This study is being done to see if tucatinib with trastuzumab, ramucirumab and paclitaxel works better than ramucirumab and paclitaxel to treat HER2-positive (HER2+) cancer of the gut (stomach or gastroesophageal cancer). This study will also 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. Study treatment will be given in 28-day cycles. In the Phase 2 part of the trial, participants and their doctors will know what drugs are being given (open-label). In the Phase 3 part, the study is "blinded." This means that participants, their doctor, and the study sponsor will not know which drugs are being given.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
17
300 mg given twice daily orally
6 mg/kg loading dose will be administered intravenously (IV; into the vein) on Cycle 1 Day 1, followed by 4 mg/kg IV on Cycle 1 Day 15 and then Days 1 and 15 of each cycle thereafter
8 mg/kg will be administered IV on Days 1 and 15 of each cycle
60 or 80 mg/m\^2 IV on Days 1, 8, and 15 of each cycle
Given twice daily orally
IV on Days 1 and 15 of each cycle
University of Alabama at Birmingham
Birmingham, Alabama, United States
Mayo Clinic Arizona
Phoenix, Arizona, United States
Arizona Cancer Center / University of Arizona
Tucson, Arizona, United States
City of Hope National Medical Center
Duarte, California, United States
UCLA Medical Center / David Geffen School of Medicine
Santa Monica, California, United States
Number of Participants With Dose-limiting Toxicities (DLT) During the First Cycle of Treatment
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.
Time frame: Cycle 1 (28 days)
Number of Participants With Treatment-emergent Adverse Events (TEAEs)
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).
Time frame: From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment (maximum treatment duration= 19.8 months, maximum follow-up duration up to 20.8 months)
Number of Participants With Treatment-emergent Laboratory Abnormalities
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.
Time frame: From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment (maximum treatment duration= 19.8 months, maximum follow-up duration up to 20.8 months)
Number of Participants With Clinically Significant Vital Signs Values
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.
Time frame: From first dose of the study treatment (Day 1) up to 30 days after the last dose of study treatment (maximum treatment duration= 19.8 months, maximum follow-up duration up to 20.8 months)
Maximum Percentage Change From Baseline in Weight
Maximum percentage decrease from baseline in weight is reported in this outcome measure.
Time frame: From Baseline (Day 1) up to 30 days after the last dose of study treatment (maximum treatment duration= 19.8 months, maximum follow-up duration up to 20.8 months)
Number of Participants With Any Dose Modifications
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.
Time frame: From first dose of the study treatment (Day 1) up to the last dose of study treatment (maximum treatment duration up to 19.8 months)
Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors (RECIST) Version (v) 1.1 By Investigator Assessment
ORR was defined as the percentage of participants with best overall response of complete response (CR) or partial response (PR) according to RECIST v 1.1 by investigator assessment. As per RECIST v1.1, CR was defined as disappearance of all target and non-target lesions and normalization of tumor markers. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (\<) 10 millimeter (mm). PR was defined as at least a 30 % decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. As per RECIST v1.1, disease progression (PD) was defined as one of the following: at least a 20% increase in the sum of diameters of target lesions (taking as reference the smallest sum on study) with an absolute increase of at least 5mm, unequivocal progression of existing non-target lesions, or the appearance of one or more new lesions.
Time frame: From the first dose of study treatment until the first documented CR or PR on or before the first documented PD or new anti-cancer therapies or death, whichever occurred first (up to 19.8 months)
Confirmed ORR Per RECIST v1.1 By Investigator Assessment
Confirmed ORR was defined as the percentage of participants with best overall response of confirmed CR or PR according to RECIST v1.1 by investigator assessment. For a response to be confirmed, the subsequent response needs to be at least 4 weeks after the initial response. As per RECIST v1.1, CR was defined as disappearance of all target and non-target lesions and normalization of tumor markers. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm. PR was defined as at least a 30 % decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. As per RECIST v1.1, disease progression (PD) was defined as one of the following: at least a 20% increase in the sum of diameters of target lesions (taking as reference the smallest sum on study) with an absolute increase of at least 5mm, unequivocal progression of existing non-target lesions, or the appearance of one or more new lesions.
Time frame: From the first dose of study treatment until the first documented confirmed CR or PR or before the first documented PD or new anti-cancer therapies or death, whichever occurred first (up to 19.8 months)
Progression-Free Survival (PFS) Per RECIST v1.1 By Investigator Assessment
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Rocky Mountain Cancer Centers - Aurora
Aurora, Colorado, United States
Cancer Centers of Colorado - Denver
Denver, Colorado, United States
SCL Health - St. Mary's Hospital & Medical Center
Grand Junction, Colorado, United States
SCL Health Good Samaritan Medical Center Cancer Centers of Colorado
Lafayette, Colorado, United States
Lutheran Medical Center - Cancer Centers of Colorado
Wheat Ridge, Colorado, United States
...and 38 more locations
PFS was defined as the time from the date of treatment initiation to the date of documented PD or death from any cause, whichever occurred first per RECIST version 1.1 by investigator assessment. As per RECIST v1.1, disease progression (PD) was defined as one of the following: at least a 20% increase in the sum of diameters (SOD) of target lesions (taking as reference the smallest sum on study) with an absolute increase of at least 5mm, unequivocal progression of existing non-target lesions, or the appearance of one or more new lesions. Participants without documentation of PD or death at the time of analysis were censored at the date of the last tumor assessment. Kaplan-Meier method was used for evaluation.
Time frame: From the date of first dose until the first documentation of PD or death or censoring date, whichever occurred first (up to 19.8 months)
Duration of Response (DOR) Per RECIST v1.1 By Investigator Assessment
DOR: time from first documentation of objective response of CR or PR to first documentation of PD or death from any cause, whichever occurred first according to RECIST v1.1 by investigator assessment. As per RECIST v1.1, CR: disappearance of all target and non-target lesions and normalization of tumor markers. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10mm. PR: at least a 30% decrease in sum of diameters of target lesions, taking as reference baseline sum diameters. PD was defined as one of the following: at least a 20% increase in sum of diameters of target lesions (taking as reference the smallest sum on study) with an absolute increase of at least 5mm, unequivocal progression of existing non-target lesions, or appearance of one or more new lesions. Participants without documentation of PD or death at time of analysis were censored at the date of last tumor assessment. Kaplan-Meier method was used for evaluation.
Time frame: From the first documented CR or PR until the first documentation of PD or death or censoring date, whichever occurred first (up to 19.8 months)
Disease Control Rate (DCR) Per RECIST v1.1 By Investigator Assessment
DCR was defined as percentage of participants with CR, PR, or stable disease (SD or non-CR/non-progressive disease) according to RECIST v1.1 by investigator assessment. As per RECIST v1.1, CR was defined as disappearance of all target and non-target lesions and normalization of tumor markers. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm. PR was defined as at least a 30 % decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters. PD was defined as one of following: at least a 20% increase in the sum of diameters of target lesions (taking as reference the smallest sum on study) with an absolute increase of at least 5mm, unequivocal progression of existing non-target lesions, or appearance of one or more new lesions. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference smallest sum of diameters.
Time frame: From the first dose study treatment until PD or death, whichever occurred first (up to 19.8 months)
Area Under the Plasma Concentration-time Curve to the Time of the Last Quantifiable Concentration (AUClast) of Paclitaxel, Tucatinib and Their Metabolites
AUClast was reported for tucatinib, tucatinib metabolite (ONT-993), paclitaxel and paclitaxel metabolites (6 alpha-hydroxy-paclitaxel, 3'-p-hydroxy-paclitaxel and 6 alpha-3'-p-Dihydroxy-paclitaxel).
Time frame: Tucatinib and ONT-993- Cycle 1 Day 8, Cycle 2 Day 1: Pre-dose, 2, 4, 6, 8 hours post-dose; Paclitaxel and its metabolites- Cycle 1 Days 1 and 8, Cycle 2 Day 1: Pre-dose, 2, 4, 6, 8 hours post-dose (each cycle length=28 days)
Maximum Observed Plasma Concentration (Cmax)
Cmax was reported for tucatinib and tucatinib metabolite ONT-993.
Time frame: Tucatinib and ONT-993- Cycle 1 Day 8, Cycle 2 Day 1: Pre-dose, 2, 4, 6, 8 hours post-dose (each cycle length=28 days)
Time to Maximum Observed Plasma Concentration (Tmax)
Tmax was reported for tucatinib and tucatinib metabolite ONT-993.
Time frame: Tucatinib and ONT-993- Cycle 1 Day 8, Cycle 2 Day 1: Pre-dose, 2, 4, 6, 8 hours post-dose (each cycle length=28 days)
Trough Concentration (Ctrough)
Ctrough was calculated for tucatinib and tucatinib metabolite ONT-993.
Time frame: Tucatinib and ONT-993- Cycle 1 Day 8, Cycle 2 Day 1: Predose (each cycle length=28 days)
Metabolite Ratio Based on AUClast (MRAUClast)
MRAUClast was defined as metabolic ratio, that is, ratio of the AUClast of a given paclitaxel metabolite over the AUClast of paclitaxel. MRAUClast for 6 alpha-hydroxypaclitaxel, 3-p-hydroxy-paclitaxel and 6 alpha-3-p-dihydroxy-paclitaxel was reported in this outcome measure.
Time frame: Paclitaxel and its metabolites- Cycle 1 Days 1 and 8, Cycle 2 Day 1: Pre-dose, 2, 4, 6, 8 hours post-dose (each cycle length=28 days)