Image-guided De-escalation of Neo-adjuvant Chemotherapy in HER2-positive Breast Cancer: the TRAIN-3 Study (TRAIN-3)

• ClinicalTrials.gov Identifier: NCT03820063
• Recruitment Status: Recruiting
• First Posted: January 29, 2019
• Last Update Posted: July 10, 2020
• Sponsor: Borstkanker Onderzoek Groep
• Collaborators: Roche Pharma AG; BOOG Study Center
• Information provided by (Responsible Party): Borstkanker Onderzoek Groep

Tracking Information

• First Submitted Date: January 25, 2019
• First Posted Date: January 29, 2019
• Last Update Posted Date: July 10, 2020
• Actual Study Start Date: February 27, 2019
• Estimated Primary Completion Date: February 1, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 25, 2019)

Event free survival at three years [ Time Frame: 3 years ]

Number of patients without progression of disease recurrence, second primary or death

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: July 8, 2020)

• Overall survival at three years [ Time Frame: 3 years ]
  Number of patients alive at three years
• Pathologic complete response in breast and axilla [ Time Frame: an average of 6 months ]
  Number of patients with absence of invasive tumor cells in breast and axilla at surgery
• Radiologic complete response [ Time Frame: an average of 6 months ]
  Number of patients with absence of pathologic enhancement on MRI
• Number of neoadjuvant chemotherapy cycles administered [ Time Frame: an average of 1 year ]
  Number of neoadjuvant chemotherapy cycles administered per patient
• Number of radical and non-radical resections [ Time Frame: an average of 6 months ]
  Number of patients with radical and non-radical resections
• Incidence and severity of adverse events [ Time Frame: an average of 1 year ]
  Number of patients with toxicity grade >= 3 (CTCAE v5.0) until 30 days after last adjuvant administration
• Incidence and severity of cardiotoxicity and neuropathy [ Time Frame: an average of 1 year ]
  Number of patients with cardiotoxicity and neuropathy grade >= 2 (CTCAE v5.0) until 30 days after last adjuvant administration
• Incidence of symptomatic LVSD (heart failure), [ Time Frame: an average of 1 year ]
  Number of patients with an asymptomatic decline in LVEF requiring treatment or leading to discontinuation of pertuzumab and Herceptin, or a decrease ≥10 percentage points from baseline to a LVEF <50%
• Grade ≥3 laboratory test abnormalities [ Time Frame: an average of 1 year ]
  Number of patients with Grade ≥3 laboratory test abnormalities
• Incidence of number of tumor positive Vacuum Assisted Core Biopsy [ Time Frame: an average 6 months ]
  Number of patients with tumor present at Vacuum Assisted Core Biopsy at the moment of radiological complete response on MRI

Original Secondary Outcome Measures (submitted: January 25, 2019)

• Overall survival at three years [ Time Frame: 3 years ]
  Number of patients alive at three years
• Pathologic complete response in breast and axilla [ Time Frame: an average of 6 months ]
  Number of patients with absence of invasive tumor cells in breast and axilla at surgery
• Radiologic complete response [ Time Frame: an average of 6 months ]
  Number of patients with absence of pathologic enhancement on MRI
• Number of neoadjuvant chemotherapy cycles administered [ Time Frame: an average of 1 year ]
  Number of neoadjuvant chemotherapy cycles administered per patient
• Number of radical and non-radical resections [ Time Frame: an average of 6 months ]
  Number of patients with radical and non-radical resections
• Incidence and severity of adverse events [ Time Frame: an average of 1 year ]
  Number of patients with toxicity grade >= 3 (CTCAE v5.0) until 30 days after last adjuvant administration
• Incidence and severity of cardiotoxicity and neuropathy [ Time Frame: an average of 1 year ]
  Number of patients with cardiotoxicity and neuropathy grade >= 2 (CTCAE v5.0) until 30 days after last adjuvant administration
• Incidence of symptomatic LVSD (heart failure), [ Time Frame: an average of 1 year ]
  Number of patients with an asymptomatic decline in LVEF requiring treatment or leading to discontinuation of pertuzumab and Herceptin, or a decrease ≥10 percentage points from baseline to a LVEF <50%
• Grade ≥3 laboratory test abnormalities [ Time Frame: an average of 1 year ]
  Number of patients with Grade ≥3 laboratory test abnormalities

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Image-guided De-escalation of Neo-adjuvant Chemotherapy in HER2-positive Breast Cancer: the TRAIN-3 Study
• Official Title: Image-guided De-escalation of Neo-adjuvant Chemotherapy in HER2-positive Breast Cancer: the TRAIN-3 Study
• Brief Summary: This is a multicenter, single arm, phase II study evaluating the efficacy of image-guided de-escalating neoadjuvant treatment with paclitaxel, Herceptin® (trastuzumab), carboplatin, and pertuzumab (PTC-Ptz) in stage II-Ill HER2-positive breast cancer.

Detailed Description

High pathological complete response (pCR)-rates are seen using different neoadjuvant chemotherapy schedules with trastuzumab and pertuzumab in HER2-positive stage II - III breast cancer patients. Total pCR rates in breast and axilla have been described as high as 64%, and with an even higher rate of >80% in patients with HER2-positive and hormone receptor (HR) negative tumors. PCR is associated with better long-term outcomes in patients with HER2-positive breast cancer. Three year progression-free survival ranges between 85-90%. Neoadjuvant treatment of HER2-positive breast cancer typically consists of six to nine cycles of treatment. Longer duration of treatment is associated with higher pCR-rates but gives more toxicity. Pathological complete responses are sometimes seen after only 10-12 days of neoadjuvant treatment. It is therefore important to investigate which patients can safely be treated with less than six cycles of chemotherapy and who requires more than six cycles for maximum activity.

The radiologic response of a breast tumor after neoadjuvant therapy is predictive of the pathologic response, although the accuracy differs between breast cancer subtypes. It is hypothesized that patients with an early complete radiologic response may not benefit from additional chemotherapy and can be referred for early surgery. Patients who have not achieved pCR after early surgery despite radiologic complete response (rCR) are candidates for further adjuvant chemotherapy to complete the initially planned number of treatment cycles and maintain maximum treatment activity. Imaged guided de-escalation in which the number of treatment cycles is determined by the radiologic response could thus reduce toxicity in neoadjuvant treatment while maintaining activity.

This study will evaluate the efficacy of image-guided de-escalation of neoadjuvant chemotherapy in patients with HER2-positive breast cancer.

To maintain efficacy, patients who do not achieve pCR will complete a total of nine cycles taxane-containing chemotherapy followed by 14 cycles of treatment with adjuvant T-DM1. Patients who achieve early pCR will continue treatment with Herceptin® and pertuzumab to complete one full year of treatment.

• Study Type: Interventional
• Study Phase: Phase 2

Study Design

Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description:

neoadjuvant courses PTC-Ptz; adjuvant courses Ptz (pCR) or T-DM1 (non-pCR)

Masking: None (Open Label)
Primary Purpose: Treatment

• Condition: Breast Cancer

Intervention

Drug: PTC-Pz

• Paclitaxel 80mg/m2 administered intravenously on day 1 and day 8
• Herceptin® 6mg/kg administered intravenously on day 1 (loading dose 8mg/kg) or Herceptin® administered subcutaneously 600mg on day 1
• Carboplatin AUC 6mg•ml/min administered intravenously on day 1
• Pertuzumab 420mg administered intravenously on day 1 (loading dose 840mg)
• Treatment cycles are repeated on day 22

In case of non pCR; Adjuvant T-DM1, 3.6mg/kg Q 22 days, for 14 cycles.

Study Arms

Experimental: PTC-Pz

• Paclitaxel 80mg/m2 administered intravenously on day 1 and day 8
• Herceptin® 6mg/kg administered intravenously on day 1 (loading dose 8mg/kg) or Herceptin® administered subcutaneously 600mg on day 1
• Carboplatin AUC 6mg•ml/min administered intravenously on day 1
• Pertuzumab 420mg administered intravenously on day 1 (loading dose 840mg)
• Treatment cycles are repeated on day 22

Patients who do not achieve pCR will complete a total of nine cycles taxane-containing chemotherapy followed by 14 cycles of treatment with adjuvant T-DM1.

Intervention: Drug: PTC-Pz

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: January 25, 2019): 462
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: February 1, 2032
• Estimated Primary Completion Date: February 1, 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Histologically confirmed primairy infiltrating breast cancer.
2. Stage II or Ill disease.
3. Overexpression and/or amplification of HER2 in an invasive component of the core biopsy.
4. Age <:18
5. ECOG Group performance status
6. LVEF >50% measured by echocardiography, MRI or MUGA
7. Known HR-status ( in percentages)

Exclusion Criteria:

1. Previous radiation therapy of chemotherapy
2. Pregnancy or breastfeeding
3. Evidence of distant metastases
4. Evidence of bilateral infiltrating breast cancer
5. Concurrent anti-cancer treatment or another investigational drug

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Anna van der Voort, MD; +3120512 ext 9111; a.vd.voort@nki.nl

Contact: G S Sonke, MD; train3@nki.nl

• Listed Location Countries: Netherlands

Administrative Information

• NCT Number: NCT03820063
• Other Study ID Numbers: BOOG 2018-01
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Responsible Party: Borstkanker Onderzoek Groep
• Study Sponsor: Borstkanker Onderzoek Groep

Collaborators

• Roche Pharma AG
• BOOG Study Center

Investigators

• Principal Investigator: G S Sonke, MD; NKI-AvL
• Study Director: A E van Leeuwen- Stok, PhD; BOOG Study Center

• PRS Account: Borstkanker Onderzoek Groep
• Verification Date: July 2020