Neoadjuvant Trastuzumab, Pertuzumab and Tucatinib Without Chemotherapy in HER2-positive Breast Cancer: the TRAIN-4 Study

Breast Cancer Clinical Trial

— TRAIN-4  

Official title:

Neoadjuvant Trastuzumab, Pertuzumab and Tucatinib Without Chemotherapy in HER2-positive Breast Cancer: the TRAIN-4 Study

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06162559
• Other study ID #: N21TRV
• Status: Recruiting
• Phase: Phase 1
• Start date: December 18, 2023
• Est. completion date: May 2036

Study information

• Verified date: January 2024
• Source: The Netherlands Cancer Institute
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a single-center, phase 1b study evaluating the safety and feasibility of a neoadjuvant treatment with tucatinib, trastuzumab and pertuzumab in stage II-IIIA HER2-positive breast cancer.

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. However, a subset of patients with stage II-III HER2-positive breast cancer can be treated with HER2-blockade alone. These patients can potentially be totally spared from chemotherapy-associated toxicity. The proportion of patients whom can successfully be treated without chemotherapy could potentially be increased by selecting great responders using DCE-MRI and by adding tucatinib to trastuzumab and pertuzumab alone. The aim of this study is to evaluate the safety and efficacy of neoadjuvant treatment with tucatinib, trastuzumab and pertuzumab.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 30
• Est. completion date: May 2036
• Est. primary completion date: August 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Signed written informed consent

2. Histologically confirmed primary invasive breast cancer

3. Stage II - IIIA primary breast cancer according to TNM-staging (8th edition, AJCC); (largest tumor diameter on DCE-MRI = 2cm (cT2-3) and/or cN1-2 confirmed with FNA or histology)

4. HER2 overexpression defined as circumferential membrane staining that is complete, intense and in >10% of invasive tumor cells (IHC 3+) on pre-treatment biopsy

5. Known estrogen- and progesterone-receptor expression of the invasive tumor

a. ER-negative or PR-negative is defined as <10% of invasive tumor cell nuclei are immunoreactive in the presence of evidence that the sample can express ER and/or PR

6. WHO performance status 0-1

7. Age = 18 years

8. LVEF =50% measured by echocardiography or MUGA

9. Eligible for neoadjuvant treatment

10. Laboratory requirements within 21 days prior to enrollment:

1. Adequate bone marrow function (ANC =1.5 x 109/l, platelets =100 x 109/l);

2. Adequate hepatic function (ALAT, ASAT and bilirubin =2.5 times upper limit of normal). Subjects with Gilbert's syndrome may have a total bilirubin =2.5 × the ULN range, if no evidence of biliary obstruction exists.

3. Adequate renal function: creatinine clearance >50 ml/min estimated using the Cockcroft-Gault equation or MDRD equation, or based on a 24-hour urine collection measurement.

Exclusion Criteria:

1. Current pregnancy or breastfeeding

2. Current or previous other malignancy unless treated without systemic therapy and more than five years ago

3. Psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol and follow-up schedule

4. Use of a strong CYP3A4 or CYP2C8 inhibitor within five half-lives of the inhibitor, or used a strong CYP3A4 or CYP2C8 inducer within five days prior to first dose of study treatment

5. Known chronic liver disease

6. History of inflammatory bowel disease or bowel resection

7. Contraindications for MRI

8. Inflammatory breast cancer, cT4 and/or cN3 tumors

9. Occult breast cancer (cT0)

Related Conditions & MeSH terms

• Breast Cancer
• Breast Neoplasms

Intervention

Drug:
• Tucatinib
Tucatinib 300mg is taken orally twice daily
• Trastuzumab
Trastuzumab 6mg/kg is administered intravenously on day 1 (loading dose 8mg/kg) or subcutaneously 600mg on day 1 of each cycle
• Pertuzumab
Pertuzumab 420mg is administered intravenously on day 1 (loading dose 840mg) or subcutaneously 600mg/kg (loading dose 1200mg) on day 1 of each cycle

Locations

Country	Name	City	State
Netherlands	Netherlands Cancer Institute	Amsterdam

Sponsors (2)

Lead Sponsor	Collaborator
The Netherlands Cancer Institute	Seagen Inc.

Country where clinical trial is conducted

Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Incidence and severity of adverse events	Number of patients with adverse events and severity of adverse events (all grades; CTCAE v5.0) until 30 days after last study treatment administration	an average of 8 months
Secondary	Incidence of serious adverse events	Number of patients with serious adverse events until 30 days after last study treatment administration	an average of 8 months
Secondary	Incidence of disease progression	Number of patients with progressive disease during neoadjuvant treatment. Progressive disease is defined as 20% increase in ?FTV or >20% increase measured in the longest diameter on DCE-MRI or unequivocal new lesions on (18)F-FDG PET	an average of 8 months
Secondary	Incidence of dose reductions and treatment discontinuations	Number of patients with dose reductions and treatment discontinuations	an average of 8 months
Secondary	Radiologic complete response	Number of patients with a radiologic complete response defined as the absence of pathologic enhancement on contrast enhanced MRI breast	an average of 8 months
Secondary	Pathological complete response	Number of patients with a pathological complete response (ypT0/is N0) at surgery in patients treated without chemotherapy, and overall	an average of 8 months
Secondary	Residual Cancer Burden	Residual Cancer burden (RCB, 0-III) at surgery in patients treated without chemotherapy, and overall	an average of 8 months
Secondary	Event-free survival	Number of patients without progression or disease recurrence, second primary or death at 3, 5 and 10 years after registration	3, 5, 10 years
Secondary	Overall survival	Number of patients alive at 3, 5 and 10 years after registration	3, 5, 10 years