • Contact: Camilla Wendt, MD, PhD; Phone Number: +46 8 616 10 00; Email: cailla.wendt@sll.se
    • Principal Investigator: Camilla Wendt, MD, PhD
  • Sundsvall, Sweden, 851 86
    • Recruiting
    • Sundsvall Hospital
    • Contact: Anna-Karin Wennstig, MD, PhD; Phone Number: +46 60 18 25 40; Email: annakarin.wennstig@lvn.se
    • Principal Investigator: Anna-Karin Wennstig, MD, PhD
  • Umeå, Sweden, 907 37
    • Recruiting
    • Norrland University Hospital, Department of Oncology
    • Contact: Anne Andersson, MD, PhD; Phone Number: +46 90 785 00 00; Email: anne.andersson@umu.se
    • Principal Investigator: Anne Andersson, MD, PhD
  • Uppsala, Sweden, 753 09
    • Recruiting
    • Academical Hospital, Department of Oncology
    • Contact: Henrik Lindman, MD, PhD; Phone Number: +46 18 611 00 00; Email: henrik.lindman@igp.uu.se
    • Principal Investigator: Henrik Lindman, MD, PhD
  • Västerås, Sweden, 721 89
    • Recruiting
    • Västmanlands Hopsital Västerås
    • Contact: Cecilia Nilsson, MD, PhD; Phone Number: +46 21 30 00; Email: Cecilia.nilsson@regionvastmanland.se
    • Principal Investigator: Cecilia Nilsson, Md, PhD
  • Växjö, Sweden, 352 34
    • Recruiting
    • Växjö Hospital, Department of Oncology
    • Contact: Ulrik Narbe, MD, PhD; Phone Number: +46 470 58 80 00; Email: ulrik.narbe@med.lu.se
    • Principal Investigator: Ulrik Narbe, MD, PhD
  • Örebro, Sweden, 701 85
    • Recruiting
    • Örebro University Hospital, Department of Oncology
    • Contact: Antonis Valachis, MD, PhD; Phone Number: +46 19 602 10 00; Email: antonis.valachis@igp.uu.se
    • Principal Investigator: Antonis Valachis, MD, PhD
  • Skåne
    • Kristianstad, Skåne, Sweden, 291 85
      • Not yet recruiting
      • Centralsjukhuset i Kristianstad
      • Contact: Lars Norberg, MD, PhD; Phone Number: 044-309 10 00; Email: Lars.Norberg@skane.se
      • Principal Investigator: Lars Norberg

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Arm A (Platinum-based dose dense EC): ddEC x 4 + pembrolizumab→ PK x 4 + pembrolizumab, Two-weekly epirubicin/cyclophosphamide (EC) x 4 (epirubicin 90 mg/m2 and cyclophosphamide 600 mg/m2), followed after a three-week interval by three-weekly carboplatin x 4 (AUC = 5) together with weekly paclitaxel x 12 (80 mg/m2). Pembrolizumab is given as a 400 mg iv dosis every 6 weeks for the duration of preoperative chemotherapy.*	Drug: epirubicin, cyclophosphamide, paclitaxel, carboplatin, pembrolizumab; Cytotoxic agents.; Other Names: anthracycline, taxane, platinum
Experimental: Arm B (Platinum-based with capecitabine): CEX x 4→ PK x 4, Three-weekly cyclophosphamide/epirubicin/capecitabine (CEX) (epirubicin 75 mg/m2, cyclophosphamide 600 mg/m2 and capecitabine 900 mg/m2) x 4, followed after a three-week interval by three-weekly carboplatin x 4 (AUC = 5) together with weekly paclitaxel x 12 (80 mg/m2).Pembrolizumab is given as a 400 mg iv dosis every 6 weeks for the duration of preoperative chemotherapy.* *The addition of pembrolizumab is strongly recommended to all participating patients. However, patients with a documented contraindication, or unwilling to receive immunotherapy may be included in the study without the administration of pembrolizumab.	Drug: epirubicin, cyclophosphamide, capecitabine, paclitaxel, carboplatin, pembrolizumab; Cytotoxic agents.; Other Names: anthracycline, taxane, antimetabolite, platinum

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pathological complete response rate.	Rate of pathological complete response, allowing residual dcis, at surgery after preoperative chemotherapy.	Immediately after surgery
Primary translational outcome.	Pathological complete response rate, allowing residual dcis, stratified for homologous repair deficiency.	Immediately after surgery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Invasive Disease Free Survival (IDFS)	Invasive disease-free survival	Throughout the study, an average of 3 years
Overall Survival (OS)	Overall survival	Throughout the study, an average of 5 years
Breast Cancer Specific Survival (BCSS)	Breast cancer specific survival	Throughout the study, an average of 3 years
Distant Recurrence Free Survival (DRFS)	Distant recurrence free survival.	Throughout the study, an average of 3 years
Dose intensity	Actual dosis/dosis per protocol	Immediately after surgery
Toxicity according to CTCAE version 5.0	Rate of included patients with toxicity grade 3 or greater during study treatment	Immediately after surgery

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Subset characterization (histological subtypes)	Distribution of different histopathological subsets of Triple Negative Breast Cancer (TNBC).	Immediately after surgery
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
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
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
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
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
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
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
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

Collaborators and Investigators

• Sponsor: Lund University Hospital
• Collaborators: Danish Breast Cancer Cooperative Group; Swedish Breast Cancer Group; Finnish Breast Cancer Group; Icelandic Breast Cancer Group
• Investigators: Study Director: Niklas Loman, MD, PhD, Lund University Hospital

Study record dates

Study Major Dates

• Study Start (Actual): December 20, 2019
• Primary Completion (Anticipated): June 25, 2023
• Study Completion (Anticipated): June 30, 2035

Study Registration Dates

• First Submitted: December 2, 2019
• First Submitted That Met QC Criteria: April 2, 2020
• First Posted (Actual): April 6, 2020

Study Record Updates

• Last Update Posted (Actual): March 27, 2023
• Last Update Submitted That Met QC Criteria: March 23, 2023
• Last Verified: November 1, 2022

More Information

Terms related to this study

• Keywords: capecitabine; paclitaxel; carboplatin; cyclophosphamide; pembrolizumab; Neoadjuvant treatment; Survival outcomes; Breast neoplasms; epirubicin; Translational research; Triple negative breast neoplasms; Pathologic response; Pathologic complete response; Homologous repair deficiency
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms by Site; Breast Diseases; Neoplasms; Breast Neoplasms; Triple Negative Breast Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antineoplastic Agents, Immunological; Antibiotics, Antineoplastic; Cyclophosphamide; Carboplatin; Paclitaxel; Capecitabine; Epirubicin; Pembrolizumab; Albumin-Bound Paclitaxel; Taxane; Antimetabolites
• Other Study ID Numbers: NBG-19-01; SWEBCG 19-01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No