Study of Tucatinib Compared to Placebo in Combination with Pertuzumab and Trastuzumab in Patients with Advanced or Metastatic HER2+ Breast Cancer

Australia, Austria, Belgium, Brazil, Canada, Chile, China, Czech Republic, Czechia, Finland, France, Germany, Greece, Italy, Japan, Korea, Republic of, Netherlands, Poland, Portugal, Spain, Switzerland, Taiwan, United Kingdom, United States (ICTRP)

ICTRP Trial ID
EUCTR2021-002491-39 (ICTRP)

Official title (approved by ethics committee)
A randomized, double-blind, phase 3 study of tucatinib or placebo in combination with trastuzumab and pertuzumab as maintenance therapy for metastatic HER2+ breast cancer (HER2CLIMB-05) (BASEC)

Academic title
A randomized, double-blind, phase 3 study of tucatinib or placebo in combination with trastuzumab and pertuzumab as maintenance therapy for metastatic HER2+ breast cancer (HER2CLIMB-05) - HER2CLIMB-05 (ICTRP)

Public title
A study of tucatinib versus placebo in combination with pertuzumab and trastuzumab for subjects with advanced or metastatic HER2+ breast cancer (ICTRP)

Disease under investigation
Unresectable locally-advanced or metastatic HER2+ breast cancer
MedDRA version: 23.0Level: PTClassification code 10065430Term: HER2 positive breast cancerSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA version: 21.1Level: LLTClassification code 10072740Term: Locally advanced breast cancerSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA version: 20.0Level: LLTClassification code 10027475Term: Metastatic breast cancerSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps);Therapeutic area: Diseases [C] - Cancer [C04] (ICTRP)

Intervention under investigation

Trade Name: TUKYSA
Product Name: Tucatinib
Product Code: ONT-380
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Tucatinib
CAS Number: 1429755-56-5
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 50-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Trade Name: TUKYSA
Product Name: Tucatinib
Product Code: ONT-380
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Tucatinib
CAS Number: 1429755-56-5
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 150-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Trade Name: Phesgo?
Product Name: Phesgo
Pharmaceutical Form: Solution for injection
INN or Proposed INN: Trastuzumab
CAS Number: 180288-69-1
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 60-
INN or Proposed INN: Pertuzumab
CAS Number: 380610-27-5
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 60-

(ICTRP)

Type of trial
Interventional clinical trial of medicinal product (ICTRP)

Trial design
Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no Number of treatment arms in the trial: 2 (ICTRP)

Inclusion/Exclusion criteria
Gender:
Female: yes
Male: yes

Inclusion criteria:
1. Have centrally confirmed HER2+ breast carcinoma according to 2018 American Society of Clinical Oncologists (ASCO)-College of American Pathologists (CAP) guidelines prior to randomization (defined as a 3+
score on immunohistochemistry (IHC) and/or 2+ IHC and concurrent
positive by ISH).
2. Have unresectable locally advanced or metastatic (hereafter referred to as ?advanced?) disease; if recurrent (after [neo]adjuvant therapy), there must be a minimum 6-month treatment-free interval from any trastuzumab and pertuzumab received in the early breast cancer setting to the diagnosis of advanced HER2+ disease. Prior standard of care therapy for early breast cancer is permitted (eg, prior T-DM1); however, Exclusion Criterion 1 should be noted.
3. Have received 4-8 cycles of pre-study induction therapy including only
with trastuzumab, pertuzumab, and taxane as first-line therapy for the
treatment of advanced breast cancer prior to study enrollment. Subjects
are eligible provided they are without evidence of disease progression
(per investigator judgement) ie, CR, PR, or SD) following completion of
induction therapy.
a. Subjects receiving <6 cycles (ie, 4-5 cycles) of taxane are only eligible if the taxane was stopped early due to intolerable toxicity (eg, documented neuropathy impacting function).
b. Subjects are permitted to receive trastuzumab and pertuzumab for 1 additional cycle (after completion of chemotherapy) during screening to allow completion of screening procedures. Study treatment should begin within 6 weeks (? 3 days) from the start of the last cycle of trastuzumab and pertuzumab.
c. Subjects are permitted to receive up to 2 cycles of carboplatin during
the start of induction therapy in combination with trastuzumab,
pertuzumab , and taxane (eg, to obtain confirmation of metastatic breast
cancer diagnosis)
d. Subjects who received traditional medications (eg, traditional Chinese
medication) and/or supplements with potential anti-cancer effects
during induction therapy will remain eligible if they discontinue these
treatments at least 4 weeks prior to the start of study treatment.
4. Known hormone receptor status (per local guidelines; may be hormone receptor positive [HR+] or negative [HR-])
5. Be at least 18 years of age, and legally an adult at time of consent and = the age of majority per regional requirements
6. Have Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1
7. Have adequate hepatic function as defined in the protocol
8. Have adequate baseline hematologic parameters as defined in the protocol
9. Have a serum or plasma creatinine =1.5 X institutional ULN.
10. Have left ventricular ejection fraction (LVEF) =50% as assessed by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA) documented within 4 weeks prior to first dose of study treatment.
11. Subjects of childbearing potential must meet the conditions as per protocol
12. Male subjects must meet the conditions as per protocol
13. Provide signed informed consent per a consent document that has been approved by an institutional review board or independent ethics committee (IRB/IEC) prior to initiation of any study-related tests or procedures that are not part of standard-of-care for the subject?s disease
14. Be willing and able to comply with study procedures
15. CNS Inclusion ? Based on screening contrast -enhanced brain magnetic resonance imaging (MRI), subjects may have any of the following:
a. No evidence of brain metastases
(ICTRP)

Exclusion criteria:
1. Have previously been treated with any tyrosine kinase inhibitor targeting anti-HER2 and/or anti-epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor including pyrotinib, lapatinib, tucatinib, neratinib, and afatinib (except neratinib if given in extended adjuvant setting and at least 12 months have elapsed from the last neratinib dose to the start of study drug) or are currently participating in another interventional clinical trial
2. Unable for any reason to undergo contrast -enhanced MRI of the brain
3. History of allergic reactions to trastuzumab, pertuzumab, or compounds chemically or biologically similar to tucatinib, except for Grade 1 or 2 infusion-related reactions (IRRs) to trastuzumab that were successfully managed, known allergy to one of the excipients in the study drugs, or hypersensitivity to murine proteins
4. Are positive for active Hepatitis B by surface antigen expression, positive for Hepatitis C infection, or the presence of known chronic liver disease. Subjects who have been treated for Hepatitis C infection are permitted if they have documented sustained virologic response of at least 12 weeks, as documented per local guidelines. The latest local guidelines should be followed regarding the testing of Hepatitis B DNA levels by polymerase chain reaction (PCR). Subjects with Hepatitis B DNA levels by PCR that require nucleoside analogue or other therapies are not eligible for the trial.
5. Subjects known to be positive for human immunodeficiency virus (HIV) are excluded if they meet any of the following criteria:
a. CD4+ T-cell count of <350 cells/?L
b. Detectable HIV viral load
c. History of an opportunistic infection within the past 12 months
d. On stable antiretroviral therapy for <4 weeks
6. Are pregnant, breastfeeding, or planning a pregnancy from time of informed consent until 7 months after the final dose of study drug
7. Have inability to swallow pills or have significant GI disease or surgery which would preclude the adequate oral absorption of medications
8. Have used a strong CYP2C8 inhibitor within 5 half-lives of the inhibitor, or have used a strong CYP3A4 or CYP2C8 inducer within 5 days prior to first dose of study treatment
9. Have current conditions of symptomatic congestive heart failure, unstable angina pectoris, uncontrolled hypertension, or cardiac arrhythmia or history of myocardial infarction within 6 months prior to randomization
10. Have any other medical, social, or psychosocial factors that, in the opinion of the investigator, could impact safety or compliance with study procedures
11. Have evidence within 2 years of the start of study treatment of another malignancy that required systemic treatment
12. Have ongoing = Grade 2 toxicity from first-line induction therapy (ie, trastuzumab, pertuzumab, and taxane) with the exceptions of alopecia, neuropathy, and nail toxicity
13. Have ongoing = Grade 2 diarrhea
14. CNS Exclusion ? Based on screening brain MRI and clinical assessment, subjects must not have any of the following:
a. Symptomatic brain metastasis after CNS-directed local therapy
b. Progression of brain metastases since starting first-line trastuzumab, pertuzumab, and taxane
c. Ongoing use of systemic corticosteroids at a total daily dose of >2 mg of dexamethasone (or equivalent). For subjects requiring systemic steroids for control of comorbidities (eg, asthma or autoimmune diseases), daily dose must not exceed 2 mg dexamethasone (or equivalent).
d. Any untreated bra

Primary and secondary end points
Main Objective: Compare progression-free survival (PFS) by investigator per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 between treatment arms;Secondary Objective: - Compare overall survival (OS) between treatment arms
- Evaluate PFS by blinded independent central review (BICR) per RECIST v1.1
- Assess the change in health-related quality of life (HRQoL)
- Evaluate PFS in the brain
- Evaluate the safety and tolerability of tucatinib in combination with trastuzumab and pertuzumab
- Evaluate the pharmacokinetics (PK) of tucatinib;Primary end point(s): PFS per RECIST v1.1 according to investigator assessment, or death from any cause, whichever occurs first;Timepoint(s) of evaluation of this end point: Once approximately 331 PFS events per investigator assessment have been observed (ICTRP)

Secondary end point(s): - OS
- PFS per RECIST v1.1, as determined by BICR, or death from any cause, whichever occurs first
- Time to deterioration of HRQoL
- CNS-PFS per RECIST v1.1 according to investigator assessment, or death from any cause, whichever occurs first
- AEs, clinical laboratory assessments, incidence of dose holding and discontinuation of study treatment, incidence of dose reductions of tucatinib
- Plasma concentrations of tucatinib
;Timepoint(s) of evaluation of this end point: - OS: final analysis will occur when approximately 252 OS events are observed
- PFS by BICR: once approx. 331 PFS events have occurred
- HRQoL: to be assessed on Day 1 of each 21-day cycle, at the end of treatment visit, and first follow-up visit
- CNS-PFS: once approx. 331 PFS events have occurred
- Safety assessments will be collected throughout the study. The safety reporting period for all AEs and SAEs is from study Cycle 1 Day 1 (predose) through 30 days after the last study treatment.
- samples for PK assessment of tucatinib drug levels will be collected on Day 1 of Cycles 2 to 6 (prior to administration of tucatinib), at EOT and
on Day 1 of Cycle 3 (after administration of tucatinib)

(ICTRP)

Registration date
18.02.2022 (ICTRP)

Incorporation of the first participant
18.08.2022 (ICTRP)

Secondary sponsors
not available

Additional contacts
Seagen Clinical Trial Information, clinicaltrials@seagen.com, +18663337436, Seagen Inc. (ICTRP)

Secondary trial IDs
SGNTUC-028, NCT05132582, 2021-002491-39-FR (ICTRP)

Results-Individual Participant Data (IPD)
not available

Further information on the trial
https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2021-002491-39 (ICTRP)