Tucatinib, Trastuzumab, Ramucirumab, and Paclitaxel Versus Paclitaxel and Ramucirumab in Previously Treated HER2+ Gastroesophageal Cancer (MOUNTAINEER-02)

A Randomized, Double-blind, Placebo-controlled, Active Comparator Phase 2/3 Study of Tucatinib in Combination With Trastuzumab, Ramucirumab, and Paclitaxel in Subjects With Previously Treated, Locally-advanced Unresectable or Metastatic HER2+ Gastric or Gastroesophageal Junction Adenocarcinoma (GEC)

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 Overview

• Status: Completed
• Conditions: Gastric Adenocarcinoma; Esophageal Adenocarcinoma; Gastroesophageal Junction Adenocarcinoma
• Intervention / Treatment: Drug: tucatinib; Drug: trastuzumab; Drug: ramucirumab; Drug: paclitaxel; Other: tucatinib placebo; Other: trastuzumab placebo

• Study Type: Interventional
• Enrollment (Actual): 17
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Australia
  • Gosford, Australia, 2250
    • Central Coast Local Health District (Gosford and Wyong Hospitals)
  • Heidelberg, Australia, 63V6 63
    • Austin Health
• Canada
  • Ontario
    • London, Ontario, Canada, N6A 5W9
      • London Regional Cancer Program, London Health Sciences Centre
  • Quebec
    • Montreal, Quebec, Canada, H2X 3E4
      • Centre Hospitalier de l'Université de Montréal
    • Montreal, Quebec, Canada, H4A 3J1
      • McGill University Department of Oncology / McGill University Health Centre
• Korea, Republic of
  • Busan, Korea, Republic of, 49201
    • Dong-A University Hospital
  • Daegu, Korea, Republic of, 41404
    • Kyungpook National University Chilgok Hospital
  • Seongnam-si, Korea, Republic of, 13605
    • Seoul National University Bundang Hospital
  • Seoul, Korea, Republic of, 03080
    • Seoul National University Hospital
  • Seoul, Korea, Republic of, 03722
    • Severance Hospital, Yonsei University Health System
  • Seoul, Korea, Republic of, 06351
    • Samsung Medical Center
  • Seoul, Korea, Republic of, 05505
    • Asan Medical Center - Oncology
  • Suwon-si, Korea, Republic of, 16499
    • Ajou University Hospital
• Taiwan
  • Kaohsiung, Taiwan, 807
    • Kaohsiung Medical University Hospital
  • Taipei, Taiwan, 10002
    • National Taiwan University Hospital
  • Taipei, Taiwan, 11217
    • Taipei Veterans General Hospital
• United Kingdom
  • London, United Kingdom, W3 0ER
    • Sarah Cannon Research Institute UK
  • Manchester, United Kingdom, M20 4BX
    • The Christie NHS Foundation Trust
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35249
      • University of Alabama at Birmingham
  • Arizona
    • Phoenix, Arizona, United States, 85054
      • Mayo Clinic Arizona
    • Tucson, Arizona, United States, 85724
      • Arizona Cancer Center / University of Arizona
  • California
    • Duarte, California, United States, 91010
      • City of Hope National Medical Center
    • Santa Monica, California, United States, 90404
      • UCLA Medical Center / David Geffen School of Medicine
  • Colorado
    • Aurora, Colorado, United States, 80012
      • Rocky Mountain Cancer Centers - Aurora
    • Denver, Colorado, United States, 80218
      • Cancer Centers of Colorado - Denver
    • Grand Junction, Colorado, United States, 81501
      • SCL Health - St. Mary's Hospital & Medical Center
    • Lafayette, Colorado, United States, 80026
      • SCL Health Good Samaritan Medical Center Cancer Centers of Colorado
    • Wheat Ridge, Colorado, United States, 80033
      • Lutheran Medical Center - Cancer Centers of Colorado
  • District of Columbia
    • Washington, District of Columbia, United States, 20007
      • Lombardi Cancer Center / Georgetown University Medical Center
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago Medical Center
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • Holden Comprehensive Cancer Center / University of Iowa
  • Kentucky
    • Louisville, Kentucky, United States, 40217
      • Norton Cancer Institute
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana Farber Cancer Institute
  • Minnesota
    • Saint Paul, Minnesota, United States, 55102
      • Minnesota Oncology Hematology P.A.
  • Nevada
    • Las Vegas, Nevada, United States, 89169
      • Comprehensive Cancer Centers of Nevada
  • New York
    • Buffalo, New York, United States, 14203
      • Roswell Park Cancer Institute
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic - Taussig Cancer Institute
  • Oregon
    • Eugene, Oregon, United States, 97401
      • Oncology Associates of Oregon
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania / Perelman Center for Advanced Medicine
    • Pittsburgh, Pennsylvania, United States, 15212
      • Allegheny General Hospital
  • Tennessee
    • Knoxville, Tennessee, United States, 37920
      • University of Tennessee
    • Nashville, Tennessee, United States, 37203
      • Tennessee Oncology-Nashville/Sarah Cannon Research Institute
  • Texas
    • Dallas, Texas, United States, 75246
      • Texas Oncology - Baylor Sammons Cancer Center
    • San Antonio, Texas, United States, 78217
      • Texas Oncology - San Antonio Medical Center
    • Tyler, Texas, United States, 75702
      • Texas Oncology - Tyler
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • Huntsman Cancer Institute/University of Utah
  • Washington
    • Vancouver, Washington, United States, 98684
      • Northwest Cancer Specialists, P.C.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 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

Exclusion Criteria:

• 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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Phase 2 Arm; Tucatinib + trastuzumab + ramucirumab + paclitaxel	Drug: tucatinib; 300 mg given twice daily orally; Other Names: TUKYSA, ONT-380, ARRY-380; Drug: trastuzumab; 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; Drug: ramucirumab; 8 mg/kg will be administered IV on Days 1 and 15 of each cycle; Other Names: CYRAMZA; Drug: paclitaxel; 60 or 80 mg/m^2 IV on Days 1, 8, and 15 of each cycle
Experimental: Arm 3A; Tucatinib + trastuzumab + ramucirumab + paclitaxel	Drug: tucatinib; 300 mg given twice daily orally; Other Names: TUKYSA, ONT-380, ARRY-380; Drug: trastuzumab; 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; Drug: ramucirumab; 8 mg/kg will be administered IV on Days 1 and 15 of each cycle; Other Names: CYRAMZA; Drug: paclitaxel; 60 or 80 mg/m^2 IV on Days 1, 8, and 15 of each cycle
Active Comparator: Arm 3B; Ramucirumab + paclitaxel + tucatinib placebo + trastuzumab placebo	Drug: ramucirumab; 8 mg/kg will be administered IV on Days 1 and 15 of each cycle; Other Names: CYRAMZA; Drug: paclitaxel; 60 or 80 mg/m^2 IV on Days 1, 8, and 15 of each cycle; Other: tucatinib placebo; Given twice daily orally; Other: trastuzumab placebo; IV on Days 1 and 15 of each cycle
Experimental: Arm 3C; Tucatinib + ramucirumab + paclitaxel + trastuzumab placebo	Drug: tucatinib; 300 mg given twice daily orally; Other Names: TUKYSA, ONT-380, ARRY-380; Drug: ramucirumab; 8 mg/kg will be administered IV on Days 1 and 15 of each cycle; Other Names: CYRAMZA; Drug: paclitaxel; 60 or 80 mg/m^2 IV on Days 1, 8, and 15 of each cycle; Other: trastuzumab placebo; IV on Days 1 and 15 of each cycle

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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).	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.	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.	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.	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.	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)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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.	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	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.	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.	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.	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).	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.	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.	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.	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.	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)

Collaborators and Investigators

• Sponsor: Seagen Inc.
• Investigators: Study Director: JoAl Mayor, PharmD, BCOP, Seagen Inc.; Study Director: Michelle Ubowski, PharmD, Seagen Inc.

Study record dates

Study Major Dates

• Study Start (Actual): March 22, 2021
• Primary Completion (Actual): April 17, 2024
• Study Completion (Actual): April 17, 2024

Study Registration Dates

• First Submitted: July 31, 2020
• First Submitted That Met QC Criteria: July 31, 2020
• First Posted (Actual): August 5, 2020

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: December 30, 2024
• Last Verified: December 1, 2024

More Information

Terms related to this study

• Keywords: Seattle Genetics; HER2-positive; HER2+; GEJ; GEC; GEA
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Head and Neck Neoplasms; Neoplasms, Glandular and Epithelial; Esophageal Diseases; Carcinoma; Esophageal Neoplasms; Adenocarcinoma; Antineoplastic Agents, Immunological; Antineoplastic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protein Kinase Inhibitors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Trastuzumab; Tucatinib; Ramucirumab; Paclitaxel
• Other Study ID Numbers: SGNTUC-022; C4251004 (Other Identifier: Pfizer)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No