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

Registration Number
NCT06162559
Lead Sponsor
The Netherlands Cancer Institute
Brief 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.

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. 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 spare...

Recruitment & Eligibility

Status
RECRUITING
Sex
All
Target Recruitment
30
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.
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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)
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Study & Design

Study Type
INTERVENTIONAL
Study Design
SINGLE_GROUP
Arm && Interventions
GroupInterventionDescription
Tucatinib + trastuzumab + pertuzumabTrastuzumabAll patients receive neoadjuvant treatment consisting of trastuzumab, pertuzumab and tucatinib. Patients with hormone receptor positive disease receive concurrent endocrine therapy with an aromatase-inhibitor. Premenopausal women are concurrently treated with a LHRH-agonist. In case of functional tumor volume decrease of at least 65% (responders) after the first three cycles, patients continue treatment for six more cycles of the chemotherapy-free regimen. If tumor response is \<65% (non-responders), patients will switch to receive six cycles paclitaxel, carboplatin, trastuzumab and pertuzumab. This is considered non-investigational treatment.
Tucatinib + trastuzumab + pertuzumabTucatinibAll patients receive neoadjuvant treatment consisting of trastuzumab, pertuzumab and tucatinib. Patients with hormone receptor positive disease receive concurrent endocrine therapy with an aromatase-inhibitor. Premenopausal women are concurrently treated with a LHRH-agonist. In case of functional tumor volume decrease of at least 65% (responders) after the first three cycles, patients continue treatment for six more cycles of the chemotherapy-free regimen. If tumor response is \<65% (non-responders), patients will switch to receive six cycles paclitaxel, carboplatin, trastuzumab and pertuzumab. This is considered non-investigational treatment.
Tucatinib + trastuzumab + pertuzumabPertuzumabAll patients receive neoadjuvant treatment consisting of trastuzumab, pertuzumab and tucatinib. Patients with hormone receptor positive disease receive concurrent endocrine therapy with an aromatase-inhibitor. Premenopausal women are concurrently treated with a LHRH-agonist. In case of functional tumor volume decrease of at least 65% (responders) after the first three cycles, patients continue treatment for six more cycles of the chemotherapy-free regimen. If tumor response is \<65% (non-responders), patients will switch to receive six cycles paclitaxel, carboplatin, trastuzumab and pertuzumab. This is considered non-investigational treatment.
Primary Outcome Measures
NameTimeMethod
Incidence and severity of adverse eventsan average of 8 months

Number of patients with adverse events and severity of adverse events (all grades; CTCAE v5.0) until 30 days after last study treatment administration

Secondary Outcome Measures
NameTimeMethod
Event-free survival3, 5, 10 years

Number of patients without progression or disease recurrence, second primary or death at 3, 5 and 10 years after registration

Radiologic complete responsean average of 8 months

Number of patients with a radiologic complete response defined as the absence of pathologic enhancement on contrast enhanced MRI breast

Pathological complete responsean average of 8 months

Number of patients with a pathological complete response (ypT0/is N0) at surgery in patients treated without chemotherapy, and overall

Residual Cancer Burdenan average of 8 months

Residual Cancer burden (RCB, 0-III) at surgery in patients treated without chemotherapy, and overall

Incidence of serious adverse eventsan average of 8 months

Number of patients with serious adverse events until 30 days after last study treatment administration

Incidence of dose reductions and treatment discontinuationsan average of 8 months

Number of patients with dose reductions and treatment discontinuations

Overall survival3, 5, 10 years

Number of patients alive at 3, 5 and 10 years after registration

Incidence of disease progressionan average of 8 months

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

Trial Locations

Locations (1)

Netherlands Cancer Institute

🇳🇱

Amsterdam, Netherlands

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