Trial Title:
Efficacy and Safety of the Combination of Trastuzumab Plus TUCAtinib Plus viNorelbine in Patients With HER2-positive Non-resectable Locally Advanced or Metastatic Breast Cancer
NCT ID:
NCT05583110
Condition:
HER2-positive Metastatic Breast Cancer
Locally Advanced HER2 Positive Breast Carcinoma
Conditions: Official terms:
Breast Neoplasms
Trastuzumab
Vinorelbine
Tucatinib
Conditions: Keywords:
tucatinib
Non-resectable locally advanced or metastatic breast cancer
HER2-positive
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Tucatinib
Description:
Run-in Phase:
- Trastuzumab either IV or SC: 8 mg/kg IV loading dose (if necessary), followed by 6
mg/kg intravenous (IV) or 600 mg subcutaneous (SC) every 3 weeks.
- Oral vinorelbine: 50 mg/m2 (in the first cycle) and 60 mg/m2 (in the following
cycles if no dose limiting toxicity [DLT] is seen) on days 1 and 8, every 3 weeks.
- Oral tucatinib 300 mg twice a day (BID) on a continuous dosing schedule.
Following patients in the phase II:
- Trastuzumab either IV or SC: 8 mg/kg IV loading dose (if necessary), followed by 6
mg/kg IV or 600 mg SC every 3 weeks.
- Oral vinorelbine: 50 mg/m2 or 60 mg/m2 (based on the run-in phase results) on days 1
and 8, every 3 weeks.
- Oral tucatinib 300 mg BID on a continuous dosing schedule.
Arm group label:
Trastuzumab-Vinorelbine-Tucatinib
Other name:
Tukysa
Intervention type:
Drug
Intervention name:
Trastuzumab
Description:
Run-in Phase:
- Trastuzumab either IV or SC: 8 mg/kg IV loading dose (if necessary), followed by 6
mg/kg intravenous (IV) or 600 mg subcutaneous (SC) every 3 weeks.
- Oral vinorelbine: 50 mg/m2 (in the first cycle) and 60 mg/m2 (in the following
cycles if no dose limiting toxicity [DLT] is seen) on days 1 and 8, every 3 weeks.
- Oral tucatinib 300 mg twice a day (BID) on a continuous dosing schedule.
Following patients in the phase II:
- Trastuzumab either IV or SC: 8 mg/kg IV loading dose (if necessary), followed by 6
mg/kg IV or 600 mg SC every 3 weeks.
- Oral vinorelbine: 50 mg/m2 or 60 mg/m2 (based on the run-in phase results) on days 1
and 8, every 3 weeks.
- Oral tucatinib 300 mg BID on a continuous dosing schedule.
Arm group label:
Trastuzumab-Vinorelbine-Tucatinib
Other name:
Herceptin
Intervention type:
Drug
Intervention name:
Vinorelbine
Description:
Run-in Phase:
- Trastuzumab either IV or SC: 8 mg/kg IV loading dose (if necessary), followed by 6
mg/kg intravenous (IV) or 600 mg subcutaneous (SC) every 3 weeks.
- Oral vinorelbine: 50 mg/m2 (in the first cycle) and 60 mg/m2 (in the following
cycles if no dose limiting toxicity [DLT] is seen) on days 1 and 8, every 3 weeks.
- Oral tucatinib 300 mg twice a day (BID) on a continuous dosing schedule.
Following patients in the phase II:
- Trastuzumab either IV or SC: 8 mg/kg IV loading dose (if necessary), followed by 6
mg/kg IV or 600 mg SC every 3 weeks.
- Oral vinorelbine: 50 mg/m2 or 60 mg/m2 (based on the run-in phase results) on days 1
and 8, every 3 weeks.
- Oral tucatinib 300 mg BID on a continuous dosing schedule.
Arm group label:
Trastuzumab-Vinorelbine-Tucatinib
Other name:
Navelbine
Summary:
Breast cancer (BC) is the most common neoplasm in the world. In Spain, one in 8 women is
diagnosed with BC. The human epidermal growth factor receptor 2 (HER2)-positive BC
subtype (that represents around 20% of all BC) was associated with poor prognosis
however, new therapeutic advances have significantly increased the cure rate of patients
in early stages.
In the metastatic setting, anti-HER2 targeted therapies have significantly improved
overall survival (OS) with good quality of life, however there is still a substantial
group of patients who die, and therefore additional drugs need to be investigated.
Trastuzumab, an anti HER2 antibody has demonstrated, in combination with chemotherapy, an
improvement of OS in early and metastatic stages.
Tucatinib is an oral selective inhibitor of the HER2 receptor tyrosine kinase subunit.
Its high affinity for this subunit causes fewer toxicities, such as rash and diarrhea,
which are common with other anti-HER tyrosine kinase inhibitors (TKIs).
Vinorelbine has been evaluated previously in combination with trastuzumab showing
interesting results.
This is a single country, multicenter, single arm phase II clinical trial with a safety
run-in phase, to study the efficacy, safety and tolerability of the administration of
tucatinib in combination with trastuzumab and vinorelbine in HER2-positive non-resectable
locally advanced or metastatic breast cancer (MBC) with measurable disease.
Detailed description:
Patients with brain metastasis are allowed (but up to maximum of 50% of included
patients).
Forty-nine patients will be enrolled in the study:
- The first 3 patients included in the study will receive trastuzumab plus tucatinib
plus oral vinorelbine at a dose of 50 mg/m2 in the first cycle. If not dose limiting
toxicity (DLT) is observed, these patients will receive oral vinorelbine at a dose
of 60 mg/m2 for the following cycles.
- If 1/3 patients experience DLT in the first cycle, 3 additional patients will be
included to receive trastuzumab plus tucatinib plus oral vinorelbine at a dose of 50
mg/m2 in the first cycle and then 60 mg/m2.
- If 0/3 or <2/6 patients experience DLT in the first cycle the vinorelbine dose will
be 60 mg/m2 for all the following patients included in the study.
- If ≥2 out of 3 or 6 patients experienced DLT in the first cycle, all the following
included patients will receive oral vinorelbine at a dose of 50 mg/m2.
DLTs are defined according to the National Cancer Institute - Common Terminology Criteria
for Adverse Events (NCI-CTCAE) version 5.0 as any of the following events considered by
the investigator to be related to investigational treatment:
- Grade 4 neutropenia lasting more than 7 consecutive days or associated with fever.
- Grade 4 thrombocytopenia lasting more than 7 consecutive days.
- Grade 3 thrombocytopenia associated with clinically significant bleeding.
- Platelet count <10,000/mm3.
- Delay of more than 7 days in the initiation of a subsequent cycle due to
treatment-related adverse events.
- Any grade 3 or higher non-hematologic toxicity (except grade 3 or higher
nausea/emesis or diarrhea in the absence of optimal symptomatic treatment for these
conditions, grade 3 or higher fatigue lasting less than 1 week and other grade 3 or
higher non-hematologic toxicity that could be controlled to grade 2 or less with
appropriate treatment).
Justification of Sample size determination:
The A'Hern one stage design will be used for this study. Taking into account the HERCLIMB
study, we assume a null hypothesis (H0) of an Objective response rate (ORR) of 23% and
alternative hypothesis (H1) of an ORR of 40%. With an alpha error of 0.05 and a
statistical power of 80%, we will need to include 46 evaluable patients. Assuming a 5%
dropout rate, 49 patients will be included in this study.
Patients included in the run-in phase will be considered for the efficacy analysis of the
phase II.
Study Duration:
The start date of the study is the date of the first site activation. Recruitment period
will occur during approximately 18 months from the first patient in.
The end date of the study is the date of the last visit of the last patient (LPLV),
including follow-up. The duration of the study will be approximately 40 months from the
first patient in.
Performing exploratory objectives will be independent of the date of the end of the
study.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
Patients are eligible to be enrolled in the study only if they meet all of the following
criteria:
1. Written and signed informed consent obtained prior to any study-specific procedure.
2. Male or female patients at least 18 years of age.
3. Availability of pre-treatment archival Formalin-Fixed Paraffin-Embedded (FFPE) tumor
tissue (preferably the most recent available), otherwise possibility to perform a
biopsy, to carry out exploratory biomarker analyses.
4. Documented HER2-positive status by local laboratory determination, preferably on the
most recent available FFPE tumor sample, according to the American Society of
Clinical Oncology (ASCO)/College of American Pathologists (CAP) international
guidelines valid at the time of the assay.
5. Previous therapy with at least two prior anti-HER2 treatment regimens (either in
early stage or advanced disease). Prior taxanes and trastuzumab are mandatory. Prior
treatment with pertuzumab, T-DM1, trastuzumab-deruxtecan and anti-HER2 TKI agents is
allowed.
6. Measurable disease according to RECIST 1.1 criteria, defined as at least 1
extra-osseous lesion that can be accurately measured in at least 1 dimension.
7. Mandatory contrast brain magnetic resonance imaging (MRI) must be performed at
baseline and patients must have at least one of the following:
1. No evidence of brain metastases.
2. Untreated brain metastases not needing immediate local therapy.
3. Previously treated brain metastases.
- Brain metastases previously treated with local therapy may either be
stable since treatment or may have progressed since prior local central
nervous system (CNS) therapy, provided that there is no clinical
indication for immediate re-treatment with local therapy.
- Subjects treated with CNS local therapy for newly identified lesions may
be eligible to enroll if all of the following criteria are met:
- Time since stereotactic radiosurgery (SRS) is at least 1 week prior
to first dose of study treatment, time since whole brain radiation
therapy (WBRT) is at least 3 weeks prior to first dose, or time since
surgical resection is at least 4 weeks.
- Other sites of evaluable disease are present.
- Relevant records of any CNS treatment must be available to allow for
classification of target and non-target lesions.
8. Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 1.
9. Life expectancy ≥ 12 weeks.
10. Adequate organ and marrow function defined as follows:
1. Absolute Neutrophil Count (ANC) ≥ 1,500/mm3 (1.5x109/L).
2. Platelet count ≥ 100,000/mm3 (100x109/L).
3. Hemoglobin ≥ 9g/dL (90g/L).
4. Serum creatinine ≤ 1,5x upper limit of the normal range (ULN) or estimated
creatinine clearance ≥ 60 mL/min as calculated using the standard method for
the institution.
5. Total serum bilirubin ≤ 1,5 x ULN (≤ 3.0 x ULN if Gilbert´s disease).
6. Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT ≤ 3.0 x
ULN (≤5.0 x ULN if liver metastases are present).
7. Alkaline phosphatase ≤ 2.5 x ULN (≤5.0 x ULN if bone or liver metastases are
present).
11. Left ventricular ejection fraction (LVEF) ≥ 50% measured by multiple-gated
acquisition scan (MUGA) or echocardiogram (ECHO).
12. Negative urine or serum pregnancy test for females of childbearing potential.
Exclusion Criteria:
Patients will be excluded from the study if they meet any of the following criteria:
1. Have received more than 4 lines of systemic therapy for locally advanced or MBC.
2. Have received prior treatment with tucatinib, vinorelbine for locally advanced or
MBC or anti-HER2 TKI agents if administered less than 12 months prior to study
entry.
3. Have used a strong CYP3A4 or CYP2C8 inhibitor or CYP3A substrate within 2 weeks, or
a strong CYP3A4 or CYP2C8 inducer within 5 days prior to the first dose of study
treatment (see Protocol Attachment 2 for more information).
4. Require therapy with warfarin or other coumarin derivatives (non-coumarin
anticoagulants are allowed).
5. Patients who received before inclusion:
1. Any investigational agent within 4 weeks.
2. Chemotherapy within a period of time that is shorter than the cycle duration
used for that treatment (e.g. < 3 weeks for fluorouracil, doxorubicine,
epirubicin or < 1 week for weekly chemotherapy).
3. Biologic therapy (e.g., antibodies): up to 4 weeks prior to starting study
treatment.
4. Endocrine therapy: tamoxifen or aromatase inhibitor (AI) within 2 weeks prior
to starting study treatment.
5. Corticosteroids within 2 weeks prior to starting study treatment. Note: the
following uses of corticosteroids are permitted at any time: single doses,
topical applications (e.g., for rash), inhaled sprays (e.g., for obstructive
airways diseases), eye drops or local injections (e.g., intra-articular).
6. Radiotherapy within 2 weeks (3 weeks if WBRT) prior to starting study treatment
(all acute toxic effects must be resolved to NCI-CTCAE version 5.0 grade <1,
except toxicities not considered a safety risk for the patient at
investigator´s discretion). Patients who received prior radiotherapy to >25% of
bone marrow are not eligible regardless of when it was administered.
7. Major surgery or other anti-cancer therapy not previously specified within 4
weeks prior to starting study treatment, Resolution of all acute toxic effects
of prior anti-cancer therapy or surgical procedures to NCI-CTCAE version 5.0
grade ≤ 1 (except alopecia or other toxicities not considered a safety risk for
the patient at investigator´s discretion) is mandatory.
6. Are unable for any reason to undergo MRI of the brain.
7. Have any of the following with regards to CNS disease:
1. Any untreated brain lesions >2 cm in size.
2. Any brain lesion thought to require immediate local therapy, including (but not
limited to) a lesion in an anatomic site where increase in size or possible
treatment-related edema may pose risk to patient (e.g. brain stem lesions).
Patients who undergo local treatment for such lesions identified by screening
contrast brain MRI may still be eligible for the study based on criteria
described under CNS inclusion criteria 7b.
3. Known or concurrent leptomeningeal disease as documented by the investigator.
4. Ongoing use of corticosteroids for control of symptoms of brain metastases at a
total daily dose of >2 mg of dexamethasone (or equivalent).
5. Poorly controlled (> 1/week) generalized or complex partial seizures or
manifest neurologic progression due to brain metastases notwithstanding
CNS-directed therapy.
8. Have clinically significant, uncontrolled heart disease and/or recent cardiac events
including any of the following:
1. Ventricular arrhythmia requiring therapy.
2. Myocardial infarction or unstable angina within 6 months prior to first dose of
study treatment.
3. Uncontrolled hypertension (defined as persistent systolic blood pressure > 150
mm Hg and/or diastolic blood pressure > 100 mm Hg on antihypertensive
medications).
4. Any history of symptomatic congestive heart failure (CHF).
5. History of LVEF decline below 50% during or after prior trastuzumab therapy or
other cardiac toxicity during previous trastuzumab treatment that necessitated
discontinuation of trastuzumab.
9. Have a diagnosis of any other malignancy within 3 years prior to inclusion, except
for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ
of the cervix or colorectal.
10. Have history of allergic reactions to trastuzumab, vinorelbine, or tucatinib (or
compounds chemically or biologically similar), except for Grade 1 or 2 infusion
related reactions to trastuzumab or vinorelbine that were successfully managed.
11. Have difficulties to swallow tablets, malabsorption syndrome, disease significantly
affecting gastrointestinal function, resection of the stomach or small bowel, or
active inflammatory bowel disease (e.g., ulcerative diseases).
12. Have positive serology for Human Immunodeficiency Virus (HIV), or active infection
for hepatitis B, hepatitis C or have other known chronic liver disease.
13. Other severe acute or chronic medical (such as neuropathy grade 3-4) or psychiatric
condition or laboratory abnormality that may increase the risk associated with study
participation or study treatment administration or may interfere with the
interpretation of study results and, in the judgment of the investigator, would make
the patient inappropriate for entry into this study.
14. Are pregnant, breastfeeding, or planning a pregnancy. Women of child-bearing
potential or partners of women of child-bearing potential, unless agreement to
remain abstinent or use of single or combined non-hormonal contraceptive methods
that result in a failure rate of < 1% per year during the treatment period and for
at least 7 months after the last dose of study treatment.
1. Abstinence is only acceptable if it is in line with the preferred and usual
lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation,
symptothermal, or post-ovulation methods) and withdrawal are not acceptable
methods of contraception.
2. Examples of non-hormonal contraceptive methods with a failure rate of < 1% per
year include tubal ligation, male sterilization (only if he is the sole partner
and have been performed at least 6 months prior to screening), and certain
intrauterine devices.
3. Alternatively, two methods (e.g., two barrier methods such as a condom and a
cervical cap) may be combined to achieve a failure rate of < 1% per year.
Barrier methods must always be supplemented with the use of a spermicide.
4. Male participants must not donate sperm during study and up to the time period
specified above.
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Hospital Universitario de Jeréz De La Frontera
Address:
City:
Cádiz
Zip:
11407
Country:
Spain
Status:
Recruiting
Facility:
Name:
Hospital Universitario Reina Sofía
Address:
City:
Córdoba
Zip:
14004
Country:
Spain
Status:
Recruiting
Facility:
Name:
Hospital Universitario de Jaén
Address:
City:
Jaén
Zip:
23007
Country:
Spain
Status:
Recruiting
Facility:
Name:
Hospital Costa del Sol
Address:
City:
Málaga
Zip:
29603
Country:
Spain
Status:
Recruiting
Facility:
Name:
Hospital Universitario Virgen de Valme
Address:
City:
Sevilla
Zip:
41014
Country:
Spain
Status:
Recruiting
Facility:
Name:
Hospital Clínico Universitario Lozano Blesa
Address:
City:
Zaragoza
Zip:
50009
Country:
Spain
Status:
Recruiting
Facility:
Name:
Hospital Universitario Central de Asturias
Address:
City:
Oviedo
Zip:
33011
Country:
Spain
Status:
Recruiting
Facility:
Name:
Hospital Clínico Universitario de Valladolid
Address:
City:
Valladolid
Zip:
47003
Country:
Spain
Status:
Recruiting
Facility:
Name:
Hospital Nuestra Señora de Sonsoles
Address:
City:
Ávila
Zip:
05004
Country:
Spain
Status:
Recruiting
Facility:
Name:
ICO Badalona
Address:
City:
Barcelona
Zip:
08916
Country:
Spain
Status:
Recruiting
Facility:
Name:
Hospital San Juan de Alicante
Address:
City:
Alicante
Zip:
03550
Country:
Spain
Status:
Recruiting
Facility:
Name:
Hospital Universitario de Bádajoz
Address:
City:
Bádajoz
Zip:
06080
Country:
Spain
Status:
Recruiting
Facility:
Name:
Hospital Álvaro Cunqueiro
Address:
City:
Vigo
Zip:
36213
Country:
Spain
Status:
Recruiting
Facility:
Name:
Complejo hospitalario Universitario Insular-Materno Infantil
Address:
City:
Las Palmas de Gran Canaria
Zip:
35016
Country:
Spain
Status:
Recruiting
Facility:
Name:
Hospital Universitario Donostia
Address:
City:
Donostia-San Sebastián
Zip:
20014
Country:
Spain
Status:
Recruiting
Facility:
Name:
Hospital General Universitario Gregorio Marañón
Address:
City:
Madrid
Zip:
28009
Country:
Spain
Status:
Recruiting
Facility:
Name:
Hospital Universitario Quironsalud Madrid
Address:
City:
Madrid
Zip:
28223
Country:
Spain
Status:
Recruiting
Facility:
Name:
Hospital Universitario de Araba
Address:
City:
Vitoria-Gasteiz
Zip:
01009
Country:
Spain
Status:
Recruiting
Start date:
March 8, 2023
Completion date:
August 2026
Lead sponsor:
Agency:
Spanish Breast Cancer Research Group
Agency class:
Other
Collaborator:
Agency:
Seagen Inc.
Agency class:
Industry
Source:
Spanish Breast Cancer Research Group
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05583110
http://www.geicam.org/
