This trial studies tucatinib to find out if it is safe when given with trastuzumab and other anti-cancer drugs (pembrolizumab, FOLFOX, and CAPOX). It will look at what side effects happen when participants take this combination of drugs. A side effect is anything the drug does other than treating cancer. It will also look at whether tucatinib works with these drugs to treat certain types of cancer. The participants in this trial have HER2-positive (HER2+) cancer in their gut, stomach, intestines, or gallbladder (gastrointestinal cancer).
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
40
For Cohort 1A, 150 mg will be administered twice daily by mouth (orally) from Cycle 1 Day 8 onwards. For all other cohorts, 300 mg (or intermediate dose) will be given orally twice daily starting on Cycle 1 Day 1.
Cohorts 1A and 1B: a 6 mg/kg loading dose will be given into the vein (IV; intravenously) on Cycle 1 Day 1, followed by a dose of 4 mg/kg IV every 2 weeks starting on Cycle 2 Day 1. Cohorts 1C, 1D, 1E, 1F, 1G, 2A, and 2B: an 8 mg/kg loading dose will be administered IV on Cycle 1 Day 1, followed by a dose of 6 mg/kg IV every 3 weeks thereafter.
85 mg/m\^2 given IV every 2 weeks for cohorts using FOLFOX. For cohorts using CAPOX regimen, 130 mg/m\^2 given every 3 weeks.
200 (mFOLFOX7) or 400 (mFOLFOX6) mg/m\^2 given IV every 2 weeks. Part of FOLFOX regimen.
400 mg/m\^2 (IV bolus after leucovorin) and/or 2400 mg/m\^2 (continuous infusion over 46 hours). Part of FOLFOX regimen.
1000 mg/m\^2 is taken twice per day orally on Days 1-14 of each 3 week cycle. Part of CAPOX regimen.
400 mg given by IV on day 1 of cycle 1, then every 6 weeks.
Mayo Clinic Hospital
Phoenix, Arizona, United States
Mayo Clinic
Scottsdale, Arizona, United States
University of Colorado Denver CTO(CTRC)
Aurora, Colorado, United States
University of Colorado Hospital - Anschutz Cancer Pavilion (ACP)
Aurora, Colorado, United States
University of Colorado Hospital - Anschutz Inpatient Pavilion (AIP)
Aurora, Colorado, United States
Number of Participants With Renal Dose-Limiting Toxicities (DLTs): Phase 1b (Cohort 1A and 1B)
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.
Time frame: From first dose of tucatinib until end of Cycle 3 (up to 42 days)
Number of Participants With Treatment Emergent Adverse Events (TEAEs): Phase 1b (Cohort 1E and 1F)
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.
Time frame: From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 20.7 months)
Number of Participants With Treatment Related TEAEs: Phase 1b (Cohort 1E and 1F)
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.
Time frame: From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 20.7 months)
Number of Participants With Greater Than or Equal to (>=) Grade 3 TEAEs: Phase 1b (Cohort 1E and 1F)
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.
Time frame: From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 20.7 months)
Number of Participants With >= Grade 3 Treatment Related TEAEs: Phase 1b (Cohort 1E and 1F)
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.
Time frame: From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 20.7 months)
Number of Participants With Any Serious Adverse Event (SAE): Phase 1b (Cohort 1E and 1F)
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.
Time frame: From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 20.7 months)
Number of Participants With Any Treatment Related SAE: Phase 1b (Cohort 1E and 1F)
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.
Time frame: From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 20.7 months)
Number of Participants With DLTs: Phase 1b (Cohort 1E)
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.
Time frame: Cycle 1 (Up to 21 days)
Number of Participants With DLTs: Phase 1b (Cohort 1F)
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.
Time frame: Cycle 1 (Up to 28 days)
Number of Participants With Treatment Emergent Hematological Laboratory Abnormalities: Phase 1b (Cohort 1E and 1F)
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.
Time frame: From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 20.7 months)
Number of Participants With Treatment Emergent Chemistry Laboratory Abnormalities: Phase 1b (Cohort 1E and 1F)
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.
Time frame: From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 20.7 months)
Number of Participants With Clinically Significant Post-Baseline Vital Signs: Phase 1b (Cohort 1E and 1F)
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).
Time frame: From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 20.7 months)
Number of Participants With TEAEs: Phase 1b (Cohort 1D)
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.
Time frame: From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 21 months)
Number of Participants With Treatment Related TEAEs: Phase 1b (Cohort 1D)
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.
Time frame: From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 21 months)
Number of Participants With >= Grade 3 TEAEs: Phase 1b (Cohort 1D)
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.
Time frame: From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 21 months)
Number of Participants With >= Grade 3 Treatment Related TEAEs: Phase 1b (Cohort 1D)
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.
Time frame: From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 21 months)
Number of Participants With Any SAE: Phase 1b (Cohort 1D)
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.
Time frame: From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 21 months)
Number of Participants With Any Treatment Related SAE: Phase 1b (Cohort 1D)
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.
Time frame: From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 21 months)
Number of Participants With DLTs: Phase 1b (Cohort 1D)
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.
Time frame: Cycle 1 (Up to 28 days)
Number of Participants With Treatment Emergent Hematological Laboratory Abnormalities: Phase 1b (Cohort 1D)
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.
Time frame: From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 21 months)
Number of Participants With Treatment Emergent Chemistry Laboratory Abnormalities: Phase 1b (Cohort 1D)
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.
Time frame: From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 21 months)
Number of Participants With Clinically Significant Post-Baseline Vital Signs: Phase 1b (Cohort 1D)
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).
Time frame: From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 21 months)
Number of Participants With TEAEs Leading to Dose Holds: Phase 1b (Cohort 1D)
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.
Time frame: From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 21 months)
Number of Participants With TEAEs Leading to Dose Reductions: Phase 1b (Cohort 1D)
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.
Time frame: From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 21 months)
Number of Participants With TEAEs Leading to Dose Discontinuations: Phase 1b (Cohort 1D)
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.
Time frame: From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 21 months)
Number of Participants With TEAEs: Phase 2 (Cohort 2B)
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.
Time frame: From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 20.9 months)
Number of Participants With Treatment Related TEAEs: Phase 2 (Cohort 2B)
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.
Time frame: From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 20.9 months)
Number of Participants With >= Grade 3 TEAEs: Phase 2 (Cohort 2B)
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.
Time frame: From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 20.9 months)
Number of Participants With >= Grade 3 Treatment Related TEAEs: Phase 2 (Cohort 2B)
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.
Time frame: From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 20.9 months)
Number of Participants With Any SAE: Phase 2 (Cohort 2B)
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.
Time frame: From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 20.9 months)
Number of Participants With Any Treatment Related SAE: Phase 2 (Cohort 2B)
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.
Time frame: From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 20.9 months)
Number of Participants With Treatment Emergent Hematological Laboratory Abnormalities: Phase 2 (Cohort 2B)
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.
Time frame: From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 20.9 months)
Number of Participants With Treatment Emergent Chemistry Laboratory Abnormalities: Phase 2 (Cohort 2B)
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.
Time frame: From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 20.9 months)
Number of Participants With Clinically Significant Post-Baseline Vital Signs: Phase 2 (Cohort 2B)
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.
Time frame: From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 20.9 months)
Number of Participants With TEAEs: Phase 1b (Cohort 1A and 1B)
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.
Time frame: From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 38.2 months)
Number of Participants With Treatment Related TEAEs: Phase 1b (Cohort 1A and 1B)
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.
Time frame: From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 38.2 months)
Number of Participants With >= Grade 3 TEAEs: Phase 1b (Cohort 1A and 1B)
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.
Time frame: From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 38.2 months)
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Number of Participants With >= Grade 3 Treatment Related TEAEs: Phase 1b (Cohort 1A and 1B)
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.
Time frame: From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 38.2 months)
Number of Participants With Any SAE: Phase 1b (Cohort 1A and 1B)
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.
Time frame: From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 38.2 months)
Number of Participants With Any Treatment Related SAE: Phase 1b (Cohort 1A and 1B)
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.
Time frame: From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 38.2 months)
Number of Participants With Treatment Emergent Hematological Laboratory Abnormalities: Phase 1b (Cohort 1A and 1B)
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; where, grade 1= mild, grade 2= moderate, grade 3= severe and grade 4= life-threatening. Participants with hematological abnormalities of any grade were reported.
Time frame: From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 38.2 months)
Number of Participants With Treatment Emergent Chemistry Laboratory Abnormalities: Phase 1b (Cohort 1A and 1B)
Following chemistry parameters were assessed: ALT increased, albumin decreased, alkaline phosphatase increased, AST increased, calcium corrected for albumin decreased, calcium corrected for albumin increased, creatinine increased, Cystatin C increased, GFR estimated decreased, lactate dehydrogenase increased, potassium decreased, potassium increased, sodium decreased 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 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.
Time frame: From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 38.2 months)
Number of Participants With Clinically Significant Post-Baseline Vital Signs: Phase 1b (Cohort 1A and 1B)
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 bpm.
Time frame: From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment, end of study date, death date, or data cutoff date, whichever was earlier (maximum of 38.2 months)
Change From Baseline in Glomerular Filtration Rate (GFR): Phase 1b (Cohort 1A and 1B)
GFR value was estimated using serum Cystatin C. Baseline was considered as the most recent non-missing measurement prior to the first dose of any study treatment.
Time frame: Baseline, Cycle 1 Day 3, Cycle 1 Day 8, Cycle 2 Day 1, Cycle 2 Day 3, Cycle 2 Day 8 (each cycle=14 days)
Area Under the Plasma Concentration-Time Curve From 0 to 8 Hours (AUC 0-8h) of Tucatinib at Cycle 1 Day 1: Phase 1b (Cohort 1A and 1B)
PK parameters were determined using noncompartmental analysis.
Time frame: Predose, 1 hour intra-dose, end of dose, 1, 2, 4, 6 hours after end of 2 hour oxaliplatin infusion (8 hours) on Day 1 of Cycle 1 and 2
Maximum Observed Concentration (Cmax) of Tucatinib: Phase 1b (Cohort 1A and 1B)
PK parameters were determined using noncompartmental analysis.
Time frame: Predose, 1 hour intra-dose, end of dose, 1, 2, 4, 6 hours after end of 2 hour oxaliplatin infusion (8 hours) on Day 1 of Cycle 1 and 2
Observed Trough Concentration in Plasma (Ctrough) of Tucatinib: Phase 1b (Cohort 1A and 1B)
PK parameters were determined using noncompartmental analysis.
Time frame: Predose on Day 1 of Cycle 2
Time at Which the Maximum Plasma Concentration Occurs (Tmax) of Tucatinib: Phase 1b (Cohort 1A and 1B)
PK parameters were determined using noncompartmental analysis.
Time frame: Predose, 1 hour intra-dose, end of dose, 1, 2, 4, 6 hours after end of 2 hour oxaliplatin infusion (8 hours) on Day 1 of Cycle 1 and 2
AUC 0-8h of Oxaliplatin: Phase 1b (Cohort 1A and 1B)
PK parameters were determined using noncompartmental analysis.
Time frame: Predose, 1 hour intra-dose, end of dose, 1, 2, 4, 6 hours after end of 2 hour oxaliplatin infusion (8 hours) on Day 1 of Cycle 1 and 2
Cmax of Oxaliplatin: Phase 1b (Cohort 1A and 1B)
PK parameters were determined using noncompartmental analysis.
Time frame: Predose, 1 hour intra-dose, end of dose, 1, 2, 4, 6 hours after end of 2 hour oxaliplatin infusion (8 hours) on Day 1 of Cycle 1 and 2
Tmax of Oxaliplatin: Phase 1b (Cohort 1A and 1B)
PK parameters were determined using noncompartmental analysis.
Time frame: Predose, 1 hour intra-dose, end of dose, 1, 2, 4, 6 hours after end of 2 hour oxaliplatin infusion (8 hours) on Day 1 of Cycle 1 and 2
Objective Response Rate (ORR) Per Investigator (INV): Phase 1b (Cohort 1E and 1F)
ORR was defined as percentage of participants with confirmed complete response (CR)/ partial response (PR) per investigator according to response evaluation criteria in solid tumors version 1.1 (RECIST) v1.1. For response to be considered confirmed, subsequent response had to be at least 4 weeks after initial response. CR: complete disappearance of all target lesions with exception of nodal disease and complete disappearance of non-target lesions and normalization of tumor marker level. Any pathological lymph nodes(whether target/ non-target) must have reduction in short axis to \<10 mm. PR: \>= 30% decrease in sum of diameters of target lesions, taking as reference baseline sum of diameters. 90% exact confidence interval (CI) was based on Clopper-Pearson method.
Time frame: From the first dose of study treatment until the first documented CR or PR or before start of any new anti-cancer therapy (up to 24.1 months)
Duration of Response (DOR) Per INV: Phase 1b (Cohort 1E and 1F)
DOR was defined as time from first documented objective response (CR or PR that was subsequently confirmed) to first documented PD per RECIST v1.1 or death due to any cause, whichever occurred first. PD: at least a 20 % increase in sum of diameters of target lesions, taking as reference smallest sum on study (this included the baseline sum if that was the smallest on study). In addition to relative increase of 20%, sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered progression. CR: complete disappearance of all target lesions with exception of nodal disease and complete disappearance of non-target lesions and normalization of tumor marker level. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR: a \>= 30 % decrease in sum of diameters of target lesions, taking as reference the baseline sum of diameters. 90% exact CI was based on Clopper-Pearson method.
Time frame: From the first documented objective response until the first documentation of PD or death due to any cause, whichever occurred first (up to 18.1 months)
Progression Free Survival (PFS) Per INV: Phase 1b (Cohort 1E and 1F)
PFS as per INV was defined as time from the date of treatment initiation to date of documented PD as assessed by INV per RECIST version 1.1 or death from any cause, whichever occurred first. Participants without documentation of progression or death at the time of analysis were censored at the date of the last disease assessment. PD: at least 20 % increase in sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to relative increase of 20%, sum must also demonstrate an absolute increase of at least 5 mm. Appearance of one or more new lesions was also considered progression.
Time frame: From the first dose of study treatment until the first documented PD or death from any cause or censoring date, whichever occurred first (up to 24.1 months)
Overall Survival (OS): Phase 1b (Cohort 1E and 1F)
OS was defined as the time from treatment initiation to death due to any cause. For a participant who was not known to have died by the end of study follow-up, observation of OS was censored on date the participant was last known to be alive (i.e., the date of last contact). Participants lacking data beyond the day of treatment initiation had their survival time censored on date of treatment initiation.
Time frame: From date of start of study treatment until date of death or censoring date
Ctrough of Tucatinib: Phase 1b (Cohort 1E and 1F)
PK parameters were determined using noncompartmental analysis.
Time frame: Predose on Day 1 of Cycle 2
Confirmed Objective Response Rate (cORR) Per INV: Phase 2 (Cohort 2B)
cORR was defined as the percentage of participants with a confirmed CR or 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: complete disappearance of all target lesions with exception of nodal disease and complete disappearance of non-target lesions and normalization of tumor marker level. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR: a \>= 30 % decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. 90% exact CI was based on Clopper-Pearson method.
Time frame: From the first dose of study treatment until the first documented CR or PR or before start of any new anti-cancer therapy (up to 20.9 months)
DOR Per INV: Phase 2 (Cohort 2B)
DOR was defined as time from first documented objective response (CR or PR that was subsequently confirmed) to first documented PD per RECIST v1.1 or death due to any cause, whichever occurred first. PD: at least a 20 % increase in sum of diameters of target lesions, taking as reference smallest sum on study (this included the baseline sum if that was the smallest on study). In addition to relative increase of 20%, sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered progression. CR: complete disappearance of all target lesions with exception of nodal disease and complete disappearance of non-target lesions and normalization of tumor marker level. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR: a \>= 30 % decrease in sum of diameters of target lesions, taking as reference the baseline sum of diameters. 90% exact CI was based on Clopper-Pearson method.
Time frame: From the first documented objective response until the first documentation of PD or death, whichever occurred first (up to 19.9 months)
PFS Per INV: Phase 2 (Cohort 2B)
PFS as per INV was defined as time from the date of treatment initiation to date of documented PD as assessed by INV per RECIST version 1.1 or death from any cause, whichever occurred first. Participants without documentation of progression or death at the time of analysis were censored at the date of the last disease assessment. PD: at least 20 % increase in sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to relative increase of 20%, sum must also demonstrate an absolute increase of at least 5 mm. Appearance of one or more new lesions was also considered progression.
Time frame: From the first dose of study treatment until the first documented PD or death from any cause or censoring date, whichever occurred first (up to 20.9 months)
OS Per INV: Phase 2 (Cohort 2B)
OS was defined as the time from treatment initiation to death due to any cause. For a participant who was not known to have died by the end of study follow-up, observation of OS was censored on date the participant was last known to be alive (i.e., the date of last contact). Participants lacking data beyond the day of treatment initiation had their survival time censored on date of treatment initiation.
Time frame: From date of start of study treatment until date of death or censoring date