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

• ClinicalTrials.gov Identifier: NCT04499924
• Recruitment Status: Active, not recruiting
• First Posted: August 5, 2020
• Last Update Posted: August 29, 2023
• Sponsor: Seagen Inc.
• Information provided by (Responsible Party): Seagen Inc.

Tracking Information

• First Submitted Date: July 31, 2020
• First Posted Date: August 5, 2020
• Last Update Posted Date: August 29, 2023
• Actual Study Start Date: March 22, 2021
• Estimated Primary Completion Date: May 31, 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 28, 2021)

• Overall survival (OS) (Phase 3 only) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: During first cycle of treatment; up to one month ]
• 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.
• Incidence of laboratory abnormalities (Phase 2 only) [ Time Frame: 18 months ]
  To be summarized using descriptive statistics.
• Incidence of dose modifications (Phase 2 only) [ Time Frame: 18 months ]

Original Primary Outcome Measures (submitted: July 31, 2020)

• Overall survival (OS) (Phase 3 only) [ Time Frame: 60 months ]
  OS is defined as the time from randomization to death due to any cause
• Progression-free survival (PFS) per 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
• Incidence of dose-limiting toxicities (DLTs) (Phase 2 only) [ Time Frame: During first cycle of treatment; up to one month ]
• Incidence of adverse events (AEs) (Phase 2 only) [ Time Frame: 18 months ]
• Incidence of dose modifications (Phase 2 only) [ Time Frame: 18 months ]

Current Secondary Outcome Measures (submitted: April 28, 2021)

• 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
• 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
• 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
• 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)
• 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
• 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
• 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
• 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
• 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)
• 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.
• Incidence of laboratory abnormalities (Phase 3 only) [ Time Frame: 36 months ]
  To be summarized using descriptive statistics.
• Incidence of dose modifications (Phase 3 only) [ Time Frame: 36 months ]
• 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
• 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
• AUC to AUClast of paclitaxel (Phase 2 only) [ Time Frame: 1 month ]
  PK parameter
• Maximum observed concentration (Cmax) of tucatinib (Phase 2 only) [ Time Frame: 1 month ]
  PK parameter
• Cmax of paclitaxel (Phase 2 only) [ Time Frame: 1 month ]
  PK parameter
• Time of Cmax (Tmax) of tucatinib (Phase 2 only) [ Time Frame: 1 month ]
  PK parameter
• Tmax of paclitaxel (Phase 2 only) [ Time Frame: 1 month ]
  PK parameter
• Trough concentration (Ctrough) of tucatinib (Phase 2 only) [ Time Frame: 18 months ]
  PK parameter
• Ctrough of paclitaxel (Phase 2 only) [ Time Frame: 18 months ]
  PK parameter
• Metabolic ratio of tucatinib based on AUC (MRAUC) (Phase 2 only) [ Time Frame: 1 month ]
  PK parameter
• MRAUC of paclitaxel (Phase 2 only) [ Time Frame: 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. [ 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.
• Change from baseline in health-related quality of life (HRQoL) [ Time Frame: 36 months ]
• 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.

Original Secondary Outcome Measures (submitted: July 31, 2020)

• Confirmed objective response rate (ORR) per Response evaluation criteria in solid tumors (RECIST) version 1.1 according to investigator assessment (Phases 2 and 3) [ Time Frame: 36 months ]
  Confirmed ORR is defined as confirmed complete response (CR) or partial response (PR) in subjects with measurable disease.
• ORR RECIST version 1.1 according to investigator assessment (Phases 2 and 3) [ Time Frame: 36 months ]
• Duration of response (DOR) per RECIST version 1.1 according to investigator assessment (Phases 2 and 3) [ Time Frame: 36 months ]
• 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)
• PFS per RECIST v1.1 according to blinded independent central review (BICR) assessment (Phase 3 only) [ Time Frame: 36 months ]
• Confirmed ORR per RECIST version 1.1 according to BICR assessment (Phase 3 only) [ Time Frame: 36 months ]
• ORR per RECIST version 1.1 according to BICR assessment (Phase 3 only) [ Time Frame: 36 months ]
• DOR per RECIST version 1.1 according to BICR assessment (Phase 3 only) [ Time Frame: 36 months ]
• DCR per RECIST version 1.1 according to BICR assessment (Phase 3 only) [ Time Frame: 36 months ]
• Incidence of AEs (Phase 3 only) [ Time Frame: 36 months ]
• Incidence of dose modifications (Phase 3 only) [ Time Frame: 36 months ]
• PFS per RECIST version 1.1 according to investigator assessment (Phase 2 only) [ Time Frame: 18 months ]
• 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
• AUC to AUClast of paclitaxel (Phase 2 only) [ Time Frame: 1 month ]
  PK parameter
• Maximum observed concentration (Cmax) of tucatinib (Phase 2 only) [ Time Frame: 1 month ]
  PK parameter
• Cmax of paclitaxel (Phase 2 only) [ Time Frame: 1 month ]
  PK parameter
• Time of Cmax (Tmax) of tucatinib (Phase 2 only) [ Time Frame: 1 month ]
  PK parameter
• Tmax of paclitaxel (Phase 2 only) [ Time Frame: 1 month ]
  PK parameter
• Trough concentration (Ctrough) of tucatinib (Phase 2 only) [ Time Frame: 18 months ]
  PK parameter
• Ctrough of tucatinib (Phase 2 only) [ Time Frame: 18 months ]
  PK parameter
• Metabolic ratio of tucatinib based on AUC (MRAUC) (Phase 2 only) [ Time Frame: 1 month ]
  PK parameter
• MRAUC of paclitaxel (Phase 2 only) [ Time Frame: 1 month ]
  PK parameter

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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)

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.

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2; Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment

Condition

• Gastric Adenocarcinoma
• Gastroesophageal Junction Adenocarcinoma
• Esophageal Adenocarcinoma

Intervention

• 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
• Other: tucatinib placebo
  Given twice daily orally
• Other: trastuzumab placebo
  IV on Days 1 and 15 of each cycle

Study Arms

• Experimental: Phase 2 Arm
  Tucatinib + trastuzumab + ramucirumab + paclitaxel
  Interventions:

  • Drug: tucatinib
  • Drug: trastuzumab
  • Drug: ramucirumab
  • Drug: paclitaxel
• Experimental: Arm 3A
  Tucatinib + trastuzumab + ramucirumab + paclitaxel
  Interventions:

  • Drug: tucatinib
  • Drug: trastuzumab
  • Drug: ramucirumab
  • Drug: paclitaxel
• Active Comparator: Arm 3B
  Ramucirumab + paclitaxel + tucatinib placebo + trastuzumab placebo
  Interventions:

  • Drug: ramucirumab
  • Drug: paclitaxel
  • Other: tucatinib placebo
  • Other: trastuzumab placebo
• Experimental: Arm 3C
  Tucatinib + ramucirumab + paclitaxel + trastuzumab placebo
  Interventions:

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

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: October 27, 2022): 17
• Original Estimated Enrollment (submitted: July 31, 2020): 566
• Estimated Study Completion Date: March 31, 2027
• Estimated Primary Completion Date: May 31, 2025 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Canada, Korea, Republic of, Taiwan, United Kingdom, United States

Administrative Information

• NCT Number: NCT04499924
• Other Study ID Numbers: SGNTUC-022
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Seagen Inc.
• Original Responsible Party: Same as current
• Current Study Sponsor: Seagen Inc.
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: JoAl Mayor, PharmD, BCOP; Seagen Inc.
• Study Director: Michelle Ubowski, PharmD; Seagen Inc.

• PRS Account: Seagen Inc.
• Verification Date: August 2023