Clinical trial NCT04499924: Tucatinib, Trastuzumab, Ramucirumab, and Paclitaxel Versus Paclitaxel and Ramucirumab in Previously Treated HER2+ Gastroesophageal Cancer
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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Gastric Adenocarcinoma
Gastroesophageal Junction Adenocarcinoma
Esophageal Adenocarcinoma
Keywords: HER2+
HER2-positive
GEA
GEC
GEJ
Seattle Genetics
Lead sponsor: Seagen Inc.
Sponsor class: INDUSTRY
First posted: 2020-08-05
Enrollment: 17
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility 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
* 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

Primary outcomes:
measure: Number of Participants With Dose-limiting Toxicities (DLT) During the First Cycle of Treatment
timeFrame: Cycle 1 (28 days)
measure: Number of Participants With Treatment-emergent Adverse Events (TEAEs)
timeFrame: 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)
measure: Number of Participants With Treatment-emergent Laboratory Abnormalities
timeFrame: 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)
measure: Number of Participants With Clinically Significant Vital Signs Values
timeFrame: 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)
measure: Maximum Percentage Change From Baseline in Weight
timeFrame: 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)
measure: Number of Participants With Any Dose Modifications
timeFrame: 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 outcomes:
measure: Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors (RECIST) Version (v) 1.1 By Investigator Assessment
timeFrame: 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)
measure: Confirmed ORR Per RECIST v1.1 By Investigator Assessment
timeFrame: 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)
measure: Progression-Free Survival (PFS) Per RECIST v1.1 By Investigator Assessment
timeFrame: 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)
measure: Duration of Response (DOR) Per RECIST v1.1 By Investigator Assessment
timeFrame: 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)
measure: Disease Control Rate (DCR) Per RECIST v1.1 By Investigator Assessment
timeFrame: From the first dose study treatment until PD or death, whichever occurred first (up to 19.8 months)
measure: Area Under the Plasma Concentration-time Curve to the Time of the Last Quantifiable Concentration (AUClast) of Paclitaxel, Tucatinib and Their Metabolites
timeFrame: 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)
measure: Maximum Observed Plasma Concentration (Cmax)
timeFrame: 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)
measure: Time to Maximum Observed Plasma Concentration (Tmax)
timeFrame: 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)
measure: Trough Concentration (Ctrough)
timeFrame: Tucatinib and ONT-993- Cycle 1 Day 8, Cycle 2 Day 1: Predose (each cycle length=28 days)
measure: Metabolite Ratio Based on AUClast (MRAUClast)
timeFrame: 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)
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Phoenix
country: United States
facility: Mayo Clinic Arizona
state: Arizona
city: Tucson
country: United States
facility: Arizona Cancer Center / University of Arizona
state: Arizona
city: Duarte
country: United States
facility: City of Hope National Medical Center
state: California
city: Santa Monica
country: United States
facility: UCLA Medical Center / David Geffen School of Medicine
state: California
city: Aurora
country: United States
facility: Rocky Mountain Cancer Centers - Aurora
state: Colorado
city: Denver
country: United States
facility: Cancer Centers of Colorado - Denver
state: Colorado
city: Grand Junction
country: United States
facility: SCL Health - St. Mary's Hospital & Medical Center
state: Colorado
city: Lafayette
country: United States
facility: SCL Health Good Samaritan Medical Center Cancer Centers of Colorado
state: Colorado
city: Wheat Ridge
country: United States
facility: Lutheran Medical Center - Cancer Centers of Colorado
state: Colorado
city: Washington
country: United States
facility: Lombardi Cancer Center / Georgetown University Medical Center
state: District of Columbia
city: Chicago
country: United States
facility: University of Chicago Medical Center
state: Illinois
city: Iowa City
country: United States
facility: Holden Comprehensive Cancer Center / University of Iowa
state: Iowa
city: Louisville
country: United States
facility: Norton Cancer Institute
state: Kentucky
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Saint Paul
country: United States
facility: Minnesota Oncology Hematology P.A.
state: Minnesota
city: Las Vegas
country: United States
facility: Comprehensive Cancer Centers of Nevada
state: Nevada
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Cleveland
country: United States
facility: Cleveland Clinic - Taussig Cancer Institute
state: Ohio
city: Eugene
country: United States
facility: Oncology Associates of Oregon
state: Oregon
city: Philadelphia
country: United States
facility: University of Pennsylvania / Perelman Center for Advanced Medicine
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Allegheny General Hospital
state: Pennsylvania
city: Knoxville
country: United States
facility: University of Tennessee
state: Tennessee
city: Nashville
country: United States
facility: Tennessee Oncology-Nashville/Sarah Cannon Research Institute
state: Tennessee
city: Dallas
country: United States
facility: Texas Oncology - Baylor Sammons Cancer Center
state: Texas
city: San Antonio
country: United States
facility: Texas Oncology - San Antonio Medical Center
state: Texas
city: Tyler
country: United States
facility: Texas Oncology - Tyler
state: Texas
city: Salt Lake City
country: United States
facility: Huntsman Cancer Institute/University of Utah
state: Utah
city: Vancouver
country: United States
facility: Northwest Cancer Specialists, P.C.
state: Washington
city: Gosford
country: Australia
facility: Central Coast Local Health District (Gosford and Wyong Hospitals)
city: Heidelberg
country: Australia
facility: Austin Health
city: London
country: Canada
facility: London Regional Cancer Program, London Health Sciences Centre
state: Ontario
city: Montreal
country: Canada
facility: Centre Hospitalier de l'Universite de Montreal
state: Quebec
city: Montreal
country: Canada
facility: McGill University Department of Oncology / McGill University Health Centre
state: Quebec
city: Busan
country: Korea, Republic of
facility: Dong-A University Hospital
city: Daegu
country: Korea, Republic of
facility: Kyungpook National University Chilgok Hospital
city: Seongnam-si
country: Korea, Republic of
facility: Seoul National University Bundang Hospital
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Severance Hospital, Yonsei University Health System
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center - Oncology
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Suwon-si
country: Korea, Republic of
facility: Ajou University Hospital
city: Kaohsiung
country: Taiwan
facility: Kaohsiung Medical University Hospital
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital
city: Taipei
country: Taiwan
facility: Taipei Veterans General Hospital
city: London
country: United Kingdom
facility: Sarah Cannon Research Institute UK
city: Manchester
country: United Kingdom
facility: The Christie NHS Foundation Trust
Study officials:
affiliation: Seagen Inc.
name: JoAl Mayor, PharmD, BCOP
role: STUDY_DIRECTOR
affiliation: Seagen Inc.
name: Michelle Ubowski, PharmD
role: STUDY_DIRECTOR
References: