Breast Cancer
Conditions
Keywords
neoadjuvant, HER2 positive, tucatinib, Breast cancer
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 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.
Interventions
DRUGTucatinib
Tucatinib 300mg is taken orally twice daily
DRUGTrastuzumab
Trastuzumab 6mg/kg is administered intravenously on day 1 (loading dose 8mg/kg) or subcutaneously 600mg on day 1 of each cycle
DRUGPertuzumab
Pertuzumab 420mg is administered intravenously on day 1 (loading dose 840mg) or subcutaneously 600mg/kg (loading dose 1200mg) on day 1 of each cycle
Sponsors
Seagen Inc.
The Netherlands Cancer Institute
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence and severity of adverse events | an 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
| Measure | Time frame | Description |
|---|---|---|
| Incidence of disease progression | an 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 |
| Incidence of dose reductions and treatment discontinuations | an average of 8 months | Number of patients with dose reductions and treatment discontinuations |
| Radiologic complete response | an average of 8 months | Number of patients with a radiologic complete response defined as the absence of pathologic enhancement on contrast enhanced MRI breast |
| Incidence of serious adverse events | an average of 8 months | Number of patients with serious adverse events until 30 days after last study treatment administration |
| Residual Cancer Burden | an average of 8 months | Residual Cancer burden (RCB, 0-III) at surgery in patients treated without chemotherapy, and overall |
| Event-free survival | 3, 5, 10 years | Number of patients without progression or disease recurrence, second primary or death at 3, 5 and 10 years after registration |
| Overall survival | 3, 5, 10 years | Number of patients alive at 3, 5 and 10 years after registration |
| Pathological complete response | an average of 8 months | Number of patients with a pathological complete response (ypT0/is N0) at surgery in patients treated without chemotherapy, and overall |
Countries
Netherlands
Outcome results
None listed