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

NCT04499924 | Completed Phase 2 Results DMC FDA Drug

• 2 other identifiers: SGNTUC-022C4251004
• Study Type: interventional
• Target: 17
• Locations: 6 countries
• Sites: 48

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.

Conditions

Gastric Adenocarcinoma; Gastroesophageal Junction Adenocarcinoma; Esophageal Adenocarcinoma

Keywords

HER2+; HER2-positive; GEA; GEC; GEJ; Seattle Genetics

Outcome Measures

Primary Outcomes (6)

• 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 Outcomes (10)

• Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors (RECIST) Version (v) 1.1 By Investigator Assessment

  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

  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

  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

  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

  From the first dose study treatment until PD or death, whichever occurred first (up to 19.8 months)

Study Arms (4)

Phase 2 Arm

EXPERIMENTAL

Tucatinib + trastuzumab + ramucirumab + paclitaxel

Drug: tucatinib; Drug: trastuzumab; Drug: ramucirumab; Drug: paclitaxel

Arm 3A

EXPERIMENTAL

Tucatinib + trastuzumab + ramucirumab + paclitaxel

Drug: tucatinib; Drug: trastuzumab; Drug: ramucirumab; Drug: paclitaxel

Arm 3B

ACTIVE COMPARATOR

Ramucirumab + paclitaxel + tucatinib placebo + trastuzumab placebo

Drug: ramucirumab; Drug: paclitaxel; Other: tucatinib placebo; Other: trastuzumab placebo

Arm 3C

EXPERIMENTAL

Tucatinib + ramucirumab + paclitaxel + trastuzumab placebo

Drug: tucatinib; Drug: ramucirumab; Drug: paclitaxel; Other: trastuzumab placebo

Interventions

tucatinib DRUG

300 mg given twice daily orally

Also known as: TUKYSA, ONT-380, ARRY-380

Arm 3A; Arm 3C; Phase 2 Arm

trastuzumab DRUG

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

Arm 3A; Phase 2 Arm

ramucirumab DRUG

8 mg/kg will be administered IV on Days 1 and 15 of each cycle

Also known as: CYRAMZA

Arm 3A; Arm 3B; Arm 3C; Phase 2 Arm

paclitaxel DRUG

60 or 80 mg/m\^2 IV on Days 1, 8, and 15 of each cycle

Arm 3A; Arm 3B; Arm 3C; Phase 2 Arm

tucatinib placebo OTHER

Given twice daily orally

Arm 3B

trastuzumab placebo OTHER

IV on Days 1 and 15 of each cycle

Arm 3B; Arm 3C

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Seagen Inc.: lead

Study Sites (48)

University of Alabama at Birmingham

Birmingham, Alabama, 35249, United States

Location

Mayo Clinic Arizona

Phoenix, Arizona, 85054, United States

Location

Arizona Cancer Center / University of Arizona

Tucson, Arizona, 85724, United States

Location

City of Hope National Medical Center

Duarte, California, 91010, United States

Location

UCLA Medical Center / David Geffen School of Medicine

Santa Monica, California, 90404, United States

Location

Rocky Mountain Cancer Centers - Aurora

Aurora, Colorado, 80012, United States

Location

Cancer Centers of Colorado - Denver

Denver, Colorado, 80218, United States

Location

SCL Health - St. Mary's Hospital & Medical Center

Grand Junction, Colorado, 81501, United States

Location

SCL Health Good Samaritan Medical Center Cancer Centers of Colorado

Lafayette, Colorado, 80026, United States

Location

Lutheran Medical Center - Cancer Centers of Colorado

Wheat Ridge, Colorado, 80033, United States

Location

Lombardi Cancer Center / Georgetown University Medical Center

Washington D.C., District of Columbia, 20007, United States

Location

University of Chicago Medical Center

Chicago, Illinois, 60637, United States

Location

Holden Comprehensive Cancer Center / University of Iowa

Iowa City, Iowa, 52242, United States

Location

Norton Cancer Institute

Louisville, Kentucky, 40217, United States

Location

Dana Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

Minnesota Oncology Hematology P.A.

Saint Paul, Minnesota, 55102, United States

Location

Comprehensive Cancer Centers of Nevada

Las Vegas, Nevada, 89169, United States

Location

Roswell Park Cancer Institute

Buffalo, New York, 14203, United States

Location

Duke University Medical Center

Durham, North Carolina, 27710, United States

Location

Cleveland Clinic - Taussig Cancer Institute

Cleveland, Ohio, 44195, United States

Location

Oncology Associates of Oregon

Eugene, Oregon, 97401, United States

Location

University of Pennsylvania / Perelman Center for Advanced Medicine

Philadelphia, Pennsylvania, 19104, United States

Location

Allegheny General Hospital

Pittsburgh, Pennsylvania, 15212, United States

Location

University of Tennessee

Knoxville, Tennessee, 37920, United States

Location

Tennessee Oncology-Nashville/Sarah Cannon Research Institute

Nashville, Tennessee, 37203, United States

Location

Texas Oncology - Baylor Sammons Cancer Center

Dallas, Texas, 75246, United States

Location

Texas Oncology - San Antonio Medical Center

San Antonio, Texas, 78217, United States

Location

Texas Oncology - Tyler

Tyler, Texas, 75702, United States

Location

Huntsman Cancer Institute/University of Utah

Salt Lake City, Utah, 84112, United States

Location

Northwest Cancer Specialists, P.C.

Vancouver, Washington, 98684, United States

Location

Central Coast Local Health District (Gosford and Wyong Hospitals)

Gosford, 2250, Australia

Location

Austin Health

Heidelberg, 63V6 63, Australia

Location

London Regional Cancer Program, London Health Sciences Centre

London, Ontario, N6A 5W9, Canada

Location

Centre Hospitalier de l'Universite de Montreal

Montreal, Quebec, H2X 3E4, Canada

Location

McGill University Department of Oncology / McGill University Health Centre

Montreal, Quebec, H4A 3J1, Canada

Location

Dong-A University Hospital

Busan, 49201, South Korea

Location

Kyungpook National University Chilgok Hospital

Daegu, 41404, South Korea

Location

Seoul National University Bundang Hospital

Seongnam-si, 13605, South Korea

Location

Seoul National University Hospital

Seoul, 03080, South Korea

Location

Severance Hospital, Yonsei University Health System

Seoul, 03722, South Korea

Location

Asan Medical Center - Oncology

Seoul, 05505, South Korea

Location

Samsung Medical Center

Seoul, 06351, South Korea

Location

Ajou University Hospital

Suwon, 16499, South Korea

Location

Kaohsiung Medical University Hospital

Kaohsiung City, 807, Taiwan

Location

National Taiwan University Hospital

Taipei, 10002, Taiwan

Location

Taipei Veterans General Hospital

Taipei, 11217, Taiwan

Location

Sarah Cannon Research Institute UK

London, W3 0ER, United Kingdom

Location

The Christie NHS Foundation Trust

Manchester, M20 4BX, United Kingdom

Location

MeSH Terms

Conditions

Adenocarcinoma Of Esophagus

Interventions

tucatinib; Trastuzumab; Ramucirumab; Paclitaxel

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Diterpenes; Terpenes

Limitations and Caveats

Study had following parts: Phase (P)2 (paclitaxel DO (dose optimization), DE (dose expansion)), and P3. P2 DE, and P3 not initiated (sponsor decision). After DO completed enrollment, long-term follow-up discontinued. Participants received treatment until protocol-defined discontinuation criteria met. After treatment discontinued, participants followed through duration of safety period. So, results in all sections reported only for paclitaxel DO (P2) not for DE (P2), and P3.

Results Point of Contact

• Title: Chief Medical Officer
• Organization: Seagen Inc.

medinfo@seagen.com

(855) 473-2436

Study Officials

• JoAl Mayor, PharmD, BCOP

  Seagen Inc.

  STUDY DIRECTOR

• Michelle Ubowski, PharmD

  Seagen Inc.

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 31, 2020
• First Posted: August 5, 2020
• Study Start: March 22, 2021
• Primary Completion: April 17, 2024
• Study Completion: April 17, 2024
• Last Updated: January 22, 2025
• Results First Posted: January 22, 2025

Record last verified: 2024-12

Locations

US (30); AU (2); CA (3); KR (8); TW (3); GB (2)