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

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)

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.

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