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

Sponsor

Seagen Inc. (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04499924

Collaborator

(none)

578

Enrollment

Locations

Arms

72.3

Anticipated Duration (Months)

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Gastric Adenocarcinoma Gastroesophageal Junction Adenocarcinoma Esophageal Adenocarcinoma	Drug: tucatinib Drug: trastuzumab Drug: ramucirumab Drug: paclitaxel Other: tucatinib placebo Other: trastuzumab placebo	Phase 2/Phase 3

Study Design

Study Type:

Interventional

Anticipated Enrollment :

578 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

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)

Actual Study Start Date :

Mar 22, 2021

Anticipated Primary Completion Date :

May 31, 2025

Anticipated Study Completion Date :

Mar 31, 2027

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

Overall survival (OS) (Phase 3 only) [60 months]
OS is defined as the time from randomization to death due to any cause
Progression-free survival (PFS) per Response evaluation criteria in solid tumors (RECIST) version 1.1 according to investigator assessment (Phase 3 only) [36 months]
PFS is defined as the time from randomization to the date of disease progression or death from any cause
Incidence of dose-limiting toxicities (DLTs) (Phase 2 only) [During first cycle of treatment; up to one month]
Incidence of adverse events (AEs) (Phase 2 only) [18 months]
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.
Incidence of laboratory abnormalities (Phase 2 only) [18 months]
To be summarized using descriptive statistics.
Incidence of dose modifications (Phase 2 only) [18 months]

Secondary Outcome Measures

Confirmed objective response rate (ORR) per RECIST version 1.1 according to investigator assessment (Phases 2 and 3) [36 months]
ORR is defined as the proportion of subjects with best overall response of CR or PR
ORR per RECIST version 1.1 according to investigator assessment (Phases 2 and 3) [36 months]
ORR is defined as the proportion of subjects with best overall response of CR or PR
Duration of response (DOR) per RECIST version 1.1 according to investigator assessment (Phases 2 and 3) [36 months]
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
Disease control rate (DCR) per RECIST version 1.1 according to investigator assessment (Phases 2 and 3) [36 months]
DCR is defined as subjects with CR, PR, or stable disease (SD or non-CR/non-progressive disease)
PFS per RECIST v1.1 according to blinded independent central review (BICR) assessment (Phase 3 only) [36 months]
PFS is defined as the time from randomization to the date of disease progression or death from any cause
Confirmed ORR per RECIST version 1.1 according to BICR assessment (Phase 3 only) [36 months]
ORR is defined as the proportion of subjects with best overall response of CR or PR
ORR per RECIST version 1.1 according to BICR assessment (Phase 3 only) [36 months]
ORR is defined as the proportion of subjects with best overall response of CR or PR
DOR per RECIST version 1.1 according to BICR assessment (Phase 3 only) [36 months]
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
DCR per RECIST version 1.1 according to BICR assessment (Phase 3 only) [36 months]
DCR is defined as subjects with CR, PR, or stable disease (SD or non-CR/non-progressive disease)
Incidence of AEs (Phase 3 only) [36 months]
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.
Incidence of laboratory abnormalities (Phase 3 only) [36 months]
To be summarized using descriptive statistics.
Incidence of dose modifications (Phase 3 only) [36 months]
PFS per RECIST version 1.1 according to investigator assessment (Phase 2 only) [18 months]
PFS is defined as the time from the date of treatment initiation to the date of disease progression or death from any cause
Area under the plasma concentration-time curve (AUC) to the time of the last quantifiable concentration (AUClast) of tucatinib (Phase 2 only) [1 month]
Pharmacokinetic (PK) parameter
AUC to AUClast of paclitaxel (Phase 2 only) [1 month]
PK parameter
Maximum observed concentration (Cmax) of tucatinib (Phase 2 only) [1 month]
PK parameter
Cmax of paclitaxel (Phase 2 only) [1 month]
PK parameter
Time of Cmax (Tmax) of tucatinib (Phase 2 only) [1 month]
PK parameter
Tmax of paclitaxel (Phase 2 only) [1 month]
PK parameter
Trough concentration (Ctrough) of tucatinib (Phase 2 only) [18 months]
PK parameter
Ctrough of paclitaxel (Phase 2 only) [18 months]
PK parameter
Metabolic ratio of tucatinib based on AUC (MRAUC) (Phase 2 only) [1 month]
PK parameter
MRAUC of paclitaxel (Phase 2 only) [1 month]
PK parameter
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. [36 months]
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.
Change from baseline in health-related quality of life (HRQoL) [36 months]
Utility index values as assessed by the EQ-5D-5L [36 months]
The EQ-5D-5L questionnaire is used as a preference based measurement of HRQoL outcomes. Data will be summarized using descriptive statistics.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham	Birmingham	Alabama	United States	35249
2	Mayo Clinic Arizona	Phoenix	Arizona	United States	85054
3	Arizona Cancer Center / University of Arizona	Tucson	Arizona	United States	85724-5024
4	City of Hope National Medical Center	Duarte	California	United States	91010
5	UCLA Medical Center / David Geffen School of Medicine	Santa Monica	California	United States	90404
6	Rocky Mountain Cancer Centers - Aurora	Aurora	Colorado	United States	80012
7	Cancer Centers of Colorado - Denver	Denver	Colorado	United States	80218
8	SCL Health - St. Mary's Hospital & Medical Center	Grand Junction	Colorado	United States	81501
9	SCL Health Good Samaritan Medical Center Cancer Centers of Colorado	Lafayette	Colorado	United States	80026
10	Lutheran Medical Center - Cancer Centers of Colorado	Wheat Ridge	Colorado	United States	80033
11	Lombardi Cancer Center / Georgetown University Medical Center	Washington	District of Columbia	United States	20007
12	University of Chicago Medical Center	Chicago	Illinois	United States	60637-1470
13	Holden Comprehensive Cancer Center / University of Iowa	Iowa City	Iowa	United States	52242
14	Norton Cancer Institute	Louisville	Kentucky	United States	40217
15	Dana Farber Cancer Institute	Boston	Massachusetts	United States	02215
16	Minnesota Oncology Hematology P.A.	Saint Paul	Minnesota	United States	55102
17	Comprehensive Cancer Centers of Nevada	Las Vegas	Nevada	United States	89169
18	Roswell Park Cancer Institute	Buffalo	New York	United States	14203
19	Duke University Medical Center	Durham	North Carolina	United States	27710
20	Cleveland Clinic - Taussig Cancer Institute	Cleveland	Ohio	United States	44195
21	Oncology Associates of Oregon	Eugene	Oregon	United States	97401
22	University of Pennsylvania / Perelman Center for Advanced Medicine	Philadelphia	Pennsylvania	United States	19104
23	Allegheny General Hospital	Pittsburgh	Pennsylvania	United States	15212
24	University of Tennessee	Knoxville	Tennessee	United States	37920
25	Tennessee Oncology-Nashville/Sarah Cannon Research Institute	Nashville	Tennessee	United States	37203
26	Texas Oncology - Baylor Sammons Cancer Center	Dallas	Texas	United States	75246
27	Texas Oncology - San Antonio Medical Center	San Antonio	Texas	United States	78217
28	Texas Oncology - Tyler	Tyler	Texas	United States	75702
29	Huntsman Cancer Institute/University of Utah	Salt Lake City	Utah	United States	84112
30	Northwest Cancer Specialists, P.C.	Vancouver	Washington	United States	98684
31	Central Coast Local Health District (Gosford and Wyong Hospitals)	Gosford	Other	Australia	2250
32	Austin Health	Heidelberg	Other	Australia
33	London Regional Cancer Program, London Health Sciences Centre	London, ON	Other	Canada	N6A 5W9
34	Centre Hospitalier de l'Universite de Montreal	Montreal	Quebec	Canada	H2X 3E4
35	McGill University Department of Oncology / McGill University Health Centre	Montreal	Quebec	Canada	H4A 3J1
36	Dong-A University Hospital	Busan	Other	Korea, Republic of	49201
37	Kyungpook National University Chilgok Hospital	Daegu	Other	Korea, Republic of	41404
38	Seoul National University Bundang Hospital	Seongnam-si	Other	Korea, Republic of	13605
39	Seoul National University Hospital	Seoul	Other	Korea, Republic of	03080
40	Severance Hospital, Yonsei University Health System	Seoul	Other	Korea, Republic of	03722
41	Asan Medical Center - Oncology	Seoul	Other	Korea, Republic of	05505
42	Samsung Medical Center	Seoul	Other	Korea, Republic of	06351
43	Ajou University Hospital	Suwon-si	Other	Korea, Republic of	16499
44	Kaohsiung Medical University Hospital	Kaohsiung	Other	Taiwan	807
45	National Taiwan University Hospital	Taipei	Other	Taiwan	10002
46	Taipei Veterans General Hospital	Taipei	Other	Taiwan	11217
47	Sarah Cannon Research Institute UK	London	Other	United Kingdom	W3 0ER
48	The Christie NHS Foundation Trust	Manchester	Other	United Kingdom	M20 4BX