Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Tucatinib · 21 trials · 36 indications
The time from the date of randomization to the BICR assessment of disease progression according to RECIST v1.1 or death from any cause
The time from the date of randomization to the investigator assessment of disease progression according to RECIST v1.1 or death from any cause
A Kaplan-Meier method will be used to estimate the survival curves and a stratified log-rank test will be used to compare the invasive disease-free survival (iDFS) of the two arms. A stratified Cox model will be used to estimate the hazard ratio. If there appears to be clinically significant imbalances of baseline variables between the treatment arms, a secondary analysis of the primary endpoint will use stratified Cox model to compare the treatment effects that include the variables that are deemed imbalanced between the arms as adjusting variables. The randomization stratification variables will be the stratified variables in the model.
PFS as per investigator was defined as the time from the date of randomization to the investigator assessment of disease progression (PD) as per RECIST v1.1 or death from any cause, whichever occurred first. PD: at least a 20 percent (%) increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 millimiter (mm). Participants without documentation of PD, or death at the time of analysis were censored at the date of the last tumor assessment.
Proportion of participants with confirmed complete response (CR) or partial response (PR) to tucatinib in combination with Doxil according to RECIST v1.1 criteria.
cORR was defined as percentage of participants with confirmed complete response (CR) or partial response (PR), per RECIST version 1.1. CR: disappearance of all target lesions. Any pathological lymph nodes must have a reduction in short axis to \<10 millimeter(mm). PR: a \>=30% decrease in the sum of diameters of target lesions, taking as a reference the baseline sum diameters. Only response assessments before first documented progressive disease(PD) or new anti-cancer therapies were considered. PD: at least a 20% increase in sum of diameters of target lesions, taking as reference the smallest sum on study(included baseline sum if smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Appearance of one or more new lesions was also considered PD. Participants with missing data were considered non-responders. cORR was determined by ICR. Two-sided 90% exact confidence interval was based on Clopper-Pearson method.
DLTs were adverse events (AEs), laboratory abnormalities, or treatment modifications that occurred during the first cycle of treatment in the Phase 2 paclitaxel dose optimization stage that were related to paclitaxel, to tucatinib, or to the combination of tucatinib, trastuzumab, ramucirumab and paclitaxel and that met any of the study protocol specified criteria. The relationship of AEs to study drugs was determined by the investigator. AEs that were attributed only to trastuzumab and/or ramucirumab, but not tucatinib or paclitaxel were not considered DLTs.
An AE was any untoward medical occurrence in a participant or clinical investigational participant administered a medicinal product and which did not necessarily have a causal relationship with this treatment. AEs were defined as treatment emergent if they were newly occurring or worsened following study treatment. A TEAE was defined as a newly occurring or worsening AE after the first dose of study treatment (tucatinib, trastuzumab, ramucirumab, or paclitaxel) and up to 30 days after the last dose of study treatment (tucatinib, trastuzumab, ramucirumab, or paclitaxel, whichever was later).
Treatment-emergent laboratory abnormalities were defined as abnormalities that are new or worsened on or after receiving the first dose of study treatment up to 30 days after the last dose of study treatment. Laboratory abnormalities included: 1) Blood chemistry: alanine aminotransferase increased, albumin decreased, alkaline phosphatase increased, aspartate aminotransferase increased, calcium corrected for albumin decreased, calcium corrected for albumin increased, creatinine increased, glomerular filtration rate estimated decreased, glucose decreased, lactate dehydrogenase increased, magnesium decreased, magnesium increased, potassium decreased, potassium increased, sodium decreased, sodium increased, and total bilirubin increased; 2) Hematological: hemoglobin decreased, leukocytes decreased, lymphocytes decreased, neutrophils decreased, and platelets decreased.
Vital sign examinations included systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate. Criteria: SBP greater than or equal to (\>=) 120 millimeters of mercury (mm Hg) or DBP \>= 80 mm Hg; SBP \>= 140 mm Hg or DBP \>= 90 mm Hg; SBP \>= 160 mm Hg or DBP \>= 100 mm Hg), heart rate greater than (\>) 100 beats per minute (min). Clinical significance in vital signs abnormalities was judged by investigator. In this outcome measure number of participants with at least 1 clinically significant abnormality in any vital sign are reported.
Maximum percentage decrease from baseline in weight is reported in this outcome measure.
Dose modification included dose hold, dose reduction, dose error and unplanned dose adjustments. Number of participants with any dose treatment modifications for paclitaxel, ramucirumab, trastuzumab, and tucatinib are reported in this outcome measure.
Confirmed ORR was defined as the percentage of participants with best overall response of complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria version (v)1.1 as assessed by investigator and was considered as confirmed when subsequent response was at least 4 weeks after initial response. As per RECIST v1.1, CR: disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (\<)10 millimeter (mm). PR: at least a greater than or equal to (\>=)30 % decrease in the sum of diameters (SOD) of target lesions (longest for non-nodal target lesions and the short axes for nodal target lesions), taking as reference the baseline sum diameters. Disease progression (PD): at least \>=20% relative increase in SOD of target lesion taking as reference the smallest sum on study (including baseline sum if that is the smallest on study).
Confirmed objective response rate was defined as the percentage of participants with a confirmed complete response (CR) or partial response (PR) per investigator according to RECIST v1.1. For a response to be considered confirmed, the subsequent response had to be at least 4 weeks after the initial response. CR: disappearance of all target lesions and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (\<)10 millimeters (mm). PR: a greater than equal to (\>=) 30 percent (%) decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. 95% exact confidence interval (CI) was based on Clopper-Pearson method.
A renal DLT was defined as an increase in serum cystatin C \>1.5\* baseline that was not related to pre-renal or post-renal etiologies (including disease progression, dehydration and intercurrent illness) and occurred during the period of treatment with tucatinib in combination with trastuzumab and FOLFOX between the first dose of tucatinib and the end of Cycle 3. Increased serum cystatin C for which there was an alternative clinical explanation (eg, clearly related to an intercurrent illness or disease progression) was not considered renal DLTs.
An adverse event (AE) was defined as any untoward medical occurrence in a clinical investigational participant administered a medicinal product and which did not necessarily have a causal relationship with this treatment. TEAE was defined as a newly occurring or worsening AE after the first dose of study treatment (tucatinib, trastuzumab, leucovorin, fluorouracil, oxaliplatin and pembrolizumab) through 30 days after the last dose of study treatment.
An AE was defined was any untoward medical occurrence in a clinical investigational participant administered a medicinal product and which did not necessarily have a causal relationship with this treatment. TEAE was defined as a newly occurring or worsening AE after the first dose of study treatment (tucatinib, trastuzumab, leucovorin, fluorouracil, oxaliplatin and pembrolizumab) through 30 days after the last dose of study treatment. Treatment related TEAEs were AEs related to any study treatment and relatedness was judged by investigator.
An AE was defined was any untoward medical occurrence in a clinical investigational participant administered a medicinal product and which did not necessarily have a causal relationship with this treatment. TEAE was defined as a newly occurring or worsening AE after the first dose of study treatment (tucatinib, trastuzumab, leucovorin, fluorouracil, oxaliplatin and pembrolizumab) through 30 days after the last dose of study treatment. TEAEs were graded according to National Cancer Institute, Common Terminology Criteria for Adverse Events (NCI-CTCAE) version (v) 5.0 where grade 1= mild, grade 2= moderate, grade 3= severe and grade 4= life-threatening. Number of participants with \>= grade 3 TEAEs are reported in this outcome measure.
An AE was defined was any untoward medical occurrence in a clinical investigational participant administered a medicinal product and which did not necessarily have a causal relationship with this treatment. TEAE was defined as a newly occurring or worsening AE after the first dose of study treatment (tucatinib, trastuzumab, leucovorin, fluorouracil, oxaliplatin and pembrolizumab) through 30 days after the last dose of study treatment. TEAEs were graded according to NCI-CTCAE v 5.0 where grade 1= mild, grade 2= moderate, grade 3= severe and grade 4= life-threatening. Treatment related TEAEs were AEs related to study treatment and relatedness was judged by investigator. Number of participants with \>= grade 3 treatment related TEAEs are reported in this outcome measure.
An SAE was any untoward medical occurrence at any dose that was fatal; life-threatening; required hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; was a congenital anomaly/birth defect or was medically significant.
An SAE was any untoward medical occurrence at any dose that was fatal; life-threatening; required hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; was a congenital anomaly/birth defect or was medically significant. Treatment related SAEs were SAEs related to any study treatment and relatedness was judged by investigator.
DLTs were AEs/ laboratory abnormalities that were considered to be related to tucatinib/ tucatinib in combination with chemotherapy(mFOLFOX6/CAPOX) and/or trastuzumab and/or pembrolizumab. DLTs was defined any of following: a-)Hepatic- any instance of aspartate aminotransferase(AST)/ alanine aminotransferase(ALT)\>3\*upper limit of normal(ULN) and total bilirubin \>2\*ULN that is not thought to be due to progressive disease(PD)/other medical illness. PD:at least 20% increase in sum of diameters of target lesions,taking as reference smallest sum on study. In addition to relative increase of 20%,sum must also demonstrate an absolute increase of at least 5 millimeters(mm). b-) Non-hematologic- any clinically significant, non-hematologic treatment-related AE\>= grade(G)3, with following exceptions:G3 fatigue=\< 7days,G3 diarrhea,nausea/vomiting without optimal use of anti-emetics/antidiarrheals c-)hematologic:\>=G3 febrile neutropenia and absolute neutrophil count(ANC) decreased G4 for \>7days.
DLTs were AEs/ laboratory abnormalities that were considered to be related to tucatinib/ tucatinib in combination with chemotherapy (mFOLFOX6/CAPOX) and/ or trastuzumab and/ or pembrolizumab. DLTs was defined any of following: a-) Hepatic- any instance of AST/ ALT \>3\*ULN and total bilirubin \>2\*ULN that is not thought to be due to PD/ other medical illness. PD: at least 20% increase in sum of diameters of target lesions, taking as reference smallest sum on study. In addition to relative increase of 20%, sum must also demonstrate an absolute increase of at least 5 mm. b-) Non-hematologic- any clinically significant, non-hematologic treatment-related AE\>= grade 3, with following exceptions: grade 3 fatigue=\< 7days, grade 3 diarrhea, nausea/vomiting without optimal use of anti-emetics/antidiarrheals c-) hematologic: \>= grade 3 febrile neutropenia and ANC decreased grade 4 for \>7days.
The following hematological parameters were assessed: hemoglobin decreased, leukocytes decreased, lymphocytes decreased, neutrophils decreased and platelets decreased. TEAE was defined as a newly occurring or worsening AE after the first dose of study treatment (tucatinib, trastuzumab, leucovorin, fluorouracil, oxaliplatin and pembrolizumab) through 30 days after the last dose of study treatment. Hematological laboratory abnormalities were graded according to NCI CTCAE v 5.0 (grade 1= mild, grade 2= moderate, grade 3= severe and grade 4= life-threatening). Participants with hematological abnormalities of any grade were reported.
The following chemistry laboratory parameters were assessed: alanine aminotransferase (ALT) increased, albumin decreased, alkaline phosphatase increased, aspartate aminotransferase (AST) increased, calcium corrected for albumin decreased, creatinine increased, calcium corrected for albumin increased, lactate dehydrogenase increased, potassium decreased, potassium increased, sodium decreased, sodium increased and total bilirubin increased. TEAE was defined as a newly occurring or worsening AE after the first dose of study treatment (tucatinib, trastuzumab, leucovorin, fluorouracil, oxaliplatin and pembrolizumab) through 30 days after the last dose of study treatment Chemistry laboratory abnormalities were graded according to NCI CTCAE v 5.0 (grade 1= mild, grade 2= moderate, grade 3= severe and grade 4= life-threatening). Participants with chemistry abnormalities of any grade were reported.
Vital signs included temperature, blood pressure, heart rate and respiratory rate. Clinically significant vital signs were defined as: temperature greater than or equal to (\>=) 38 degrees Celsius, respiratory rate greater than (\>) 20 breaths per minute, systolic blood pressure (SBP) \>= 120 millimeter of mercury (mmHg) or diastolic blood pressure (DBP) \>= 80 mmHg, SBP \>= 140 mmHg or DBP \>= 90 mmHg and heart rate \> 100 beats per minute (bpm).
An AE was defined as any untoward medical occurrence in a clinical investigational participant administered a medicinal product and which did not necessarily have a causal relationship with this treatment. TEAE was defined as a newly occurring or worsening AE after the first dose of study treatment (tucatinib, trastuzumab, leucovorin, fluorouracil and oxaliplatin) through 30 days after the last dose of study treatment.
An AE was defined was any untoward medical occurrence in a clinical investigational participant administered a medicinal product and which did not necessarily have a causal relationship with this treatment. TEAE was defined as a newly occurring or worsening AE after the first dose of study treatment (tucatinib, trastuzumab, leucovorin, fluorouracil and oxaliplatin) through 30 days after the last dose of study treatment. Treatment related TEAEs were AEs related to study treatment and relatedness was judged by investigator.
An AE was defined was any untoward medical occurrence in a clinical investigational participant administered a medicinal product and which did not necessarily have a causal relationship with this treatment. TEAE was defined as a newly occurring or worsening AE after the first dose of study treatment (tucatinib, trastuzumab, leucovorin, fluorouracil and oxaliplatin) through 30 days after the last dose of study treatment. TEAEs were graded according to NCI-CTCAE v 5.0 where grade 1= mild, grade 2= moderate, grade 3= severe and grade 4= life-threatening. Number of participants with \>= grade 3 TEAEs are reported in this outcome measure.
An AE was defined was any untoward medical occurrence in a clinical investigational participant administered a medicinal product and which did not necessarily have a causal relationship with this treatment. TEAE was defined as a newly occurring or worsening AE after the first dose of study treatment (tucatinib, trastuzumab, leucovorin, fluorouracil and oxaliplatin) through 30 days after the last dose of study treatment. TEAEs were graded according to NCI-CTCAE v 5.0 where grade 1= mild, grade 2= moderate, grade 3= severe and grade 4= life-threatening. Treatment related TEAEs were AEs related to study treatment and relatedness was judged by investigator. Number of participants with \>= grade 3 treatment related TEAEs are reported in this outcome measure.
An SAE was any untoward medical occurrence at any dose that was fatal; life-threatening; required hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; was a congenital anomaly/birth defect or was medically significant.
An SAE was any untoward medical occurrence at any dose that was fatal; life-threatening; required hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; was a congenital anomaly/birth defect or was medically significant. Treatment related SAEs were SAEs related to any study treatment and relatedness was judged by investigator.
DLTs were AEs/ laboratory abnormalities that were considered to be related to tucatinib/ tucatinib in combination with chemotherapy (mFOLFOX6/CAPOX) and/ or trastuzumab and/ or pembrolizumab. DLTs was defined any of following: a-) Hepatic- any instance of AST/ ALT \>3\*ULN and total bilirubin \>2\*ULN that is not thought to be due to PD/ other medical illness. PD: at least 20% increase in sum of diameters of target lesions, taking as reference smallest sum on study. In addition to relative increase of 20%, sum must also demonstrate an absolute increase of at least 5 mm. b-) Non-hematologic- any clinically significant, non-hematologic treatment-related AE\>= grade 3, with following exceptions: grade 3 fatigue=\< 7days, grade 3 diarrhea, nausea/vomiting without optimal use of anti-emetics/antidiarrheals c-) hematologic: \>= grade 3 febrile neutropenia and ANC decreased grade 4 for \>7days.
The following hematological parameters were assessed: hemoglobin decreased, leukocytes decreased, lymphocytes decreased, neutrophils decreased and platelets decreased. TEAE was defined as a newly occurring or worsening AE after the first dose of study treatment (tucatinib, trastuzumab, leucovorin, fluorouracil and oxaliplatin) through 30 days after the last dose of study treatment. Hematological laboratory abnormalities were graded according to NCI CTCAE v 5.0 (grade 1= mild, grade 2= moderate, grade 3= severe and grade 4= life-threatening). Participants with hematological abnormalities of any grade were reported.
The following chemistry parameters were assessed: ALT increased, albumin decreased, alkaline phosphatase increased, AST increased, calcium corrected for albumin decreased, creatinine increased, lactate dehydrogenase increased, potassium decreased, potassium increased, sodium decreased and sodium increased. TEAE was defined as a newly occurring or worsening AE after the first dose of study treatment (tucatinib, trastuzumab, leucovorin, fluorouracil and oxaliplatin) through 30 days after the last dose of study treatment. Chemistry laboratory parameters abnormalities were graded according to NCI CTCAE v 5.0 (grade 1= mild, grade 2= moderate, grade 3= severe and grade 4= life-threatening). Participants with chemistry abnormalities of any grade were reported.
Vital signs included temperature, blood pressure, heart rate and respiratory rate. Clinically significant vital signs were defined as: temperature \>= 38 degrees Celsius, respiratory rate \> 20 breaths per minute, SBP \>= 120 mmHg or DBP \>= 80 mmHg, SBP \>= 140 mmHg or DBP \>= 90 mmHg and heart rate \> 100 beats per minute (bpm).
An AE was defined as any untoward medical occurrence in a clinical investigational participant administered a medicinal product and which did not necessarily have a causal relationship with this treatment. TEAE was defined as a newly occurring or worsening AE after the first dose of study treatment (tucatinib, trastuzumab, leucovorin, fluorouracil and oxaliplatin) through 30 days after the last dose of study treatment. Dose hold was considered as dose delay and dose elimination. Number of participants with TEAEs leading to dose holds are reported in this outcome measure.
An AE was defined as any untoward medical occurrence in a clinical investigational participant administered a medicinal product and which did not necessarily have a causal relationship with this treatment. TEAE was defined as a newly occurring or worsening AE after the first dose of study treatment (tucatinib, trastuzumab, leucovorin, fluorouracil and oxaliplatin) through 30 days after the last dose of study treatment. Number of participants with TEAEs leading to dose reductions are reported in this outcome measure.
An AE was defined as any untoward medical occurrence in a clinical investigational participant administered a medicinal product and which did not necessarily have a causal relationship with this treatment. TEAE was defined as a newly occurring or worsening AE after the first dose of study treatment (tucatinib, trastuzumab, leucovorin, fluorouracil and oxaliplatin) through 30 days after the last dose of study treatment. Number of participants with TEAEs leading to dose discontinuations (i.e. permanent withdrawal of tucatinib, trastuzumab, oxaliplatin, fluorouracil and leucovorin) are reported in this outcome measure.
An AE was defined was any untoward medical occurrence in a clinical investigational participant administered a medicinal product and which did not necessarily have a causal relationship with this treatment. TEAE was defined as a newly occurring or worsening AE after the first dose of study treatment (tucatinib, trastuzumab, leucovorin, fluorouracil and oxaliplatin) through 30 days after the last dose of study treatment.
An AE was defined was any untoward medical occurrence in a clinical investigational participant administered a medicinal product and which did not necessarily have a causal relationship with this treatment. TEAE was defined as a newly occurring or worsening AE after the first dose of study treatment (tucatinib, trastuzumab, leucovorin, fluorouracil and oxaliplatin) through 30 days after the last dose of study treatment. Treatment related TEAEs were AEs related to study treatment and relatedness was judged by investigator.
An AE was defined was any untoward medical occurrence in a clinical investigational participant administered a medicinal product and which did not necessarily have a causal relationship with this treatment. TEAE was defined as a newly occurring or worsening AE after the first dose of study treatment (tucatinib, trastuzumab, leucovorin, fluorouracil and oxaliplatin) through 30 days after the last dose of study treatment. TEAEs were graded according to NCI-CTCAE v 5.0 (grade 1= mild, grade 2= moderate, grade 3= severe and grade 4= life-threatening). Number of participants with \>= grade 3 TEAEs are reported in this outcome measure.
An AE was defined was any untoward medical occurrence in a clinical investigational participant administered a medicinal product and which did not necessarily have a causal relationship with this treatment. TEAE was defined as a newly occurring or worsening AE after the first dose of study treatment (tucatinib, trastuzumab, leucovorin, fluorouracil and oxaliplatin) through 30 days after the last dose of study treatment. TEAEs were graded according to NCI-CTCAE v 5.0 (grade 1= mild, grade 2= moderate, grade 3= severe and grade 4= life-threatening). Treatment related TEAEs were AEs related to study treatment and relatedness was judged by investigator. Number of participants with \>= grade 3 treatment related TEAEs are reported in this outcome measure.
An SAE was any untoward medical occurrence at any dose that was fatal; life-threatening; required hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; was a congenital anomaly/birth defect or was medically significant.
An SAE was any untoward medical occurrence at any dose that was fatal; life-threatening; required hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; was a congenital anomaly/birth defect or was medically significant. Treatment related SAEs were SAEs related to any study treatment and relatedness was judged by investigator.
Following hematological parameters were assessed: hemoglobin decreased, leukocytes decreased, lymphocytes decreased, neutrophils decreased and platelets decreased. TEAE was defined as a newly occurring or worsening AE after the first dose of study treatment (tucatinib, trastuzumab, leucovorin, fluorouracil and oxaliplatin) through 30 days after the last dose of study treatment. Hematological abnormalities were graded according to NCI CTCAE v 5.0; where, grade 1= mild, grade 2= moderate, grade 3= severe and grade 4= life-threatening). Participants with hematologic abnormalities of any grade were reported.
Following chemistry parameters were assessed: ALT increased, albumin decreased, alkaline phosphatase increased, AST increased, creatinine increased, glomerular filtration rate (GFR) estimated decreased, lactate dehydrogenase increased, potassium decreased, potassium increased, sodium decreased, sodium increased and total bilirubin increased. TEAE was defined as a newly occurring or worsening AE after the first dose of study treatment (tucatinib, trastuzumab, leucovorin, fluorouracil and oxaliplatin) through 30 days after the last dose of study treatment. Chemistry abnormalities were graded according to NCI CTCAE v 5.0; where, grade 1= mild, grade 2= moderate, grade 3= severe and grade 4= life-threatening. Participants with chemistry abnormalities of any grade were reported.
Vital signs included temperature, blood pressure and heart rate. Clinically significant vital signs were defined as: temperature \>= 38 degrees Celsius, respiratory rate \> 20 breaths per minute, SBP \>= 120 mmHg or DBP \>= 80 mmHg, SBP \>= 140 mmHg or DBP \>= 90 mmHg and heart rate \> 100 bpm.
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.
Defined as the time from the date of randomization to the date of documented disease progression.
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention.
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention.
QTcF is the QT interval corrected for heart rate using Fridericia's method.
Pharmacokinetic (PK) endpoint of tucatinib
PK endpoint of tucatinib
PK endpoint of tucatinib
PK endpoint of tucatinib
PK endpoint of tucatinib
PK endpoint of tucatinib
PK endpoint of tucatinib
PK endpoint of tucatinib
PK endpoint of tucatinib
PK endpoint of tucatinib
PK parameters for tucatinib (Parts A, B, and C); repaglinide and its M4 metabolite (Part D), tolbutamide and its 4-hydroxytolbutamide metabolite (Part D), midazolam and its 1-hydroxymidazolam metabolite (Part D), and digoxin (Part E)
PK parameters for tucatinib (Parts A, B, and C); repaglinide and its M4 metabolite (Part D), tolbutamide and its 4-hydroxytolbutamide metabolite (Part D), midazolam and its 1-hydroxymidazolam metabolite (Part D), and digoxin (Part E)
PK parameters for tucatinib (Parts A, B, and C); repaglinide and its M4 metabolite (Part D), tolbutamide and its 4-hydroxytolbutamide metabolite (Part D), midazolam and its 1-hydroxymidazolam metabolite (Part D), and digoxin (Part E)
PK parameters for tucatinib (Parts A, B, and C); repaglinide and its M4 metabolite (Part D), tolbutamide and its 4-hydroxytolbutamide metabolite (Part D), midazolam and its 1-hydroxymidazolam metabolite (Part D), and digoxin (Part E)
PK parameters for tucatinib (Parts A, B, and C); repaglinide and its M4 metabolite (Part D), tolbutamide and its 4-hydroxytolbutamide metabolite (Part D), midazolam and its 1-hydroxymidazolam metabolite (Part D), and digoxin (Part E)
PK parameters for tucatinib (Parts A, B, and C); repaglinide and its M4 metabolite (Part D), tolbutamide and its 4-hydroxytolbutamide metabolite (Part D), midazolam and its 1-hydroxymidazolam metabolite (Part D), and digoxin (Part E)
PK parameters for tucatinib (Parts A, B, and C); repaglinide (Part D), tolbutamide (Part D), midazolam (Part D), and digoxin (Part E).
PK parameters for M4 metabolite, 4-hydroxytolbutamide metabolite, and 1-hydroxymidazolam metabolite (Part D only)
| Arm | Type | Description |
|---|---|---|
| Tucatinib Arm | EXPERIMENTAL | Tucatinib + trastuzumab + mFOLFOX6 |
| Standard of Care Arm | ACTIVE_COMPARATOR | Either (1) mFOLFOX6, (2) mFOLFOX6 and bevacizumab, or (3) mFOLFOX6 and cetuximab |
| Tucatinib + trastuzumab + pertuzumab | EXPERIMENTAL | Tucatinib + trastuzumab + pertuzumab |
| Placebo + trastuzumab + pertuzumab | ACTIVE_COMPARATOR | Placebo + trastuzumab + pertuzumab |
| Arm I (trastuzumab emtansine, placebo) | ACTIVE_COMPARATOR | Patients receive T-DM1 IV over 30-90 minutes on day 1 and placebo PO BID on days 1-21. Treatment repeats every 21 days for up to 14 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo echocardiography/multigated acquisition (MUGA) scan and blood sample collection throughout the study. Patients undergo echocardiography/multigated acquisition (MUGA) scan and blood sample collection throughout the study. |
| Arm II (trastuzumab emtansine, tucatinib) | EXPERIMENTAL | Patients receive T-DM1 IV over 30-90 minutes on day 1 and tucatinib PO BID on days 1-21. Treatment repeats every 21 days for up to 14 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo echocardiography/multigated acquisition (MUGA) scan and blood sample collection throughout the study. |
| Tucatinib + T-DM1 | EXPERIMENTAL | Tucatinib + T-DM1 |
| Placebo + T-DM1 | ACTIVE_COMPARATOR | Placebo + T-DM1 |
| Tucatinib Experimental Treatment Arm | EXPERIMENTAL | Participants will receive tucatinib 300mg by mouth twice daily continuously in combination with Doxil 40mg/m2 given intravenously on day 1 of each cycle. Cycles will be 28 days. Up to 36 participants will be enrolled in this Phase 2 study. |
| Tucatinib and Adotrastuzumab Emtansine (T-DM1) | EXPERIMENTAL | Each study cycle is 21 days (3 weeks) Participants will take tablets of tucatinib two (2) times a day, about 8-12 hours apart. Participants will receive T-DM1 by vein over about 30 minutes on Day 1 of each cycle |
| Tucatinib + Trastuzumab + Capecitabine | EXPERIMENTAL | Participants will receive tucatinib plus trastuzumab plus capecitabine. Tucatinib 300 mg will be administered orally twice daily (BID). Trastuzumab 8 mg/kg loading dose followed by 6 mg/kg maintenance dose thereafter, will be administered intravenously (IV) on Day 1 of each 21-day cycle. Capecitabine 1000 mg/m\^2 will be administered orally BID on Days 1-14 of each 21-day cycle. Tucatinib, trastuzumab and capecitabine treatment will continue until unacceptable toxicity, disease progression, death, withdrawal of consent or study closure. |
| Phase 2 Arm | EXPERIMENTAL | Tucatinib + trastuzumab + ramucirumab + paclitaxel |
| Arm 3A | EXPERIMENTAL | Tucatinib + trastuzumab + ramucirumab + paclitaxel |
| Arm 3B | ACTIVE_COMPARATOR | Ramucirumab + paclitaxel + tucatinib placebo + trastuzumab placebo |
| Arm 3C | EXPERIMENTAL | Tucatinib + ramucirumab + paclitaxel + trastuzumab placebo |
| Tucatinib + Trastuzumab (+ Fulvestrant) | EXPERIMENTAL | Tucatinib + trastuzumab (+ fulvestrant in hormone-receptor positive HER2-mutant breast cancer only) |
| Single Arm | EXPERIMENTAL | Tucatinib + trastuzumab deruxtecan |
| Cohort 1A | EXPERIMENTAL | Tucatinib + trastuzumab + FOLFOX given in 14-day cycles |
| Cohort 1B | EXPERIMENTAL | Tucatinib + trastuzumab + FOLFOX given in 14-day cycles |
| Cohort 1C | EXPERIMENTAL | Tucatinib + trastuzumab + CAPOX given in 21-day cycles |
| Cohort 1D | EXPERIMENTAL | Tucatinib + trastuzumab + FOLFOX. Tucatinib and FOLFOX given in 14-day cycles and trastuzumab given every 21 days |
| Cohort 1E | EXPERIMENTAL | Tucatinib + trastuzumab + pembrolizumab + FOLFOX. Tucatinib and FOLFOX given in 14-day cycles, trastuzumab given in 21-day cycles, and pembrolizumab given in 42-day cycles |
| Cohort 1F | EXPERIMENTAL | Tucatinib + trastuzumab + pembrolizumab + CAPOX. Tucatinib, trastuzumab, and CAPOX given in 21-day cycles and pembrolizumab given in 42-day cycles. |
| Cohort 1G | EXPERIMENTAL | Tucatinib + trastuzumab + pembrolizumab. Tucatinib and trastuzumab given in 21-day cycles and pembrolizumab given in 42-day cycles. |
| Cohort 2A | EXPERIMENTAL | Tucatinib + trastuzumab + pembrolizumab + (FOLFOX or CAPOX). Either (1) tucatinib and FOLFOX given in 14-day cycles or (2) tucatinib and CAPOX given in 21-day cycles. Trastuzumab given in 21-day cycles and pembrolizumab given in 42-day cycles. |
| Cohort 2B | EXPERIMENTAL | Tucatinib + trastuzumab + FOLFOX given in 14-day cycles. |
| Cohort A: Tucatinib + Trastuzumab | EXPERIMENTAL | Non-randomized cohort. Participants take tucatinib twice per day orally on Days 1-21 and trastuzumab intravenously (into the vein; IV) on Day 1. Cycles repeat every 21 days. |
| Cohort B: Tucatinib + Trastuzumab | EXPERIMENTAL | Randomized cohort. Participants take tucatinib twice per day orally on Days 1-21 and trastuzumab intravenously (into the vein; IV) on Day 1. Cycles repeat every 21 days. |
| Cohort C: Tucatinib Monotherapy | EXPERIMENTAL | Randomized cohort. Participants take tucatinib twice per orally every day. Participants who do not respond to therapy may have the option to receive tucatinib and trastuzumab. |
| Tucatinib in combination with capecitabine & trastuzumab | EXPERIMENTAL | Tucatinib + capecitabine + trastuzumab |
| Placebo in combination with capecitabine & trastuzumab | ACTIVE_COMPARATOR | Placebo + capecitabine + trastuzumab |
| Tucatinib Treatment | EXPERIMENTAL | Chinese participants with HER2+ advanced breast cancer, gastric or gastroesophageal junction adenocarcinoma, or colorectal cancer receive tucatinib 300 mg by mouth twice daily during 21-day cycles. Treatment continues until there is evidence of unacceptable toxicity or documented progression. |
| Cohort 1 | EXPERIMENTAL | 50 mg twice daily on Days 1-13 and once daily on Day 14 |
| Cohort 2 | EXPERIMENTAL | 150 mg twice daily on Days 1-13 and once daily on Day 14 |
| Cohort 3 | EXPERIMENTAL | 300 mg twice daily on Days 1-13 and once daily on Day 14 |
| Tucatinib plus metformin | EXPERIMENTAL | Tucatinib administered twice daily on Days 2-8. Metformin administered as a single dose on Days 1 and 8. Iohexol administered via IV push on Days 1 and 8 |
| Treatment Sequence ABC | EXPERIMENTAL | tucatinib + placebo + moxifloxacin (administered in sequential treatment periods) |
| Treatment Sequence CAB | EXPERIMENTAL | moxifloxacin + tucatinib + placebo (administered in sequential treatment periods) |
| Treatment Sequence BCA | EXPERIMENTAL | placebo + moxifloxacin + tucatinib (administered in sequential treatment periods) |
| Treatment Sequence CBA | EXPERIMENTAL | moxifloxacin + placebo + tucatinib (administered in sequential treatment periods) |
| Treatment Sequence ACB | EXPERIMENTAL | tucatinib + moxifloxacin + placebo (administered in sequential treatment periods) |
| Treatment Sequence BAC | EXPERIMENTAL | placebo + tucatinib + moxifloxacin (administered in sequential treatment periods) |
| Group 1: Healthy | ACTIVE_COMPARATOR | Match-controlled healthy subjects with normal hepatic function |
| Group 2: Mild Hepatic Impairment | EXPERIMENTAL | Subjects with Mild hepatic impairment (Child-Pugh Class A, score of 5 or 6) |
| Group 3: Moderate Hepatic Impairment | EXPERIMENTAL | Subjects with Moderate hepatic impairment (Child-Pugh Class B, score of 7 to 9) |
| Group 4: Severe Hepatic Impairment | EXPERIMENTAL | Subjects with Severe hepatic impairment (Child-Pugh Class C, score of 10 to 14) |
| Part A | EXPERIMENTAL | Tucatinib plus Itraconazole |
| Part B | EXPERIMENTAL | Tucatinib plus Rifampin |
| Part C | EXPERIMENTAL | Tucatinib plus Gemfibrozil |
| Part D | EXPERIMENTAL | Tucatinib plus Repaglinide plus Tolbutamide plus Midazolam |
| Part E | EXPERIMENTAL | Tucatinib plus Digoxin |
| Tucatinib (ONT-380) in combination with T-DM1 | EXPERIMENTAL | - |
| Tucatinib (ONT-380) in combination with capecitabine | EXPERIMENTAL | - |
| Tucatinib (ONT-380) in combination with trastuzumab | EXPERIMENTAL | - |
| Tucatinib (ONT-380) combined with capecitabine and trastuzumab | EXPERIMENTAL | - |
| Name | Type | Description |
|---|---|---|
| tucatinib | DRUG | 300mg given by mouth (orally) twice daily |
| trastuzumab | DRUG | 8mg/kg loading dose will be given into the vein (IV; intravenously) on Cycle 1 day 1, followed by 6mg/kg given by IV every 3 weeks thereafter. |
| bevacizumab | DRUG | 5mg/kg given by IV every 2 weeks |
| cetuximab | DRUG | 400mg/m2 loading dose will be given by IV on Cycle 1 day 1, followed by 250mg/m2 given by IV weekly |
| oxaliplatin | DRUG | 85mg/m2 given by IV every 2 weeks. Component of mFOLFOX6. |
| leucovorin | DRUG | 400mg/ m2 given by IV every 2 weeks. Component of mFOLFOX6. |
| levoleucovorin | DRUG | 200mg/ m2 given by IV every 2 weeks. May be given in place of leucovorin. Component of mFOLFOX6. |
| fluorouracil | DRUG | 400mg/m2 given by IV bolus then 2400mg/m2 given by continuous IV infusion (over 46-48 hours) every 2 weeks. Component of mFOLFOX6. |
| Pertuzumab | DRUG | 420mg given by IV every 21 days |
| Combination product: Trastuzumab + Pertuzumab | DRUG | 600 mg pertuzumab, 600 mg trastuzumab, and 20,000 units hyaluronidase will be given by subcutaneous injection every 21 days. May be given in place of trastuzumab and pertuzumab individually. |
| Placebo | DRUG | Given orally twice daily |
| Trastuzumab Emtansine | BIOLOGICAL | Given IV |
| Placebo Administration | DRUG | Given PO |
| Questionnaire Administration | OTHER | Ancillary studies |
| Quality-of-Life Assessment | OTHER | Ancillary studies |
| T-DM1 | DRUG | 3.6 mg/kg given into the vein (IV; intravenously) every 21 days |
| Doxil | DRUG | Participants will receive Doxil 40mg/m2 intravenously on day 1 of each 28 day cycle (with a maximum cumulative dose of 550mg/m2). |
| Capecitabine | DRUG | Capecitabine 1000 mg/m\^2 administered BID via oral tablet |
| ramucirumab | DRUG | 8 mg/kg will be administered IV on Days 1 and 15 of each cycle |
| paclitaxel | DRUG | 60 or 80 mg/m\^2 IV on Days 1, 8, and 15 of each cycle |
| tucatinib placebo | OTHER | Given twice daily orally |
| trastuzumab placebo | OTHER | IV on Days 1 and 15 of each cycle |
| fulvestrant | DRUG | Given into the muscle (intramuscular; IM) once every 4 weeks starting from Cycle 1 Day 1, plus one dose on Cycle 1 Day 15. Only administered to participants with hormone-receptor positive breast cancer. |
| trastuzumab deruxtecan | DRUG | 5.4 mg/kg via intravenous (into the vein; IV) infusion on Day 1 of each of 21-day cycle |
| pembrolizumab | DRUG | 400 mg given by IV on day 1 of cycle 1, then every 6 weeks. |
| Metformin | DRUG | 850mg administered orally |
| Iohexol | DRUG | 1500 mg administered intravenously (IV) |
| moxifloxacin | DRUG | 400mg single oral dose |
| itraconazole | DRUG | 200mg dose |
| rifampin | DRUG | 600mg dose |
| gemfibrozil | DRUG | 600mg tablets |
| repaglinide | DRUG | 1mg dose |
| tolbutamide | DRUG | 500mg dose |
| midazolam | DRUG | 2mg dose |
| digoxin | DRUG | 0.5 mg dose |
| Tucatinib (ONT-380) | DRUG | Given twice per day, orally |
Inclusion Criteria: * Histologically and/or cytologically confirmed adenocarcinoma of the colon or rectum which is locally advanced unresectable or metastatic * Able to provide the most recently available formalin-fixed paraffin-embedded (FFPE) tumor tissue blocks (or freshly sectioned slides) obta...