HER2 Positive Breast Cancer
Conditions
Keywords
HER2+ breast cancer, Breast Cancer, Metastatic breast cancer, Seattle Genetics
Brief summary
This study is being done to see if tucatinib works better than placebo when given with other drugs to treat participants with HER2-positive breast cancer. A placebo is a pill that looks the same as tucatinib but has no medicine in it. This study will also test what side effects happen when participants take this combination of drugs. A side effect is anything a drug does to the body besides treating your disease. Participants will have cancer that has spread in the body near where it started (locally advanced) and cannot be removed (unresectable) or has spread through the body (metastatic). In this study, all participants will get either tucatinib or placebo. Participants will be assigned randomly to a group. This is a blinded study, so patients and their doctors will not know which group a participant is in. All participants will also get trastuzumab and pertuzumab. These are 2 drugs used to treat this type of cancer.
Detailed description
Control arm: Placebo given orally twice daily plus trastuzumab and pertuzumab every 21 days Experimental arm: Tucatinib 300 mg given orally twice daily plus trastuzumab and pertuzumab every 21 days Trastuzumab and pertuzumab will be administered as follows: • Trastuzumab will be given intravenously (IV) at a dose of 6 mg/kg or subcutaneously (SC) at a fixed dose of 600 mg, once every 21 days. AND * Pertuzumab will be given IV at 420 mg every 21 days. OR * Fixed dose combination of 600 mg pertuzumab, 600 mg trastuzumab, and 20,000 units hyaluronidase will be given SC, once every 21 days, in lieu of trastuzumab and pertuzumab individually.
Interventions
DRUGTucatinib
300mg given by mouth (orally) twice daily
DRUGTrastuzumab
6mg/kg given into the vein (IV; intravenously) or 600mg injected under the skin (SC; subcutaneous) every 21 days
DRUGPertuzumab
420mg given by IV every 21 days
600 mg pertuzumab, 600 mg trastuzumab, and 20,000 units hyaluronidase will be given by subcutaneous injection every 21 days. May be given in place of trastuzumab and pertuzumab individually.
DRUGPlacebo
Given orally twice daily
Sponsors
Seagen, a wholly owned subsidiary of Pfizer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Centrally confirmed HER2+ breast carcinoma according to the 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). * Have unresectable locally advanced or metastatic disease. * If recurrent (after \[neo\]adjuvant therapy), must be at least 6 month treatment free from any trastuzumab and pertuzumab received in the early breast cancer setting for advanced HER2+ disease. * Have received 4-8 cycles of pre-study induction therapy including only trastuzumab, pertuzumab, and taxane as first-line of therapy for the treatment of advanced breast cancer prior to study enrollment. Participants are eligible provided they are without evidence of disease progression following completion of induction therapy. * Known hormone receptor status (per local guidelines; may be hormone receptor positive \[HR+\] or negative \[HR-\]) * Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 * CNS Inclusion - Based on screening contrast-enhanced brain magnetic resonance imaging (MRI), participants may have any of the following: * No evidence of brain metastases * Untreated brain metastases which are asymptomatic not needing immediate local treatment and, if identified on prior brain imaging, without evidence of progression since starting first-line induction therapy with trastuzumab, pertuzumab, and taxane * Previously treated brain metastases which are asymptomatic * Brain metastases previously treated with local therapy must not have progressed since treatment
Exclusion criteria
* Prior treatment with any tyrosine kinase inhibitor targeting HER2 and/or epidermal growth factor receptor (EGFR) including pyrotinib, lapatinib, tucatinib, neratinib, and afatinib (except neratinib if given in extended adjuvant setting and ≥ 12 months have elapsed since last neratinib dose prior to start of study drug) * Unable to undergo contrast-enhanced MRI of the brain * CNS Exclusion - Based on screening brain MRI and clinical assessment * Symptomatic brain metastasis after CNS-directed local therapy * Progression of brain metastases since starting first line trastuzumab, pertuzumab, and taxane * Ongoing use of systemic corticosteroids at a total daily dose of \>2 mg of dexamethasone (or equivalent) * Any untreated brain lesion in an anatomic site which may pose risk to participant * Known or suspected leptomeningeal disease (LMD) * Poorly controlled (\>1/week) seizures, or other persistent neurologic symptoms
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) as Assessed by Investigator Per Response Evaluation Criteria in Solid Tumors (RECIST) Version (v) 1.1 | From randomization until the first documentation of PD or death from any cause or censoring date, whichever occurred first (maximum treatment exposure was of 41.3 months) | PFS: time from randomization to the first documented disease progression (PD) (as assessed by investigator per RECIST 1.1) or death from any cause, whichever occurred first. PD: \>=20% increase in sum of diameters of target lesions, taking as reference the smallest sum of diameter recorded since the treatment started or the appearance of 1 or more new lesions. Participants without documentation of PD/ death at the time of analysis, were censored at date of last tumor assessment with an overall response of complete response (CR), partial response (PR), stable disease (SD), non-CR/non-PD or no evidence of disease (NED). CR: disappearance of all target lesions; PR: \>=30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters; SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of diameter since the treatment started. Kaplan-Meier method was used for analysis. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | From the date of randomization until date of death or censoring date (approximately 66.7 months) | OS: time from randomization to death due to any cause. For a participant who would not known to have died by the end of study follow-up, observation of OS would be censored on the date the participant was last known to be alive (i.e., the date of last contact). |
| PFS as Assessed by Blinded Independent Central Review (BICR) Per RECIST v1.1 | From randomization until the first documentation of PD or death from any cause or censoring date, whichever occurred first (maximum treatment exposure was of 41.3 months) | PFS per BICR was defined as the time from the date of randomization to the documented disease progression assessed by BICR according to RECIST v1.1 or death from any cause, whichever occurred first. As per RECIST v1.1, PD: \>=20% increase in sum of diameter of target lesions, taking as reference the smallest sum of diameters recorded since treatment started or appearance of 1 or more new lesions, unequivocal progression of existing non-target lesions. Participants without documentation of PD/ death were censored at date of last tumor assessment with an overall response of CR, PR, SD, non-CR/non-PD or NED. CR: disappearance of all target lesions; PR: \>=30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters; SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of diameter since the treatment started. Kaplan-Meier method was used for analysis. |
| Time to Deterioration (TTD) of Health-Related Quality of Life (HRQoL) | Approximately 66.7 months | Time to deterioration of HRQoL was defined as time to 10-point decrease in the global health status/QoL scale of the European Organization for Research and Treatment of Cancer (EORTC) quality of life questionnaire (QLQ-C30). EORTC QLQ-C30 is 30 item questionnaires composed of 5 multi-item functional domains (physical, role, cognitive, emotional, and social), 3 symptom scales (fatigue, pain, nausea, and vomiting) and 6 single items for symptoms (shortness of breath, loss of appetite, sleep disturbance, constipation, diarrhea and financial impact of the disease), 2 global items (health, overall QoL). Higher functional/global QoL score = better functioning and higher symptom score = greater degree of symptoms. |
| Central Nervous System (CNS) PFS as Assessed by Investigator Per RECIST v1.1 | From randomization until the first documentation of PD or death from any cause or censoring date, whichever occurred first (maximum treatment exposure was of 41.3 months) | CNS-PFS was defined as the time from randomization to investigator assessed disease progression in brain according to RECIST v1.1, or death from any cause, whichever occurred first. As per RECIST v1.1, PD: \>= 20% increase in sum of diameter of target lesions, taking as reference the smallest sum of diameters recorded since the treatment started or appearance of 1 or more new lesions, unequivocal progression of existing non-target lesions. Participants without documentation of PD/ death at the time of analysis were censored at date of last tumor assessment with an overall response of CR, PR, SD, non-CR/non-PD or NED. CR: disappearance of all target lesions; PR: \>=30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters; SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of diameter since the treatment started. Kaplan-Meier method was used for analysis. |
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) | From first dose of study treatment (Day 1) up to 30 days after the last dose of study treatment (maximum up to 42.3 months) | An adverse event (AE) was any untoward medical occurrence in a clinical investigational participant administered a medicinal product and which did not necessarily had a causal relationship with this treatment. TEAEs were defined as events that were new or worsened on or after receiving the first dose of study treatment and up through 30 days after the last dose of study treatment. AEs included both Serious AE (SAEs) and all other AEs. An AE should be classified as a serious SAE if it meets one of the following criteria: fatal, life threatening, requires or prolongs hospitalization, disabling/ incapacitating, congenital anomaly or birth defect, medically significant. |
| Number of Participants With Treatment Emergent Laboratory Abnormalities | From first dose of study treatment (Day 1) up to 30 days after the last dose of study treatment (maximum up to 66.7 months) | TEAEs were defined as events that were new or worsened on or after receiving the first dose of study treatment and up through 30 days after the last dose of study treatment. Treatment emergent laboratory abnormalities include: hematology (hemoglobin decreased, hemoglobin increased, leukocytes decreased, neutrophils decreased, platelets decreased); chemistry (alanine aminotransferase increased, alkaline phosphatase increased, aspartate aminotransferase increased, creatinine increased, potassium decreased, potassium increased, sodium decreased, sodium increased, total bilirubin increased). |
| Number of Participants With TEAEs Leading to Dose Discontinuations | From first dose of study treatment (Day 1) up to 30 days after the last dose of study treatment (maximum up to 66.7 months) | TEAEs were defined as events that were new or worsened on or after receiving the first dose of study treatment and up through 30 days after the last dose of study treatment. In this outcome measure, number of participants with TEAEs leading to dose discontinuations with study treatment will be reported. |
| Number of Participants With TEAEs Leading to Dose Hold | From first dose of study treatment (Day 1) up to 30 days after the last dose of study treatment (maximum up to 66.7 months) | TEAEs were defined as events that were new or worsened on or after receiving the first dose of study treatment and up through 30 days after the last dose of study treatment. In this outcome measure, number of participants with TEAEs leading to dose hold with study treatment will be reported. Dose hold requirements are defined per protocol. |
| Number of Participants With TEAEs Leading to Dose Reductions | From first dose of study treatment (Day 1) up to 30 days after the last dose of study treatment (maximum up to 66.7 months) | TEAEs were defined as events that were new or worsened on or after receiving the first dose of study treatment and up through 30 days after the last dose of study treatment. In this outcome measure, number of participants with TEAEs leading to dose reductions with tucatinib, trastuzumab and pertuzumab are reported. Dose reduction requirements are defined per protocol. |
| Trough Concentration (Ctrough) of Tucatinib | Pre-dose on Day 1 of Cycles 2, 3, 4, 5 and 6 | Concentration at Trough was defined as predose/trough concentration observed directly from data. |
Countries
Australia, Austria, Belgium, Brazil, Canada, Chile, China, Czechia, Finland, France, Germany, Greece, Italy, Japan, Netherlands, Poland, Portugal, South Korea, Spain, Switzerland, Taiwan, United Kingdom, United States
Contacts
STUDY_DIRECTORPfizer CT.gov Call Center
Pfizer
Participant flow
Pre-assignment details
Results reported are based on the primary completion date (PCD) of the study; data for only those secondary outcome measures are reported for which analyses were complete at PCD. Remaining outcome measures would be reported upon completion of their analyses at study completion.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 53.2 Years STANDARD_DEVIATION 11.3 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants |
| Race/Ethnicity, Customized Asian | 119 Participants |
| Race/Ethnicity, Customized Black or African American | 19 Participants |
| Race/Ethnicity, Customized Hispanic, Latino/a, or of Spanish Origin | 126 Participants |
| Race/Ethnicity, Customized Multiple | 1 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 2 Participants |
| Race/Ethnicity, Customized Not Hispanic, Latino/a, or of Spanish Origin | 212 Participants |
| Race/Ethnicity, Customized Not reportable | 79 Participants |
| Race/Ethnicity, Customized Other | 8 Participants |
| Race/Ethnicity, Customized Unknown | 4 Participants |
| Race/Ethnicity, Customized White | 294 Participants |
| Sex: Female, Male Female | 328 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 18 / 326 | 33 / 328 |
| other Total, other adverse events | 323 / 326 | 313 / 324 |
| serious Total, serious adverse events | 55 / 326 | 26 / 324 |
Outcome results
None listed