Tucatinib, Trastuzumab, Ramucirumab, and Paclitaxel Versus Paclitaxel and Ramucirumab in Previously Treated HER2+ Gastroesophageal Cancer
- Conditions
- Gastric AdenocarcinomaGastroesophageal Junction AdenocarcinomaEsophageal Adenocarcinoma
- Interventions
- Other: tucatinib placeboOther: trastuzumab placebo
- Registration Number
- NCT04499924
- Lead Sponsor
- Seagen Inc.
- Brief Summary
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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 17
-
Histologically or cytologically confirmed diagnosis of locally-advanced unresectable or metastatic HER2+ gastric or gastroesophageal junction adenocarcinoma (GEC)
-
HER2+ disease documented since progression of the most recent line of systemic therapy, as follows:
-
Phase 2 paclitaxel dose optimization stage:
- HER2 amplification in a blood-based NGS assay performed at a central laboratory, or
- HER2 overexpression/amplification immunohistochemistry (IHC) and in situ hybridization (ISH) (IHC3+ or IHC2+/ISH+) assay of a tumor tissue sample
-
Phase 2 dose expansion stage:
- Cohort 2A: HER2 amplification in a blood-based NGS assay performed at a central laboratory
- Cohort 2B: No HER2 amplification by blood-based NGS assay, but HER2 overexpression/amplification by IHC and ISH (IHC3+ or IHC2+/ISH+) assay of a tumor tissue sample
-
Phase 3: HER2 amplification in a blood-based NGS assay performed at a central laboratory
-
-
History of prior treatment with a HER2-directed antibody
-
Progressive disease during or after first-line therapy for locally-advanced unresectable or metastatic GEC
-
Phase 2: Measurable disease according to RECIST version 1.1
-
Phase 3: Measurable or non-measurable disease according to RECIST version 1.1
-
Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1
-
Life expectancy of at least 3 months, in the opinion of the investigator
- Subjects with squamous cell or undifferentiated GEC
- Having received more than 1 line of prior systemic therapy for locally-advanced unresectable or metastatic disease
- Having received taxanes ≤12 months prior to enrollment, prior treatment with ramucirumab, or prior treatment with tucatinib, lapatinib, neratinib, afatinib, or any other investigational anti-HER2 and/or anti-EGFR tyrosine kinase inhibitor, or with T-DM1, T-Dxd, or any other HER2-directed antibody-drug conjugate
- Phase 2 paclitaxel dose optimization stage only: history of prior partial or total gastrectomy
- Unable to swallow pills
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Phase 2 Arm trastuzumab Tucatinib + trastuzumab + ramucirumab + paclitaxel Phase 2 Arm ramucirumab Tucatinib + trastuzumab + ramucirumab + paclitaxel Phase 2 Arm paclitaxel Tucatinib + trastuzumab + ramucirumab + paclitaxel Arm 3A trastuzumab Tucatinib + trastuzumab + ramucirumab + paclitaxel Arm 3B trastuzumab placebo Ramucirumab + paclitaxel + tucatinib placebo + trastuzumab placebo Arm 3C tucatinib Tucatinib + ramucirumab + paclitaxel + trastuzumab placebo Arm 3B tucatinib placebo Ramucirumab + paclitaxel + tucatinib placebo + trastuzumab placebo Arm 3C paclitaxel Tucatinib + ramucirumab + paclitaxel + trastuzumab placebo Arm 3B ramucirumab Ramucirumab + paclitaxel + tucatinib placebo + trastuzumab placebo Arm 3B paclitaxel Ramucirumab + paclitaxel + tucatinib placebo + trastuzumab placebo Arm 3C ramucirumab Tucatinib + ramucirumab + paclitaxel + trastuzumab placebo Arm 3C trastuzumab placebo Tucatinib + ramucirumab + paclitaxel + trastuzumab placebo Phase 2 Arm tucatinib Tucatinib + trastuzumab + ramucirumab + paclitaxel Arm 3A tucatinib Tucatinib + trastuzumab + ramucirumab + paclitaxel Arm 3A ramucirumab Tucatinib + trastuzumab + ramucirumab + paclitaxel Arm 3A paclitaxel Tucatinib + trastuzumab + ramucirumab + paclitaxel
- Primary Outcome Measures
Name Time Method Number of Participants With Dose-limiting Toxicities (DLT) During the First Cycle of Treatment Cycle 1 (28 days) 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.
Number of Participants With Treatment-emergent Adverse Events (TEAEs) 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) 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).
Maximum Percentage Change From Baseline in Weight 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) Maximum percentage decrease from baseline in weight is reported in this outcome measure.
Number of Participants With Any Dose Modifications 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) 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.
Number of Participants With Treatment-emergent Laboratory Abnormalities 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) 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.
Number of Participants With Clinically Significant Vital Signs Values 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) 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.
- Secondary Outcome Measures
Name Time Method Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors (RECIST) Version (v) 1.1 By Investigator Assessment 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) 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.
Confirmed ORR Per RECIST v1.1 By Investigator Assessment 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) 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.
Progression-Free Survival (PFS) Per RECIST v1.1 By Investigator Assessment 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) 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.
Duration of Response (DOR) Per RECIST v1.1 By Investigator Assessment 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) 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.
Disease Control Rate (DCR) Per RECIST v1.1 By Investigator Assessment From the first dose study treatment until PD or death, whichever occurred first (up to 19.8 months) 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.
Area Under the Plasma Concentration-time Curve to the Time of the Last Quantifiable Concentration (AUClast) of Paclitaxel, Tucatinib and Their Metabolites 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) 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).
Maximum Observed Plasma Concentration (Cmax) 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) Cmax was reported for tucatinib and tucatinib metabolite ONT-993.
Time to Maximum Observed Plasma Concentration (Tmax) 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) Tmax was reported for tucatinib and tucatinib metabolite ONT-993.
Trough Concentration (Ctrough) Tucatinib and ONT-993- Cycle 1 Day 8, Cycle 2 Day 1: Predose (each cycle length=28 days) Ctrough was calculated for tucatinib and tucatinib metabolite ONT-993.
Metabolite Ratio Based on AUClast (MRAUClast) 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) 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.
Trial Locations
- Locations (48)
University of Chicago Medical Center
🇺🇸Chicago, Illinois, United States
Comprehensive Cancer Centers of Nevada
🇺🇸Las Vegas, Nevada, United States
Duke University Medical Center
🇺🇸Durham, North Carolina, United States
Cancer Centers of Colorado - Denver
🇺🇸Denver, Colorado, United States
Lutheran Medical Center - Cancer Centers of Colorado
🇺🇸Wheat Ridge, Colorado, United States
SCL Health - St. Mary's Hospital & Medical Center
🇺🇸Grand Junction, Colorado, United States
Rocky Mountain Cancer Centers - Aurora
🇺🇸Aurora, Colorado, United States
SCL Health Good Samaritan Medical Center Cancer Centers of Colorado
🇺🇸Lafayette, Colorado, United States
Mayo Clinic Arizona
🇺🇸Phoenix, Arizona, United States
McGill University Department of Oncology / McGill University Health Centre
🇨🇦Montreal, Quebec, Canada
Dong-A University Hospital
🇰🇷Busan, Korea, Republic of
Oncology Associates of Oregon
🇺🇸Eugene, Oregon, United States
Centre Hospitalier de l'Universite de Montreal
🇨🇦Montreal, Quebec, Canada
Lombardi Cancer Center / Georgetown University Medical Center
🇺🇸Washington, District of Columbia, United States
Kyungpook National University Chilgok Hospital
🇰🇷Daegu, Korea, Republic of
Dana Farber Cancer Institute
🇺🇸Boston, Massachusetts, United States
Severance Hospital, Yonsei University Health System
🇰🇷Seoul, Korea, Republic of
University of Tennessee
🇺🇸Knoxville, Tennessee, United States
City of Hope National Medical Center
🇺🇸Duarte, California, United States
Seoul National University Bundang Hospital
🇰🇷Seongnam-si, Korea, Republic of
Asan Medical Center - Oncology
🇰🇷Seoul, Korea, Republic of
University of Alabama at Birmingham
🇺🇸Birmingham, Alabama, United States
Minnesota Oncology Hematology P.A.
🇺🇸Saint Paul, Minnesota, United States
Allegheny General Hospital
🇺🇸Pittsburgh, Pennsylvania, United States
Tennessee Oncology-Nashville/Sarah Cannon Research Institute
🇺🇸Nashville, Tennessee, United States
Texas Oncology - Baylor Sammons Cancer Center
🇺🇸Dallas, Texas, United States
Texas Oncology - San Antonio Medical Center
🇺🇸San Antonio, Texas, United States
Huntsman Cancer Institute/University of Utah
🇺🇸Salt Lake City, Utah, United States
Texas Oncology - Tyler
🇺🇸Tyler, Texas, United States
Northwest Cancer Specialists, P.C.
🇺🇸Vancouver, Washington, United States
London Regional Cancer Program, London Health Sciences Centre
🇨🇦London, Ontario, Canada
Central Coast Local Health District (Gosford and Wyong Hospitals)
🇦🇺Gosford, Australia
Austin Health
🇦🇺Heidelberg, Australia
Seoul National University Hospital
🇰🇷Seoul, Korea, Republic of
Samsung Medical Center
🇰🇷Seoul, Korea, Republic of
Ajou University Hospital
🇰🇷Suwon-si, Korea, Republic of
National Taiwan University Hospital
🇨🇳Taipei, Taiwan
Kaohsiung Medical University Hospital
🇨🇳Kaohsiung, Taiwan
Taipei Veterans General Hospital
🇨🇳Taipei, Taiwan
The Christie NHS Foundation Trust
🇬🇧Manchester, United Kingdom
Arizona Cancer Center / University of Arizona
🇺🇸Tucson, Arizona, United States
UCLA Medical Center / David Geffen School of Medicine
🇺🇸Santa Monica, California, United States
Norton Cancer Institute
🇺🇸Louisville, Kentucky, United States
Holden Comprehensive Cancer Center / University of Iowa
🇺🇸Iowa City, Iowa, United States
Roswell Park Cancer Institute
🇺🇸Buffalo, New York, United States
Cleveland Clinic - Taussig Cancer Institute
🇺🇸Cleveland, Ohio, United States
University of Pennsylvania / Perelman Center for Advanced Medicine
🇺🇸Philadelphia, Pennsylvania, United States
Sarah Cannon Research Institute UK
🇬🇧London, United Kingdom