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

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ClinicalTrials.gov Identifier: NCT04499924
Recruitment Status : Recruiting
First Posted : August 5, 2020
Last Update Posted : June 1, 2021
Sponsor:
Information provided by (Responsible Party):
Seagen Inc.

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

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Study Type : Interventional  (Clinical Trial)
Estimated 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 : March 22, 2021
Estimated Primary Completion Date : May 31, 2025
Estimated Study Completion Date : March 31, 2027

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Phase 2 Arm
Tucatinib + trastuzumab + ramucirumab + paclitaxel
Drug: tucatinib
300 mg given twice daily orally
Other Name: 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 Name: 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 Name: 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 Name: 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 Name: 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 Name: TUKYSA, ONT-380, ARRY-380

Drug: ramucirumab
8 mg/kg will be administered IV on Days 1 and 15 of each cycle
Other Name: 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




Primary Outcome Measures :
  1. Overall survival (OS) (Phase 3 only) [ Time Frame: 60 months ]
    OS is defined as the time from randomization to death due to any cause

  2. Progression-free survival (PFS) per Response evaluation criteria in solid tumors (RECIST) version 1.1 according to investigator assessment (Phase 3 only) [ Time Frame: 36 months ]
    PFS is defined as the time from randomization to the date of disease progression or death from any cause

  3. Incidence of dose-limiting toxicities (DLTs) (Phase 2 only) [ Time Frame: During first cycle of treatment; up to one month ]
  4. Incidence of adverse events (AEs) (Phase 2 only) [ Time Frame: 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.

  5. Incidence of laboratory abnormalities (Phase 2 only) [ Time Frame: 18 months ]
    To be summarized using descriptive statistics.

  6. Incidence of dose modifications (Phase 2 only) [ Time Frame: 18 months ]

Secondary Outcome Measures :
  1. Confirmed objective response rate (ORR) per RECIST version 1.1 according to investigator assessment (Phases 2 and 3) [ Time Frame: 36 months ]
    ORR is defined as the proportion of subjects with best overall response of CR or PR

  2. ORR per RECIST version 1.1 according to investigator assessment (Phases 2 and 3) [ Time Frame: 36 months ]
    ORR is defined as the proportion of subjects with best overall response of CR or PR

  3. Duration of response (DOR) per RECIST version 1.1 according to investigator assessment (Phases 2 and 3) [ Time Frame: 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

  4. Disease control rate (DCR) per RECIST version 1.1 according to investigator assessment (Phases 2 and 3) [ Time Frame: 36 months ]
    DCR is defined as subjects with CR, PR, or stable disease (SD or non-CR/non-progressive disease)

  5. PFS per RECIST v1.1 according to blinded independent central review (BICR) assessment (Phase 3 only) [ Time Frame: 36 months ]
    PFS is defined as the time from randomization to the date of disease progression or death from any cause

  6. Confirmed ORR per RECIST version 1.1 according to BICR assessment (Phase 3 only) [ Time Frame: 36 months ]
    ORR is defined as the proportion of subjects with best overall response of CR or PR

  7. ORR per RECIST version 1.1 according to BICR assessment (Phase 3 only) [ Time Frame: 36 months ]
    ORR is defined as the proportion of subjects with best overall response of CR or PR

  8. DOR per RECIST version 1.1 according to BICR assessment (Phase 3 only) [ Time Frame: 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

  9. DCR per RECIST version 1.1 according to BICR assessment (Phase 3 only) [ Time Frame: 36 months ]
    DCR is defined as subjects with CR, PR, or stable disease (SD or non-CR/non-progressive disease)

  10. Incidence of AEs (Phase 3 only) [ Time Frame: 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.

  11. Incidence of laboratory abnormalities (Phase 3 only) [ Time Frame: 36 months ]
    To be summarized using descriptive statistics.

  12. Incidence of dose modifications (Phase 3 only) [ Time Frame: 36 months ]
  13. PFS per RECIST version 1.1 according to investigator assessment (Phase 2 only) [ Time Frame: 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

  14. Area under the plasma concentration-time curve (AUC) to the time of the last quantifiable concentration (AUClast) of tucatinib (Phase 2 only) [ Time Frame: 1 month ]
    Pharmacokinetic (PK) parameter

  15. AUC to AUClast of paclitaxel (Phase 2 only) [ Time Frame: 1 month ]
    PK parameter

  16. Maximum observed concentration (Cmax) of tucatinib (Phase 2 only) [ Time Frame: 1 month ]
    PK parameter

  17. Cmax of paclitaxel (Phase 2 only) [ Time Frame: 1 month ]
    PK parameter

  18. Time of Cmax (Tmax) of tucatinib (Phase 2 only) [ Time Frame: 1 month ]
    PK parameter

  19. Tmax of paclitaxel (Phase 2 only) [ Time Frame: 1 month ]
    PK parameter

  20. Trough concentration (Ctrough) of tucatinib (Phase 2 only) [ Time Frame: 18 months ]
    PK parameter

  21. Ctrough of paclitaxel (Phase 2 only) [ Time Frame: 18 months ]
    PK parameter

  22. Metabolic ratio of tucatinib based on AUC (MRAUC) (Phase 2 only) [ Time Frame: 1 month ]
    PK parameter

  23. MRAUC of paclitaxel (Phase 2 only) [ Time Frame: 1 month ]
    PK parameter

  24. 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. [ Time Frame: 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.

  25. Change from baseline in health-related quality of life (HRQoL) [ Time Frame: 36 months ]
  26. Utility index values as assessed by the EQ-5D-5L [ Time Frame: 36 months ]
    The EQ-5D-5L questionnaire is used as a preference based measurement of HRQoL outcomes. Data will be summarized using descriptive statistics.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04499924


Contacts
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Contact: Seagen Trial Information Support 866-333-7436 clinicaltrials@seagen.com

Locations
Show Show 22 study locations
Sponsors and Collaborators
Seagen Inc.
Investigators
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Study Director: Joal Mayor, PharmD, BCOP Seagen Inc.
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Responsible Party: Seagen Inc.
ClinicalTrials.gov Identifier: NCT04499924    
Other Study ID Numbers: SGNTUC-022
First Posted: August 5, 2020    Key Record Dates
Last Update Posted: June 1, 2021
Last Verified: May 2021

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Seagen Inc.:
HER2+
HER2-positive
GEA
GEC
GEJ
Seattle Genetics
Additional relevant MeSH terms:
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Adenocarcinoma
Esophageal Neoplasms
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Head and Neck Neoplasms
Digestive System Diseases
Esophageal Diseases
Gastrointestinal Diseases
Paclitaxel
Trastuzumab
Ramucirumab
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents, Immunological