MOUNTAINEER-02: Tucatinib, Trastuzumab, Ramucirumab, and Paclitaxel Versus Paclitaxel and Ramucirumab in Previously Treated HER2+ Gastroesophageal Cancer
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 |
---|---|---|
|
Phase 2/Phase 3 |
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
---|---|
Experimental: Phase 2 Arm Tucatinib + trastuzumab + ramucirumab + paclitaxel |
Drug: tucatinib
300 mg given twice daily orally
Other Names:
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:
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:
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:
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:
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:
Drug: ramucirumab
8 mg/kg will be administered IV on Days 1 and 15 of each cycle
Other Names:
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
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
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Progressive disease during or after first-line therapy for locally-advanced unresectable or metastatic GEC
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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
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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 |
Sponsors and Collaborators
- Seagen Inc.
Investigators
- Study Director: Joal Mayor, PharmD, BCOP, Seagen Inc.
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- SGNTUC-022