Metastatic Colorectal Adenocarcinoma
Conditions
Keywords
HER2, ERBB2, Colorectal cancer, Seattle Genetics
Brief summary
This trial studies how well the drug tucatinib works when given with trastuzumab and when given by itself. The participants in this trial have HER2-positive (HER2+) metastatic colorectal cancer (mCRC). 'Metastatic' means that the cancer has spread to other parts of the body. In the first part of this study, participants enrolled into Cohort A and received both tucatinib and trastuzumab. In the second part of this study, participants are randomly assigned to either Cohort B or Cohort C. Participants in Cohort B will receive tucatinib and trastuzumab. Participants in Cohort C will receive tucatinib. Participants in Cohort C who do not respond to therapy may have an option to receive tucatinib plus trastuzumab.
Interventions
DRUGTrastuzumab
Given intravenously (into the vein; IV)
DRUGTucatinib
Given orally
Sponsors
National Cancer Institute (NCI)
Academic and Community Cancer Research United
Seagen Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically and/or cytologically documented adenocarcinoma of the colon or rectum that is metastatic and/or unresectable * Unless contraindicated, participants must have received and failed regimens containing the following agents: fluoropyrimidine (e.g., 5-fluorouracil or capecitabine), oxaliplatin, irinotecan, an anti-VEGF monoclonal antibody (bevacizumab, ramucirumab, or ziv-aflibercept), and an anti-PD-(L)1 therapy (nivolumab or pembrolizumab) if tumor has deficient mismatch repair proteins or is MSI-High. * Have progression of unresectable or metastatic CRC after the last systemic therapy, or be intolerant of last systemic therapy * Have RAS wild-type in primary or metastatic tumor tissue, based on expanded RAS testing * Willing and able to provide the most recently available tissue blocks obtained prior to treatment initiation. If archival tissue is not available, then a newly-obtained baseline biopsy of an accessible tumor * Have confirmed HER2-positive mCRC, as defined by having tumor tissue tested at a Clinical Laboratory Improvement Act (CLIA)-certified or International Organization for Standardization (ISO)-accredited laboratory, meeting at least one of the following criteria: * HER2+ overexpression (3+ immunohistochemistry \[IHC\]) by an FDA-approved or Conformité Européene (CE)-marked HER2 ICH test * HER2 2+ IHC is eligible if the tumor is amplified by an FDA-approved or CE-marked HER2 in situ hybridization assay (FISH or chromogenic in situ hybridization \[CISH\])) * HER2 (ERBB2) amplification by CLIA-certified or ISO-accredited next generation sequencing (NGS) sequencing assay * Have radiographically measurable disease assessable by RECIST 1.1, with at least one site of disease that is measurable and that has not been previously irradiated; or, if the participant has had previous radiation to the target lesion(s), there must be evidence of progression since the radiation * Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, 1, or 2 * Life expectancy greater than 3 months * Have adequate hematological, hepatic, renal, coagulation, and cardiac function
Exclusion criteria
* Previous treatment with anti-HER2 targeting therapy * Previous treatment with any systemic anticancer therapy, non-central nervous system radiation, or experimental agent within 3 weeks of first dose of study treatment * Toxicity related to prior cancer therapies that has not resolved to ≤ Grade 1, with the following exceptions: * Alopecia and neuropathy, which must have resolved to ≤ Grade 2 * Congestive heart failure (CHF), which must have been ≤ Grade 1 in severity at the time of occurrence, and must have resolved completely * Anemia, which must have resolved to ≤ Grade 2 * Decreased ANC, which must have resolved to ≤ Grade 2 * Have clinically significant cardiopulmonary disease * Have known myocardial infarction, unstable angina, cardiac or other vascular stenting, angioplasty, or cardiac surgery within 6 months prior to first dose of study treatment * Major surgical procedure, open biopsy, or significant traumatic injury ≤28 days prior to enrollment (≤56 days for hepatectomy, open thoracotomy, or major neurosurgery) or anticipation of need for major surgical procedure during the study * Serious, non-healing wound, ulcer, or bone fracture * Known to be positive for hepatitis B by surface antigen expression * Known to have active hepatitis C infection * Exception for participants with a documented sustained virologic response of 12 weeks * Known to be positive for human immunodeficiency virus (HIV) * Subjects who are pregnant, breastfeeding, or planning a pregnancy * Inability to swallow pills or any significant gastrointestinal disease which would preclude the adequate oral absorption of medications * Have used strong CYP2C8 inhibitor within 5 half-lives of the inhibitor, or have used a strong CYP2C8 or CYP3A4 inducer within 5 days prior to first dose of study treatment * History of another malignancy within 3 years before the first dose of study drug, or any evidence of residual disease from a previously diagnosed malignancy. * Exceptions are malignancies with a negligible risk of metastasis or death * Subjects with known active CNS metastasis * Irradiated or resected lesions are permitted, provided the lesions are fully treated and inactive, subject is asymptomatic, and no steroids have been administered for at least 30 days
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Confirmed Objective Response Rate (cORR) Per RECIST v1.1 Per Blinded Independent Central Review (BICR) in Pooled Cohorts A+B | Up to 46.6 months | cORR was defined as the percentage of participants with confirmed CR or PR according to RECIST v1.1. CR was defined as the disappearance of all target lesions and each target lymph node must have reduction in short axis to less than (\<)1.0 centimeter (cm). PR was defined as at least a 30 percentage (%) decrease in post-baseline sum of the diameters (sum of the longest diameter for all target lesions plus the sum of the short axis of all the target lymph nodes at current evaluation) taking as reference the baseline sum of diameters. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| ORR by 12 Weeks of Treatment Per RECIST v1.1 According to BICR Assessment | Up to 3 months | ORR per BICR by 12 Weeks was defined as the percentage of participants with CR or PR by 12 weeks of treatment, and before time of crossover (Cohort C), whichever came earlier. CR was defined as the disappearance of all target lesions and each target lymph node must have reduction in short axis to more than \<1.0 cm. PR was defined as at least a 30% decrease in post-baseline sum of the diameters (sum of the longest diameter for all target lesions plus the sum of the short axis of all the target lymph nodes at current evaluation) taking as reference the baseline sum of diameter. |
| Duration of Response (DOR) Per RECIST v1.1 According to BICR Assessment | Up to 64.1 months | DOR was defined as the time from the first objective response (CR or PR that is subsequently confirmed) to documented PD per RECIST v1.1 or death from any cause, whichever occurred first. CR was defined as the disappearance of all target lesions and each target lymph node must have reduction in short axis to more than \<1.0 cm. PR was defined as at least a 30% decrease in post-baseline sum of the diameters (PBSD) (sum of the longest diameter for all target lesions plus the sum of the short axis of all the target lymph nodes at current evaluation) taking as reference the BSD. PD was defined as: at least one new malignant lesion, which also includes any lymph node that was normal at baseline (\<1.0 cm short axis) and increased to more than or equal to (\>=)1.0 cm short axis during follow-up or at least a 20% increase in PBSD taking as reference the minimum sum of the diameters (MSD). In addition, the PBSD must also demonstrate an absolute increase of at least 0.5 cm from the MSD. |
| Progression-Free Survival (PFS) Per RECIST v1.1 According to BICR Assessment for Pooled Cohorts A+B | Up to 64.1 months | PFS was defined as the time from start of study treatment (Cohort A) or date of randomization (Cohort B) to documented disease progression (as determined by BICR per RECIST v1.1) or death from any cause, whichever occurred first. PD was defined as: at least one new malignant lesion, which also included any lymph node that was normal at baseline (\<1.0 cm short axis) and increased to \>=1.0 cm short axis during follow-up or at least a 20% increase in post-baseline sum of the diameters (PBSD) taking as reference the minimum sum of the diameters (MSD). In addition, the PBSD must also demonstrate an absolute increase of at least 0.5 cm from the MSD. |
| Overall Survival (OS) in Pooled Cohorts A+B | Up to 71.8 months | OS was defined as the time from start of study treatment (Cohort A) or randomization (Cohort B) to date of death due to any cause. |
| Number of Participants With Adverse Events (AEs): Interim Analysis | Up to 49.3 months | AE: Any untoward medical occurrence in a participant or clinical investigational participant administered a medicinal product and which does not necessarily have a causal relationship with this treatment. Treatment emergent AEs (TEAEs): Events that were new or worsened on or after receiving the first dose of study treatment (tucatinib or trastuzumab) and up through 30 days after the last dose of study treatment (tucatinib or trastuzumab). Serious AE (SAE): An event that at any dose led to death; life-threatening; required inpatient hospitalization/prolongation of existing hospitalization; persistent/significant disability/incapacity; congenital anomaly/birth defect/ important medical event. Treatment related AEs, SAEs, deaths also included. Relatedness was judged by investigator According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03: Grade(G) 3=severe AE, G4=life-threatening, urgent intervention indicated, G5=death related to AE. |
| Number of Participants With AEs: Final Analysis | Up to 65.1 months | AE: Any untoward medical occurrence in a participant or clinical investigational participant administered a medicinal product and which does not necessarily have a causal relationship with this treatment. Treatment emergent AEs (TEAEs): Events that were new or worsened on or after receiving the first dose of study treatment (tucatinib or trastuzumab) and up through 30 days after the last dose of study treatment (tucatinib or trastuzumab). SAE: An event that at any dose led to death; life-threatening; required inpatient hospitalization/prolongation of existing hospitalization; persistent/significant disability/incapacity; congenital anomaly/birth defect/ important medical event. Treatment related AEs, SAEs, deaths also included. Relatedness was judged by investigator According to NCI CTCAE version 4.03: Grade(G) 3=severe AE, G4=life-threatening, urgent intervention indicated, G5=death related to AE. |
| Number of Participants With AEs Resulting in Dose Modification: Interim Analysis | Up to 49.3 months | Dose modification included dose reduction and dose withheld by investigator due to AEs. Dose holds were defined as any instances where planned administration of the study drug was temporarily withheld or interrupted at the direction of the treating physician. Dose reductions of trastuzumab were not allowed; if trastuzumab could not be restarted after being held for a TEAE, it was discontinued. |
| Number of Participants With AEs Resulting in Dose Modification: Final Analysis | Up to 65.1 months | Dose modification included dose reduction and dose withheld by investigator due to AEs. Dose holds were defined as any instances where planned administration of the study drug was temporarily withheld or interrupted at the direction of the treating physician. Dose reductions of trastuzumab were not allowed; if trastuzumab could not be restarted after being held for a TEAE, it was discontinued. Drug interruption included infusion interrupted (full dose received within 24hrs). |
| Number of Participants With Treatment-Emergent Laboratory Abnormalities (Hematology): Interim Analysis | Up to 49.3 months | The following hematology laboratory parameters were assessed: Hemoglobin decreased; leukocytes decreased; neutrophils decreased and Platelets decreased. Treatment emergent laboratory abnormalities were defined as abnormalities 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. NCI CTCAE v4.03 was used for the lab parameters. Grade 1: mild; Grade 2: moderate; Grade 3: severe or clinically significant; Grade 4: life-threatening. |
| Number of Participants With Treatment-Emergent Laboratory Abnormalities (Hematology): Final Analysis | Up to 65.1 months | The following hematology laboratory parameters were assessed: Hemoglobin decreased; hemoglobin increased; leukocytes decreased; lymphocytes decreased; neutrophils decreased and Platelets decreased. Treatment emergent laboratory abnormalities were defined as abnormalities 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. NCI CTCAE v4.03 was used for the lab parameters. Grade 1: mild; Grade 2: moderate; Grade 3: severe or clinically significant; Grade 4: life-threatening. |
| Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Interim Analysis | Up to 49.3 months | The following chemistry laboratory parameters were assessed: Potassium increased; potassium decreased; aspartate aminotransferase increased; creatinine increased; alkaline phosphatase increased; total bilirubin increased. Treatment emergent laboratory abnormalities were defined as abnormalities 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. NCI CTCAE v5.0 was used for creatinine increased. NCI CTCAE v4.03 was used for the other laboratory parameters. Grade 1: mild; Grade 2: moderate; Grade 3: severe or clinically significant; Grade 4: life-threatening. |
| Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Up to 65.1 months | The following chemistry laboratory parameters were assessed: Potassium increased; potassium decreased; aspartate aminotransferase increased; creatinine increased; alkaline phosphatase increased; total bilirubin increased; albumin decreased; calcium corrected for albumin decreased; calcium corrected for albumin increased; glomerular filtration rate (GFR), estimated decreased; glucose decreased; glucose increased; sodium decreased; sodium increased; calcium and ionized increased. Treatment emergent laboratory abnormalities: Abnormalities 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. NCI CTCAE v5.0 used for creatinine increased. NCI CTCAE v4.03 used for the other laboratory parameters. Grade 1: mild; Grade 2: moderate; Grade 3: severe or clinically significant; Grade 4: life-threatening. |
| Number of Participants With Clinically Significant Vital Signs: Final Analysis | Up to 65.1 months | Vital signs included temperature, oxygen saturation, systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate and weight. Vital signs were considered clinically significant: temperature: \>= 38 degree Celsius (C); oxygen saturation less than (\<)88%; SBP \>=120 millimeters of mercury (mmHg) or DBP \>=80 mmHg; SBP \>=140 mmHg or DBP \>=90 mmHg; SBP \>=160 mmHg or DBP \>=100 mmHg and heart rate \>100 beats per minute (bpm) and maximum decrease from baseline in weight in kilograms (kg). |
Countries
Belgium, France, Italy, Spain, United States
Participant flow
Recruitment details
A total of 117 participants were enrolled at a total of 56 sites in the United States, Italy, France, Belgium, and Spain. The date of first participant enrollment was 23-Jun-2017. The date of last participant randomization was 02-Nov-2023.
Participants by arm
| Arm | Count |
|---|---|
| Tucatinib+Trastuzumab (Cohort A) Non-randomized cohort. Participants received Tucatinib 300 mg PO BID on Days 1 to 21 of each 21-day cycle. Trastuzumab 8 mg/kg by IV infusion on Day 1 of Cycle 1 and 6 mg/kg on Day 1 of each subsequent cycle until PD, death, withdrawal of consent, study closure, or alternative therapy. | 45 |
| Tucatinib+Trastuzumab (Cohort B) Randomized cohort. Participants received Tucatinib 300 mg PO BID on Days 1 to 21 of each 21-day cycle. Trastuzumab 8 mg/kg by IV infusion on Day 1 of Cycle 1 and 6 mg/kg on Day 1 of each subsequent cycle until PD, death, withdrawal of consent, study closure, or alternative therapy. | 39 |
| Tucatinib Monotherapy (Cohort C) Participants received Tucatinib 300 mg PO BID on Days 1 to 21 of each 21-day cycle. Participants who did not respond to monotherapy were given the option to receive tucatinib and trastuzumab until PD, death, withdrawal of consent, study closure, or alternative therapy based on radiographic progression (as determined by investigator assessment using RECIST v1.1), or if they had not achieved a PR or CR by the week 12 assessment. | 30 |
| Total | 114 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Death | 28 | 26 | 17 |
| Overall Study | Lost to Follow-up | 1 | 1 | 0 |
| Overall Study | Participation terminated by sponsor | 11 | 13 | 13 |
| Overall Study | Withdrawal by Subject | 5 | 1 | 1 |
Baseline characteristics
| Characteristic | Tucatinib+Trastuzumab (Cohort A) | Tucatinib+Trastuzumab (Cohort B) | Tucatinib Monotherapy (Cohort C) | Total |
|---|---|---|---|---|
| Age, Continuous | 52 Years | 57 Years | 59.5 Years | 56 Years |
| Eastern Cooperative Oncology Group (ECOG) Performance Status Grade 0 | 24 Participants | 26 Participants | 17 Participants | 67 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status Grade 1 | 20 Participants | 11 Participants | 13 Participants | 44 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status Grade 2 | 1 Participants | 2 Participants | 0 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 1 Participants | 1 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 35 Participants | 29 Participants | 25 Participants | 89 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 8 Participants | 9 Participants | 4 Participants | 21 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 1 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 2 Participants | 3 Participants | 6 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants | 8 Participants | 4 Participants | 15 Participants |
| Race (NIH/OMB) White | 37 Participants | 28 Participants | 23 Participants | 88 Participants |
| Region of Enrollment Europe | 0 Participants | 15 Participants | 14 Participants | 29 Participants |
| Region of Enrollment North America | 45 Participants | 24 Participants | 16 Participants | 85 Participants |
| Sex: Female, Male Female | 19 Participants | 14 Participants | 15 Participants | 48 Participants |
| Sex: Female, Male Male | 26 Participants | 25 Participants | 15 Participants | 66 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 54 / 86 | 2 / 31 | 15 / 28 |
| other Total, other adverse events | 82 / 86 | 28 / 30 | 23 / 28 |
| serious Total, serious adverse events | 20 / 86 | 3 / 30 | 6 / 28 |
Outcome results
Primary
Confirmed Objective Response Rate (cORR) Per RECIST v1.1 Per Blinded Independent Central Review (BICR) in Pooled Cohorts A+B
cORR was defined as the percentage of participants with confirmed CR or PR according to RECIST v1.1. CR was defined as the disappearance of all target lesions and each target lymph node must have reduction in short axis to less than (\<)1.0 centimeter (cm). PR was defined as at least a 30 percentage (%) decrease in post-baseline sum of the diameters (sum of the longest diameter for all target lesions plus the sum of the short axis of all the target lymph nodes at current evaluation) taking as reference the baseline sum of diameters.
Time frame: Up to 46.6 months
Population: The Full Analysis Set included all participants who were enrolled and received any amount of study treatment and had HER2+ tumors as defined by one or more protocol required local tests. Data for cohort A and B was combined as prespecified in the statistical analysis plan (SAP).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tucatinib+Trastuzumab (Cohorts A+B) | Confirmed Objective Response Rate (cORR) Per RECIST v1.1 Per Blinded Independent Central Review (BICR) in Pooled Cohorts A+B | 39.3 Percentage of Participants |
Secondary
Duration of Response (DOR) Per RECIST v1.1 According to BICR Assessment
DOR was defined as the time from the first objective response (CR or PR that is subsequently confirmed) to documented PD per RECIST v1.1 or death from any cause, whichever occurred first. CR was defined as the disappearance of all target lesions and each target lymph node must have reduction in short axis to more than \<1.0 cm. PR was defined as at least a 30% decrease in post-baseline sum of the diameters (PBSD) (sum of the longest diameter for all target lesions plus the sum of the short axis of all the target lymph nodes at current evaluation) taking as reference the BSD. PD was defined as: at least one new malignant lesion, which also includes any lymph node that was normal at baseline (\<1.0 cm short axis) and increased to more than or equal to (\>=)1.0 cm short axis during follow-up or at least a 20% increase in PBSD taking as reference the minimum sum of the diameters (MSD). In addition, the PBSD must also demonstrate an absolute increase of at least 0.5 cm from the MSD.
Time frame: Up to 64.1 months
Population: The Full Analysis Set included all participants who were enrolled and received any amount of study treatment and had HER2+ tumors as defined by one or more protocol required local tests. Data for cohort A and B was combined as prespecified in SAP. Here, Number of Participants Analyzed signifies participants who had CR or PR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tucatinib+Trastuzumab (Cohorts A+B) | Duration of Response (DOR) Per RECIST v1.1 According to BICR Assessment | 15.2 Months |
| Tucatinib Pre-Crossover (Cohort C) | Duration of Response (DOR) Per RECIST v1.1 According to BICR Assessment | NA Months |
Secondary
Number of Participants With Adverse Events (AEs): Interim Analysis
AE: Any untoward medical occurrence in a participant or clinical investigational participant administered a medicinal product and which does not necessarily have a causal relationship with this treatment. Treatment emergent AEs (TEAEs): Events that were new or worsened on or after receiving the first dose of study treatment (tucatinib or trastuzumab) and up through 30 days after the last dose of study treatment (tucatinib or trastuzumab). Serious AE (SAE): An event that at any dose led to death; life-threatening; required inpatient hospitalization/prolongation of existing hospitalization; persistent/significant disability/incapacity; congenital anomaly/birth defect/ important medical event. Treatment related AEs, SAEs, deaths also included. Relatedness was judged by investigator According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03: Grade(G) 3=severe AE, G4=life-threatening, urgent intervention indicated, G5=death related to AE.
Time frame: Up to 49.3 months
Population: The safety analysis set included participants who received any amount of study treatment. Data for cohort A and B was combined as prespecified in SAP.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Adverse Events (AEs): Interim Analysis | Tucatinib-related TESAE | 3 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Adverse Events (AEs): Interim Analysis | Trastuzumab-related TESAE | 2 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Adverse Events (AEs): Interim Analysis | Trastuzumab-related grade 3-5 TEAE | 6 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Adverse Events (AEs): Interim Analysis | TEAE leading to death | 0 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Adverse Events (AEs): Interim Analysis | Trastuzumab-related TEAE | 58 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Adverse Events (AEs): Interim Analysis | Discontinuation of any study treatment due to TEAE | 5 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Adverse Events (AEs): Interim Analysis | Tucatinib-related grade 3-5 TEAE | 8 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Adverse Events (AEs): Interim Analysis | Discontinuation of tucatinib due to TEAE | 5 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Adverse Events (AEs): Interim Analysis | Tucatinib-related TEAE | 63 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Adverse Events (AEs): Interim Analysis | Discontinuation of tucatinib due to tucatinib-related TEAE | 2 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Adverse Events (AEs): Interim Analysis | Any Treatment-Emergent Serious AE (TESAE) | 19 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Adverse Events (AEs): Interim Analysis | Discontinuation of trastuzumab due to TEAE | 3 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Adverse Events (AEs): Interim Analysis | Any grade 3-5 TEAE | 33 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Adverse Events (AEs): Interim Analysis | Discontinuation of trastuzumab due to trastuzumab-related TEAE | 0 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Adverse Events (AEs): Interim Analysis | Any TEAE | 82 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Adverse Events (AEs): Interim Analysis | Discontinuation of trastuzumab due to trastuzumab-related TEAE | NA Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Adverse Events (AEs): Interim Analysis | Any TEAE | 28 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Adverse Events (AEs): Interim Analysis | Tucatinib-related TEAE | 22 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Adverse Events (AEs): Interim Analysis | Trastuzumab-related TEAE | NA Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Adverse Events (AEs): Interim Analysis | Any grade 3-5 TEAE | 8 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Adverse Events (AEs): Interim Analysis | Trastuzumab-related grade 3-5 TEAE | NA Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Adverse Events (AEs): Interim Analysis | Tucatinib-related grade 3-5 TEAE | 2 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Adverse Events (AEs): Interim Analysis | Any Treatment-Emergent Serious AE (TESAE) | 3 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Adverse Events (AEs): Interim Analysis | Tucatinib-related TESAE | 1 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Adverse Events (AEs): Interim Analysis | Trastuzumab-related TESAE | NA Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Adverse Events (AEs): Interim Analysis | TEAE leading to death | 0 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Adverse Events (AEs): Interim Analysis | Discontinuation of any study treatment due to TEAE | 0 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Adverse Events (AEs): Interim Analysis | Discontinuation of tucatinib due to TEAE | 0 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Adverse Events (AEs): Interim Analysis | Discontinuation of tucatinib due to tucatinib-related TEAE | 0 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Adverse Events (AEs): Interim Analysis | Discontinuation of trastuzumab due to TEAE | NA Participants |
Secondary
Number of Participants With AEs: Final Analysis
AE: Any untoward medical occurrence in a participant or clinical investigational participant administered a medicinal product and which does not necessarily have a causal relationship with this treatment. Treatment emergent AEs (TEAEs): Events that were new or worsened on or after receiving the first dose of study treatment (tucatinib or trastuzumab) and up through 30 days after the last dose of study treatment (tucatinib or trastuzumab). SAE: An event that at any dose led to death; life-threatening; required inpatient hospitalization/prolongation of existing hospitalization; persistent/significant disability/incapacity; congenital anomaly/birth defect/ important medical event. Treatment related AEs, SAEs, deaths also included. Relatedness was judged by investigator According to NCI CTCAE version 4.03: Grade(G) 3=severe AE, G4=life-threatening, urgent intervention indicated, G5=death related to AE.
Time frame: Up to 65.1 months
Population: The safety analysis set included participants who received any amount of study treatment. Data for cohort A and B was combined as prespecified in SAP.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With AEs: Final Analysis | Discontinuation of trastuzumab due to treatment-related TEAE | 1 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With AEs: Final Analysis | Discontinuation of trastuzumab due to trastuzumab-related TEAE | 0 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With AEs: Final Analysis | Any TEAE | 82 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With AEs: Final Analysis | Tucatinib-related TEAE | 64 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With AEs: Final Analysis | Trastuzumab-related TEAE | 59 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With AEs: Final Analysis | More than or equal to (>=) Grade 3 TEAE | 35 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With AEs: Final Analysis | Tucatinib-related >= grade 3 TEAE | 8 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With AEs: Final Analysis | Trastuzumab-related >= grade 3 TEAE | 6 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With AEs: Final Analysis | Any Treatment-Emergent Serious AE (TESAE) | 20 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With AEs: Final Analysis | Tucatinib-related TESAE | 3 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With AEs: Final Analysis | Trastuzumab-related TESAE | 2 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With AEs: Final Analysis | TEAE leading to death | 0 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With AEs: Final Analysis | Discontinuation of any study treatment due to TEAE | 5 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With AEs: Final Analysis | Discontinuation of tucatinib due to treatment-related TEAE | 2 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With AEs: Final Analysis | Discontinuation of tucatinib due to tucatinib-related TEAE | 2 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With AEs: Final Analysis | Trastuzumab-related TESAE | 2 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With AEs: Final Analysis | Discontinuation of trastuzumab due to treatment-related TEAE | 1 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With AEs: Final Analysis | Trastuzumab-related >= grade 3 TEAE | 2 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With AEs: Final Analysis | Discontinuation of trastuzumab due to trastuzumab-related TEAE | 0 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With AEs: Final Analysis | Discontinuation of tucatinib due to treatment-related TEAE | 2 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With AEs: Final Analysis | Discontinuation of any study treatment due to TEAE | 2 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With AEs: Final Analysis | Any TEAE | 23 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With AEs: Final Analysis | Any Treatment-Emergent Serious AE (TESAE) | 6 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With AEs: Final Analysis | Tucatinib-related TEAE | 15 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With AEs: Final Analysis | TEAE leading to death | 0 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With AEs: Final Analysis | Trastuzumab-related TEAE | 13 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With AEs: Final Analysis | Tucatinib-related TESAE | 0 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With AEs: Final Analysis | More than or equal to (>=) Grade 3 TEAE | 9 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With AEs: Final Analysis | Discontinuation of tucatinib due to tucatinib-related TEAE | 2 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With AEs: Final Analysis | Tucatinib-related >= grade 3 TEAE | 2 Participants |
Secondary
Number of Participants With AEs Resulting in Dose Modification: Final Analysis
Dose modification included dose reduction and dose withheld by investigator due to AEs. Dose holds were defined as any instances where planned administration of the study drug was temporarily withheld or interrupted at the direction of the treating physician. Dose reductions of trastuzumab were not allowed; if trastuzumab could not be restarted after being held for a TEAE, it was discontinued. Drug interruption included infusion interrupted (full dose received within 24hrs).
Time frame: Up to 65.1 months
Population: The safety analysis set included participants who received any amount of study treatment. Data for cohorts A and B was combined as prespecified in SAP.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With AEs Resulting in Dose Modification: Final Analysis | Trastuzumab infusion interrupted | 6 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With AEs Resulting in Dose Modification: Final Analysis | Tucatinib dose reduced | 9 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With AEs Resulting in Dose Modification: Final Analysis | Trastuzumab dose held | 27 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With AEs Resulting in Dose Modification: Final Analysis | Tucatinib dose held | 23 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With AEs Resulting in Dose Modification: Final Analysis | Trastuzumab dose held | 2 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With AEs Resulting in Dose Modification: Final Analysis | Tucatinib dose held | 7 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With AEs Resulting in Dose Modification: Final Analysis | Trastuzumab infusion interrupted | 0 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With AEs Resulting in Dose Modification: Final Analysis | Tucatinib dose reduced | 2 Participants |
Secondary
Number of Participants With AEs Resulting in Dose Modification: Interim Analysis
Dose modification included dose reduction and dose withheld by investigator due to AEs. Dose holds were defined as any instances where planned administration of the study drug was temporarily withheld or interrupted at the direction of the treating physician. Dose reductions of trastuzumab were not allowed; if trastuzumab could not be restarted after being held for a TEAE, it was discontinued.
Time frame: Up to 49.3 months
Population: The safety analysis set included participants who received any amount of study treatment. Data for cohort A and B was combined as prespecified in SAP.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With AEs Resulting in Dose Modification: Interim Analysis | Trastuzumab infusion stopped early (full dose not received) | 1 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With AEs Resulting in Dose Modification: Interim Analysis | Tucatinib dose reduced | 8 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With AEs Resulting in Dose Modification: Interim Analysis | Trastuzumab infusion interrupted (received full dose within 24 hrs) | 6 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With AEs Resulting in Dose Modification: Interim Analysis | Trastuzumab dose held | 24 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With AEs Resulting in Dose Modification: Interim Analysis | Tucatinib dose held | 20 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With AEs Resulting in Dose Modification: Interim Analysis | Trastuzumab dose held | NA Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With AEs Resulting in Dose Modification: Interim Analysis | Trastuzumab infusion interrupted (received full dose within 24 hrs) | NA Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With AEs Resulting in Dose Modification: Interim Analysis | Trastuzumab infusion stopped early (full dose not received) | NA Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With AEs Resulting in Dose Modification: Interim Analysis | Tucatinib dose held | 3 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With AEs Resulting in Dose Modification: Interim Analysis | Tucatinib dose reduced | 1 Participants |
Secondary
Number of Participants With Clinically Significant Vital Signs: Final Analysis
Vital signs included temperature, oxygen saturation, systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate and weight. Vital signs were considered clinically significant: temperature: \>= 38 degree Celsius (C); oxygen saturation less than (\<)88%; SBP \>=120 millimeters of mercury (mmHg) or DBP \>=80 mmHg; SBP \>=140 mmHg or DBP \>=90 mmHg; SBP \>=160 mmHg or DBP \>=100 mmHg and heart rate \>100 beats per minute (bpm) and maximum decrease from baseline in weight in kilograms (kg).
Time frame: Up to 65.1 months
Population: The safety analysis set included participants who received any amount of study treatment. Data for cohorts A and B was combined as prespecified in SAP.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Clinically Significant Vital Signs: Final Analysis | Heart rate > 100 bpm | 26 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Clinically Significant Vital Signs: Final Analysis | SBP >= 140 mmHg or DBP >= 90 mmHg | 49 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Clinically Significant Vital Signs: Final Analysis | SBP >= 160 mmHg or DBP >= 100 mmHg | 21 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Clinically Significant Vital Signs: Final Analysis | Maximum decrease from baseline in weight (kg) | 65 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Clinically Significant Vital Signs: Final Analysis | Temperature >=38 degree C | 1 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Clinically Significant Vital Signs: Final Analysis | Oxygen saturation <88% | 8 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Clinically Significant Vital Signs: Final Analysis | SBP >= 120 mmHg or DBP >= 80 mmHg | 80 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Clinically Significant Vital Signs: Final Analysis | Temperature >=38 degree C | 0 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Clinically Significant Vital Signs: Final Analysis | SBP >= 120 mmHg or DBP >= 80 mmHg | 27 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Clinically Significant Vital Signs: Final Analysis | Maximum decrease from baseline in weight (kg) | 23 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Clinically Significant Vital Signs: Final Analysis | SBP >= 140 mmHg or DBP >= 90 mmHg | 13 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Clinically Significant Vital Signs: Final Analysis | Oxygen saturation <88% | 0 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Clinically Significant Vital Signs: Final Analysis | SBP >= 160 mmHg or DBP >= 100 mmHg | 4 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Clinically Significant Vital Signs: Final Analysis | Heart rate > 100 bpm | 5 Participants |
Secondary
Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis
The following chemistry laboratory parameters were assessed: Potassium increased; potassium decreased; aspartate aminotransferase increased; creatinine increased; alkaline phosphatase increased; total bilirubin increased; albumin decreased; calcium corrected for albumin decreased; calcium corrected for albumin increased; glomerular filtration rate (GFR), estimated decreased; glucose decreased; glucose increased; sodium decreased; sodium increased; calcium and ionized increased. Treatment emergent laboratory abnormalities: Abnormalities 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. NCI CTCAE v5.0 used for creatinine increased. NCI CTCAE v4.03 used for the other laboratory parameters. Grade 1: mild; Grade 2: moderate; Grade 3: severe or clinically significant; Grade 4: life-threatening.
Time frame: Up to 65.1 months
Population: The safety analysis set included all participants who received any amount of study treatment. Data for cohorts A and B was combined as prespecified in SAP. Here, Number of Participants Analyzed signifies participants evaluable for this outcome measure and Number Analyzed signifies number evaluable for specified rows.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Calcium, Ionized increased: Grade 3 | 0 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Aspartate Aminotransferase increased, Grade 4 | 3 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Calcium, Ionized increased: Grade 4 | 0 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Glucose decreased, Grade 3 | 0 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Total Bilirubin increased, Grade 3 | 3 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Potassium decreased, Grade 4 | 0 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Glucose decreased, Grade 4 | 0 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Aspartate Aminotransferase increased, All grades | 29 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Potassium increased, All grades | 6 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Creatinine increased, Grade 4 | 0 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Potassium increased, Grade 3 | 0 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Glucose increased, All grades | 48 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Potassium increased, Grade 4 | 0 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Potassium decreased, All grades | 15 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Potassium decreased, Grade 3 | 1 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Albumin decreased, All grades | 23 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Glucose increased, Grade 3 | 2 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Aspartate Aminotransferase increased, Grade 3 | 2 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Calcium Corrected for Albumin decreased, All grades | 11 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Alanine Aminotransferase increased, Grade 3 | 2 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Creatinine increased, All grades | 50 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Glucose increased, Grade 4 | 0 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Creatinine increased, Grade 3 | 0 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Calcium Corrected for Albumin decreased, Grade 3 | 0 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Alkaline Phosphatase increased, All grades | 21 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Sodium decreased, All grades | 18 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Alkaline Phosphatase increased, Grade 3 | 1 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Alanine Aminotransferase increased, All grades | 39 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Sodium decreased, Grade 3 | 5 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Total Bilirubin increased, Grade 4 | 2 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Alanine Aminotransferase increased, Grade 4 | 2 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Albumin decreased, Grade 3 | 1 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Sodium decreased, Grade 4 | 0 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Albumin decreased, Grade 4 | 0 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Sodium increased, All grades | 7 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Alkaline Phosphatase increased, Grade 4 | 0 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Calcium Corrected for Albumin decreased, Grade 4 | 0 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Sodium increased, Grade 3 | 0 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Calcium Corrected for Albumin increased, All grades | 8 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Total Bilirubin increased, All grades | 25 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Calcium Corrected for Albumin increased, Grade 3 | 0 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Calcium Corrected for Albumin increased, Grade 4 | 0 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Glomerular Filtration Rate, Estimated decreased, All grades | 51 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Sodium increased, Grade 4 | 0 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Glomerular Filtration Rate, Estimated decreased, Grade 3 | 6 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Glomerular Filtration Rate, Estimated decreased, Grade 4 | 0 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Calcium, Ionized increased: All grades | 2 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Glucose decreased, All grades | 10 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Calcium, Ionized increased: Grade 4 | 0 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Alanine Aminotransferase increased, All grades | 7 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Alanine Aminotransferase increased, Grade 3 | 2 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Alanine Aminotransferase increased, Grade 4 | 0 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Creatinine increased, Grade 4 | 0 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Alkaline Phosphatase increased, Grade 3 | 0 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Total Bilirubin increased, All grades | 4 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Total Bilirubin increased, Grade 4 | 0 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Calcium Corrected for Albumin decreased, Grade 3 | 0 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Calcium Corrected for Albumin increased, Grade 3 | 0 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Calcium Corrected for Albumin increased, Grade 4 | 0 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Glomerular Filtration Rate, Estimated decreased, Grade 3 | 0 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Glucose decreased, All grades | 1 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Glucose decreased, Grade 3 | 0 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Glucose decreased, Grade 4 | 0 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Glucose increased, All grades | 9 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Glucose increased, Grade 3 | 0 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Glucose increased, Grade 4 | 0 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Sodium decreased, All grades | 1 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Sodium decreased, Grade 3 | 0 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Sodium increased, All grades | 4 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Sodium increased, Grade 3 | 0 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Sodium increased, Grade 4 | 0 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Calcium, Ionized increased: All grades | 0 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Calcium, Ionized increased: Grade 3 | 0 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Potassium increased, Grade 4 | 0 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Potassium decreased, All grades | 4 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Potassium decreased, Grade 4 | 0 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Potassium increased, All grades | 4 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Potassium increased, Grade 3 | 0 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Potassium decreased, Grade 3 | 0 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Aspartate Aminotransferase increased, All grades | 9 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Aspartate Aminotransferase increased, Grade 4 | 0 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Creatinine increased, All grades | 10 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Creatinine increased, Grade 3 | 0 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Alkaline Phosphatase increased, All grades | 3 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Alkaline Phosphatase increased, Grade 4 | 0 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Total Bilirubin increased, Grade 3 | 0 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Albumin decreased, All grades | 8 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Albumin decreased, Grade 3 | 0 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Albumin decreased, Grade 4 | 0 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Calcium Corrected for Albumin decreased, All grades | 5 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Calcium Corrected for Albumin decreased, Grade 4 | 0 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Calcium Corrected for Albumin increased, All grades | 5 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Glomerular Filtration Rate, Estimated decreased, All grades | 6 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Glomerular Filtration Rate, Estimated decreased, Grade 4 | 0 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Sodium decreased, Grade 4 | 0 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis | Aspartate Aminotransferase increased, Grade 3 | 3 Participants |
Secondary
Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Interim Analysis
The following chemistry laboratory parameters were assessed: Potassium increased; potassium decreased; aspartate aminotransferase increased; creatinine increased; alkaline phosphatase increased; total bilirubin increased. Treatment emergent laboratory abnormalities were defined as abnormalities 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. NCI CTCAE v5.0 was used for creatinine increased. NCI CTCAE v4.03 was used for the other laboratory parameters. Grade 1: mild; Grade 2: moderate; Grade 3: severe or clinically significant; Grade 4: life-threatening.
Time frame: Up to 49.3 months
Population: The safety analysis set included all participants who received any amount of study treatment. Data for cohorts A and B was combined as prespecified in SAP. Here, Number of Participants Analyzed signifies participants evaluable for this outcome measure.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Interim Analysis | Alanine Aminotransferase increased, Grade 2 | 4 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Interim Analysis | Total Bilirubin increased, Grade 2 | 5 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Interim Analysis | Potassium decreased, Grade 2 | 0 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Interim Analysis | Potassium increased, Grade 1 | 5 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Interim Analysis | Potassium increased, Grade 2 | 1 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Interim Analysis | Potassium increased, Grade 3 | 0 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Interim Analysis | Potassium decreased, Grade 3 | 1 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Interim Analysis | Potassium decreased, Grade 4 | 0 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Interim Analysis | Aspartate Aminotransferase increased, Grade 1 | 20 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Interim Analysis | Aspartate Aminotransferase increased, Grade 2 | 3 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Interim Analysis | Potassium decreased, Grade 1 | 13 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Interim Analysis | Total Bilirubin increased, Grade 1 | 14 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Interim Analysis | Alanine Aminotransferase increased, Grade 3 | 2 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Interim Analysis | Alanine Aminotransferase increased, Grade 4 | 2 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Interim Analysis | Creatinine increased, Grade 1 | 38 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Interim Analysis | Aspartate Aminotransferase increased, Grade 3 | 2 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Interim Analysis | Aspartate Aminotransferase increased, Grade 4 | 3 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Interim Analysis | Creatinine increased, Grade 2 | 11 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Interim Analysis | Creatinine increased, Grade 3 | 0 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Interim Analysis | Creatinine increased, Grade 4 | 0 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Interim Analysis | Alkaline Phosphatase increased, Grade 1 | 16 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Interim Analysis | Alkaline Phosphatase increased, Grade 2 | 4 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Interim Analysis | Total Bilirubin increased, Grade 3 | 3 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Interim Analysis | Total Bilirubin increased, Grade 4 | 2 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Interim Analysis | Alkaline Phosphatase increased, Grade 3 | 1 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Interim Analysis | Alkaline Phosphatase increased, Grade 4 | 0 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Interim Analysis | Alanine Aminotransferase increased, Grade 1 | 31 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Interim Analysis | Potassium increased, Grade 4 | 0 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Interim Analysis | Creatinine increased, Grade 1 | 9 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Interim Analysis | Total Bilirubin increased, Grade 2 | 0 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Interim Analysis | Potassium decreased, Grade 1 | 3 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Interim Analysis | Aspartate Aminotransferase increased, Grade 3 | 2 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Interim Analysis | Potassium decreased, Grade 2 | 0 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Interim Analysis | Alanine Aminotransferase increased, Grade 1 | 4 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Interim Analysis | Potassium increased, Grade 1 | 1 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Interim Analysis | Total Bilirubin increased, Grade 1 | 6 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Interim Analysis | Potassium increased, Grade 2 | 0 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Interim Analysis | Total Bilirubin increased, Grade 3 | 0 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Interim Analysis | Creatinine increased, Grade 2 | 0 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Interim Analysis | Potassium decreased, Grade 3 | 1 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Interim Analysis | Alkaline Phosphatase increased, Grade 4 | 0 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Interim Analysis | Potassium decreased, Grade 4 | 0 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Interim Analysis | Creatinine increased, Grade 3 | 0 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Interim Analysis | Aspartate Aminotransferase increased, Grade 1 | 6 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Interim Analysis | Total Bilirubin increased, Grade 4 | 0 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Interim Analysis | Aspartate Aminotransferase increased, Grade 2 | 0 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Interim Analysis | Potassium increased, Grade 3 | 1 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Interim Analysis | Potassium increased, Grade 4 | 0 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Interim Analysis | Creatinine increased, Grade 4 | 0 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Interim Analysis | Aspartate Aminotransferase increased, Grade 4 | 0 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Interim Analysis | Alanine Aminotransferase increased, Grade 2 | 2 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Interim Analysis | Alkaline Phosphatase increased, Grade 1 | 4 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Interim Analysis | Alanine Aminotransferase increased, Grade 3 | 2 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Interim Analysis | Alkaline Phosphatase increased, Grade 3 | 0 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Interim Analysis | Alanine Aminotransferase increased, Grade 4 | 0 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Interim Analysis | Alkaline Phosphatase increased, Grade 2 | 2 Participants |
Secondary
Number of Participants With Treatment-Emergent Laboratory Abnormalities (Hematology): Final Analysis
The following hematology laboratory parameters were assessed: Hemoglobin decreased; hemoglobin increased; leukocytes decreased; lymphocytes decreased; neutrophils decreased and Platelets decreased. Treatment emergent laboratory abnormalities were defined as abnormalities 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. NCI CTCAE v4.03 was used for the lab parameters. Grade 1: mild; Grade 2: moderate; Grade 3: severe or clinically significant; Grade 4: life-threatening.
Time frame: Up to 65.1 months
Population: The safety analysis set included all participants who received any amount of study treatment. Data for cohorts A and B was combined as prespecified in SAP. Here, Number of Participants Analyzed signifies participants evaluable for this outcome measure.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Hematology): Final Analysis | Hemoglobin decreased, All grades | 42 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Hematology): Final Analysis | Leukocytes decreased, Grade 3 | 0 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Hematology): Final Analysis | Neutrophils decreased: All grades | 10 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Hematology): Final Analysis | Leukocytes decreased, Grade 4 | 0 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Hematology): Final Analysis | Hemoglobin decreased, Grade 3 | 3 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Hematology): Final Analysis | Lymphocytes decreased, Grade 3 | 6 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Hematology): Final Analysis | Hemoglobin increased: All grades | 3 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Hematology): Final Analysis | Lymphocytes decreased, Grade 4 | 0 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Hematology): Final Analysis | Neutrophils decreased: Grade 3 | 0 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Hematology): Final Analysis | Lymphocytes decreased, All grades | 25 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Hematology): Final Analysis | Neutrophils decreased: Grade 4 | 0 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Hematology): Final Analysis | Hemoglobin increased: Grade 3 | 0 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Hematology): Final Analysis | Platelets decreased, All grades | 15 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Hematology): Final Analysis | Hemoglobin increased: Grade 4 | 0 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Hematology): Final Analysis | Platelets decreased, Grade 3 | 0 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Hematology): Final Analysis | Leukocytes decreased, All grades | 21 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Hematology): Final Analysis | Platelets decreased, Grade 4 | 0 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Hematology): Final Analysis | Hemoglobin decreased, Grade 4 | 0 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Hematology): Final Analysis | Platelets decreased, Grade 4 | 1 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Hematology): Final Analysis | Hemoglobin decreased, Grade 4 | 0 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Hematology): Final Analysis | Lymphocytes decreased, Grade 4 | 0 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Hematology): Final Analysis | Neutrophils decreased: All grades | 0 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Hematology): Final Analysis | Hemoglobin increased: Grade 3 | 0 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Hematology): Final Analysis | Hemoglobin decreased, All grades | 9 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Hematology): Final Analysis | Hemoglobin decreased, Grade 3 | 0 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Hematology): Final Analysis | Hemoglobin increased: All grades | 0 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Hematology): Final Analysis | Hemoglobin increased: Grade 4 | 0 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Hematology): Final Analysis | Leukocytes decreased, All grades | 5 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Hematology): Final Analysis | Leukocytes decreased, Grade 3 | 0 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Hematology): Final Analysis | Leukocytes decreased, Grade 4 | 0 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Hematology): Final Analysis | Lymphocytes decreased, All grades | 11 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Hematology): Final Analysis | Lymphocytes decreased, Grade 3 | 1 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Hematology): Final Analysis | Neutrophils decreased: Grade 3 | 0 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Hematology): Final Analysis | Neutrophils decreased: Grade 4 | 0 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Hematology): Final Analysis | Platelets decreased, All grades | 4 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Hematology): Final Analysis | Platelets decreased, Grade 3 | 0 Participants |
Secondary
Number of Participants With Treatment-Emergent Laboratory Abnormalities (Hematology): Interim Analysis
The following hematology laboratory parameters were assessed: Hemoglobin decreased; leukocytes decreased; neutrophils decreased and Platelets decreased. Treatment emergent laboratory abnormalities were defined as abnormalities 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. NCI CTCAE v4.03 was used for the lab parameters. Grade 1: mild; Grade 2: moderate; Grade 3: severe or clinically significant; Grade 4: life-threatening.
Time frame: Up to 49.3 months
Population: The safety analysis set included all participants who received any amount of study treatment. Data for cohorts A and B was combined as prespecified in SAP. Here, Number of Participants Analyzed signifies participants evaluable for this outcome measure.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Hematology): Interim Analysis | Platelets decreased, Grade 3 | 0 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Hematology): Interim Analysis | Neutrophils decreased, Grade 1 | 6 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Hematology): Interim Analysis | Hemoglobin decreased, Grade 3 | 3 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Hematology): Interim Analysis | Neutrophils decreased, Grade 2 | 2 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Hematology): Interim Analysis | Hemoglobin decreased, Grade 1 | 28 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Hematology): Interim Analysis | Leukocytes decreased, Grade 1 | 14 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Hematology): Interim Analysis | Hemoglobin decreased, Grade 4 | 0 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Hematology): Interim Analysis | Neutrophils decreased, Grade 4 | 0 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Hematology): Interim Analysis | Leukocytes decreased, Grade 2 | 5 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Hematology): Interim Analysis | Platelets decreased, Grade 1 | 11 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Hematology): Interim Analysis | Hemoglobin decreased, Grade 2 | 8 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Hematology): Interim Analysis | Platelets decreased, Grade 2 | 2 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Hematology): Interim Analysis | Leukocytes decreased, Grade 3 | 0 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Hematology): Interim Analysis | Neutrophils decreased, Grade 3 | 0 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Hematology): Interim Analysis | Platelets decreased, Grade 4 | 0 Participants |
| Tucatinib+Trastuzumab (Cohorts A+B) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Hematology): Interim Analysis | Leukocytes decreased, Grade 4 | 0 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Hematology): Interim Analysis | Platelets decreased, Grade 4 | 0 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Hematology): Interim Analysis | Hemoglobin decreased, Grade 2 | 2 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Hematology): Interim Analysis | Neutrophils decreased, Grade 2 | 1 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Hematology): Interim Analysis | Hemoglobin decreased, Grade 4 | 0 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Hematology): Interim Analysis | Leukocytes decreased, Grade 1 | 3 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Hematology): Interim Analysis | Leukocytes decreased, Grade 2 | 0 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Hematology): Interim Analysis | Leukocytes decreased, Grade 3 | 0 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Hematology): Interim Analysis | Leukocytes decreased, Grade 4 | 0 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Hematology): Interim Analysis | Neutrophils decreased, Grade 1 | 1 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Hematology): Interim Analysis | Hemoglobin decreased, Grade 3 | 0 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Hematology): Interim Analysis | Neutrophils decreased, Grade 3 | 0 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Hematology): Interim Analysis | Neutrophils decreased, Grade 4 | 0 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Hematology): Interim Analysis | Platelets decreased, Grade 1 | 1 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Hematology): Interim Analysis | Platelets decreased, Grade 2 | 2 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Hematology): Interim Analysis | Platelets decreased, Grade 3 | 0 Participants |
| Tucatinib Pre-Crossover (Cohort C) | Number of Participants With Treatment-Emergent Laboratory Abnormalities (Hematology): Interim Analysis | Hemoglobin decreased, Grade 1 | 6 Participants |
Secondary
ORR by 12 Weeks of Treatment Per RECIST v1.1 According to BICR Assessment
ORR per BICR by 12 Weeks was defined as the percentage of participants with CR or PR by 12 weeks of treatment, and before time of crossover (Cohort C), whichever came earlier. CR was defined as the disappearance of all target lesions and each target lymph node must have reduction in short axis to more than \<1.0 cm. PR was defined as at least a 30% decrease in post-baseline sum of the diameters (sum of the longest diameter for all target lesions plus the sum of the short axis of all the target lymph nodes at current evaluation) taking as reference the baseline sum of diameter.
Time frame: Up to 3 months
Population: The Full Analysis Set included all participants who were enrolled and received any amount of study treatment and had HER2+ tumors as defined by one or more protocol required local tests. Data for cohort A and B was combined as prespecified in SAP.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tucatinib+Trastuzumab (Cohorts A+B) | ORR by 12 Weeks of Treatment Per RECIST v1.1 According to BICR Assessment | 28.6 Percentage of Participants |
| Tucatinib Pre-Crossover (Cohort C) | ORR by 12 Weeks of Treatment Per RECIST v1.1 According to BICR Assessment | 3.3 Percentage of Participants |
Secondary
Overall Survival (OS) in Pooled Cohorts A+B
OS was defined as the time from start of study treatment (Cohort A) or randomization (Cohort B) to date of death due to any cause.
Time frame: Up to 71.8 months
Population: The Full Analysis Set included all participants who were enrolled and received any amount of study treatment and had HER2+ tumors as defined by one or more protocol required local tests. Data for cohort A and B was combined as prespecified in SAP.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tucatinib+Trastuzumab (Cohorts A+B) | Overall Survival (OS) in Pooled Cohorts A+B | 23.9 Months |
Secondary
Progression-Free Survival (PFS) Per RECIST v1.1 According to BICR Assessment for Pooled Cohorts A+B
PFS was defined as the time from start of study treatment (Cohort A) or date of randomization (Cohort B) to documented disease progression (as determined by BICR per RECIST v1.1) or death from any cause, whichever occurred first. PD was defined as: at least one new malignant lesion, which also included any lymph node that was normal at baseline (\<1.0 cm short axis) and increased to \>=1.0 cm short axis during follow-up or at least a 20% increase in post-baseline sum of the diameters (PBSD) taking as reference the minimum sum of the diameters (MSD). In addition, the PBSD must also demonstrate an absolute increase of at least 0.5 cm from the MSD.
Time frame: Up to 64.1 months
Population: The Full Analysis Set included all participants who were enrolled and received any amount of study treatment and had HER2+ tumors as defined by one or more protocol required local tests. Data for cohort A and B was combined as prespecified in SAP.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tucatinib+Trastuzumab (Cohorts A+B) | Progression-Free Survival (PFS) Per RECIST v1.1 According to BICR Assessment for Pooled Cohorts A+B | 8.1 Months |