This study has been transitioned to CTIS with ID 2024-518192-61-00 check the CTIS register for the current data. To evaluate safety and feasibility of neoadjuvant chemotherapy-free regimen with trastuzumab, pertuzumab and tucatinib in stage II-III…
ID
Source
Brief title
Condition
- Breast neoplasms malignant and unspecified (incl nipple)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Incidence and severity of adverse events (all grades) until 30 days after last
study treatment administration.
Secondary outcome
- Incidence of serious adverse events until 30 days after last study treatment
administration
- Incidence of progressive disease during neoadjuvant treatment O progressive
disease: defined as 20% increase *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
- Radiologic complete response defined as the absence of pathologic enhancement
on contrast enhanced MRI breast
- Pathological complete response (ypT0/is N0) at surgery in patients treated
without chemotherapy, and overall
- Residual Cancer burden (RCB, 0-III) at surgery in patients treated without
chemotherapy, and overall
- Event-free survival (EFS) defined as the interval from registration to
disease progression resulting in inoperability, recurrence, or death from any
cause, whichever comes first at 3, 5 and 10 years after registration
- Overall survival (OS) defined as the time from registration to death from any
cause at 3, 5 and 10 years after registration
Background summary
Breast cancer can be classified into four different types based on the
treatment options: hormone sensitive and HER2-negative, hormone sensitive and
HER2-positive, hormone insensitive and HER2-positive, and hormone insensitive
and HER2-negative. This study concerns exclusively HER2-positive (hormone
sensitive or insensitive) breast cancer. HER2-positive breast cancer is
characterized by many HER2 on the cancer cells. As a result, cancer cells get a
lot of signals to grow and to divide. With this type of breast cancer patients
are eligible for targeted therapy, which uses agents that specifically target
the HER2 protein. Examples of such targeted medicines are trastuzumab and
pertuzumab. Since the advent of these medicines, patient*s outcomes have been
improved dramatically. In addition, they give less frequently and less
dangerous side effects compared to chemotherapy because they mainly target
tumor cells (instead of chemotherapy). However, targeted therapy is nowadays
still combined with chemotherapy. Previous studies have shown that some
patients can be treated with a chemotherapy-free regimen consisting of solely
targeted therapy (with trastuzumab and pertuzumab). However, this applies to a
minority of patients.
Tucatinib is a relatively new medicine that also targets HER2. Tucatinib is
already being used to treat patients with metastatic breast cancer, and has
shown to be effective. Just like trastuzumab and pertuzumab, one of the
benefits of tucatinib is that it leads to less frequent and less dangerous side
effects compared to chemotherapy. In addition, previous studies have
demonstrated that tucatinib also leads to good results in patients with brain
metastasis, which until now remains an unmet medical need in HER2+ breast
cancer. By combining tucatinib with trastuzumab and pertuzumab and by selecting
patients who are likely to have a high chance of response to the targeted
therapy, we aim to treat even more patients successfully with a
chemotherapy-free regimen. Since it is known that chemotherapy causes many
adverse side effects on both the short term and the long term, this new
treatment would be a great improvement in the treatment of HER2-positive breast
cancer.
Study objective
This study has been transitioned to CTIS with ID 2024-518192-61-00 check the CTIS register for the current data.
To evaluate safety and feasibility of neoadjuvant chemotherapy-free regimen
with trastuzumab, pertuzumab and tucatinib in stage II-III HER2-positive breast
cancer.
Study design
TRAIN-4 is a non-randomized, non-comparative, single-center phase 1b study.
All subjects start with three cycles of trastuzumab, pertzumab and tucatinib.
One cycle takes three weeks. Trastuzumab and pertuzumab are administered
intravenously on day 1 of every cycle, whereas tucatinib is administered orally
on daily basis. During treatment in the TRAIN4-study, an MRI scan of the breast
is performed every three cycles. If the tumor volume has decreased sufficiently
after the third cycle, treatment with trastuzumab plus pertuzumab plus
tucatinib will be continued for six more cycles. However, if the tumor volume
has not decreased sufficiently, the administration of tucatinib will stop and
chemotherapy will be added to the treatment, creating the scheme of paclitaxel,
trastuzumab, carboplatin and pertuzumab (PTC-Ptz). Chemotherapy with PTC-Ptz is
nowadays standard-of-care for patients with HER2-positive breast cancer.
After completion of neoadjuvant treatment subjects will be operated. After
surgery patients will be treated according to national guidelines, for instance
with chemotherapy, radiation therapy or hormonal therapy.
Intervention
This study has no intervention or control group. Patients will be treated
according to the above mentioned scheme (see *Study design*).
Study burden and risks
Burden
Due to extra checks/investigations subjects need to visit the hospital more
frequently than when they get standard-of-care:
- During the first three cycles weekly (including medical check by the
investigating doctor and laboratory assessments), cycle 4-9 once every three
weeks. In case a patients switches to chemotherapy with PTC-Ptz after three
cycles, laboratory investigations are conducted according to the local
treatment protocol.
- Two times more often a MRI scan of the breast.
- One time more often a PET scan.
- Two times (at screening and after three cycles) some extra blood (20ml in
total, EDTA tubes) will be taken for ctDNA analysis.
- Three more extra biopsies at screening for translational research.
Risks
Trastuzumab, pertuzumab and chemotherapy with PTC-Ptz are already registered as
neoadjuvant treatment of HER2-positive breast cancer and considered standard of
care. However, tucatinib is no standard treatment yet. The most important side
effects of tucatinib are diarrhea, stomatitis, hepatotoxicity, skin rash and
nosebleeds. Because of the increased chance of developing diarrhea, subjects
will be prescribed loperamide. In addition, subjects will be monitored more
frequently than standard-of-care.
Plesmanlaan 121
Amsterdam 1066 CX
NL
Plesmanlaan 121
Amsterdam 1066 CX
NL
Listed location countries
Age
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 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 of age)
7. LVEF >=50% measured by echocardiography or MUGA
8. Eligible for neoadjuvant treatment
9. Laboratory requirements within 21 days prior to enrollment: a. Adequate bone
marrow function (ANC >=1.5 x 109/l, platelets >=100 x 109/l); b. 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; c. 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)
10. Bilateral breast cancer
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EU-CTR | CTIS2024-518192-61-00 |
| EudraCT | EUCTR2022-002784-29-NL |
| CCMO | NL81763.041.22 |