Tucatinib, Trastuzumab, Ramucirumab, and Paclitaxel Versus Paclitaxel and Ramucirumab in Previously Treated HER2+ Gastroesophageal Cancer

Gastric Adenocarcinoma Clinical Trial

— MOUNTAINEER-02  

Official title:

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)

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04499924
• Other study ID #: SGNTUC-022
• Status: Active, not recruiting
• Phase: Phase 2/Phase 3
• Start date: March 22, 2021
• Est. completion date: March 31, 2027

Study information

• Verified date: August 2023
• Source: Seagen Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 17
• Est. completion date: March 31, 2027
• Est. primary completion date: May 31, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Adenocarcinoma
• Esophageal Adenocarcinoma
• Esophageal Neoplasms
• Gastric Adenocarcinoma
• Gastroesophageal Junction Adenocarcinoma

Intervention

Drug:
• tucatinib
300 mg given twice daily orally
• 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
• ramucirumab
8 mg/kg will be administered IV on Days 1 and 15 of each cycle
• paclitaxel
60 or 80 mg/m^2 IV on Days 1, 8, and 15 of each cycle

Other:
• tucatinib placebo
Given twice daily orally
• trastuzumab placebo
IV on Days 1 and 15 of each cycle

Locations

Country	Name	City	State
Australia	Central Coast Local Health District (Gosford and Wyong Hospitals)	Gosford
Australia	Austin Health	Heidelberg
Canada	London Regional Cancer Program, London Health Sciences Centre	London	Ontario
Canada	Centre Hospitalier de l'Universite de Montreal	Montreal	Quebec
Canada	McGill University Department of Oncology / McGill University Health Centre	Montreal	Quebec
Korea, Republic of	Dong-A University Hospital	Busan
Korea, Republic of	Kyungpook National University Chilgok Hospital	Daegu
Korea, Republic of	Seoul National University Bundang Hospital	Seongnam-si
Korea, Republic of	Asan Medical Center - Oncology	Seoul
Korea, Republic of	Samsung Medical Center	Seoul
Korea, Republic of	Seoul National University Hospital	Seoul
Korea, Republic of	Severance Hospital, Yonsei University Health System	Seoul
Korea, Republic of	Ajou University Hospital	Suwon-si
Taiwan	Kaohsiung Medical University Hospital	Kaohsiung
Taiwan	National Taiwan University Hospital	Taipei
Taiwan	Taipei Veterans General Hospital	Taipei
United Kingdom	Sarah Cannon Research Institute UK	London
United Kingdom	The Christie NHS Foundation Trust	Manchester
United States	Rocky Mountain Cancer Centers - Aurora	Aurora	Colorado
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	Dana Farber Cancer Institute	Boston	Massachusetts
United States	Roswell Park Cancer Institute	Buffalo	New York
United States	University of Chicago Medical Center	Chicago	Illinois
United States	Cleveland Clinic - Taussig Cancer Institute	Cleveland	Ohio
United States	Texas Oncology - Baylor Sammons Cancer Center	Dallas	Texas
United States	Cancer Centers of Colorado - Denver	Denver	Colorado
United States	City of Hope National Medical Center	Duarte	California
United States	Duke University Medical Center	Durham	North Carolina
United States	Oncology Associates of Oregon	Eugene	Oregon
United States	SCL Health - St. Mary's Hospital & Medical Center	Grand Junction	Colorado
United States	Holden Comprehensive Cancer Center / University of Iowa	Iowa City	Iowa
United States	University of Tennessee	Knoxville	Tennessee
United States	SCL Health Good Samaritan Medical Center Cancer Centers of Colorado	Lafayette	Colorado
United States	Comprehensive Cancer Centers of Nevada	Las Vegas	Nevada
United States	Norton Cancer Institute	Louisville	Kentucky
United States	Tennessee Oncology-Nashville/Sarah Cannon Research Institute	Nashville	Tennessee
United States	University of Pennsylvania / Perelman Center for Advanced Medicine	Philadelphia	Pennsylvania
United States	Mayo Clinic Arizona	Phoenix	Arizona
United States	Allegheny General Hospital	Pittsburgh	Pennsylvania
United States	Minnesota Oncology Hematology P.A.	Saint Paul	Minnesota
United States	Huntsman Cancer Institute/University of Utah	Salt Lake City	Utah
United States	Texas Oncology - San Antonio Medical Center	San Antonio	Texas
United States	UCLA Medical Center / David Geffen School of Medicine	Santa Monica	California
United States	Arizona Cancer Center / University of Arizona	Tucson	Arizona
United States	Texas Oncology - Tyler	Tyler	Texas
United States	Northwest Cancer Specialists, P.C.	Vancouver	Washington
United States	Lombardi Cancer Center / Georgetown University Medical Center	Washington	District of Columbia
United States	Lutheran Medical Center - Cancer Centers of Colorado	Wheat Ridge	Colorado

Sponsors (1)

Lead Sponsor	Collaborator
Seagen Inc.

Countries where clinical trial is conducted

United States,  Australia,  Canada,  Korea, Republic of,  Taiwan,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall survival (OS) (Phase 3 only)	OS is defined as the time from randomization to death due to any cause	60 months
Primary	Progression-free survival (PFS) per Response evaluation criteria in solid tumors (RECIST) version 1.1 according to investigator assessment (Phase 3 only)	PFS is defined as the time from randomization to the date of disease progression or death from any cause	36 months
Primary	Incidence of dose-limiting toxicities (DLTs) (Phase 2 only)		During first cycle of treatment; up to one month
Primary	Incidence of adverse events (AEs) (Phase 2 only)	An adverse event is any untoward medical occurrence in a subject or clinical investigational subject administered a medicinal product and which does not necessarily have a causal relationship with this treatment.	18 months
Primary	Incidence of laboratory abnormalities (Phase 2 only)	To be summarized using descriptive statistics.	18 months
Primary	Incidence of dose modifications (Phase 2 only)		18 months
Secondary	Confirmed objective response rate (ORR) per RECIST version 1.1 according to investigator assessment (Phases 2 and 3)	ORR is defined as the proportion of subjects with best overall response of CR or PR	36 months
Secondary	ORR per RECIST version 1.1 according to investigator assessment (Phases 2 and 3)	ORR is defined as the proportion of subjects with best overall response of CR or PR	36 months
Secondary	Duration of response (DOR) per RECIST version 1.1 according to investigator assessment (Phases 2 and 3)	DOR is defined as the time from first documentation of objective response of CR or PR to the first documentation of disease progression or death from any cause	36 months
Secondary	Disease control rate (DCR) per RECIST version 1.1 according to investigator assessment (Phases 2 and 3)	DCR is defined as subjects with CR, PR, or stable disease (SD or non-CR/non-progressive disease)	36 months
Secondary	PFS per RECIST v1.1 according to blinded independent central review (BICR) assessment (Phase 3 only)	PFS is defined as the time from randomization to the date of disease progression or death from any cause	36 months
Secondary	Confirmed ORR per RECIST version 1.1 according to BICR assessment (Phase 3 only)	ORR is defined as the proportion of subjects with best overall response of CR or PR	36 months
Secondary	ORR per RECIST version 1.1 according to BICR assessment (Phase 3 only)	ORR is defined as the proportion of subjects with best overall response of CR or PR	36 months
Secondary	DOR per RECIST version 1.1 according to BICR assessment (Phase 3 only)	DOR is defined as the time from first documentation of objective response of CR or PR to the first documentation of disease progression or death from any cause	36 months
Secondary	DCR per RECIST version 1.1 according to BICR assessment (Phase 3 only)	DCR is defined as subjects with CR, PR, or stable disease (SD or non-CR/non-progressive disease)	36 months
Secondary	Incidence of AEs (Phase 3 only)	An adverse event is any untoward medical occurrence in a subject or clinical investigational subject administered a medicinal product and which does not necessarily have a causal relationship with this treatment.	36 months
Secondary	Incidence of laboratory abnormalities (Phase 3 only)	To be summarized using descriptive statistics.	36 months
Secondary	Incidence of dose modifications (Phase 3 only)		36 months
Secondary	PFS per RECIST version 1.1 according to investigator assessment (Phase 2 only)	PFS is defined as the time from the date of treatment initiation to the date of disease progression or death from any cause	18 months
Secondary	Area under the plasma concentration-time curve (AUC) to the time of the last quantifiable concentration (AUClast) of tucatinib (Phase 2 only)	Pharmacokinetic (PK) parameter	1 month
Secondary	AUC to AUClast of paclitaxel (Phase 2 only)	PK parameter	1 month
Secondary	Maximum observed concentration (Cmax) of tucatinib (Phase 2 only)	PK parameter	1 month
Secondary	Cmax of paclitaxel (Phase 2 only)	PK parameter	1 month
Secondary	Time of Cmax (Tmax) of tucatinib (Phase 2 only)	PK parameter	1 month
Secondary	Tmax of paclitaxel (Phase 2 only)	PK parameter	1 month
Secondary	Trough concentration (Ctrough) of tucatinib (Phase 2 only)	PK parameter	18 months
Secondary	Ctrough of paclitaxel (Phase 2 only)	PK parameter	18 months
Secondary	Metabolic ratio of tucatinib based on AUC (MRAUC) (Phase 2 only)	PK parameter	1 month
Secondary	MRAUC of paclitaxel (Phase 2 only)	PK parameter	1 month
Secondary	Time to deterioration of GEC symptoms as assessed by the European Organisation for Research and Treatment or Cancer (EORTC) quality of life questionnaire (QLQ)-C30 and EORTC QLQ-OG25 questionnaires.	The EORTC questionnaires measure aspects of health-related quality of life (HRQoL). Time to deterioration will be assessed in specific pre-specified single items from either the EORTC QLQ-C30 or EORTC QLQ OG25 and deterioration is defined as a 10-point increase from baseline in the symptom scales and a 10-point decrease from baseline for overall HRQoL.	36 months
Secondary	Change from baseline in health-related quality of life (HRQoL)		36 months
Secondary	Utility index values as assessed by the EQ-5D-5L	The EQ-5D-5L questionnaire is used as a preference based measurement of HRQoL outcomes. Data will be summarized using descriptive statistics.	36 months