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

Overview

About this study

This is an international, multicenter Phase 2/3 study in subjects with locally-advanced unresectable or metastatic HER2+ GEC who have received prior treatment with a HER2-directed antibody, and have received 1 prior line of therapy in the advanced disease setting.

Participation eligibility

Participant eligibility includes age, gender, type and stage of disease, and previous treatments or health concerns. Guidelines differ from study to study, and identify who can or cannot participate. There is no guarantee that every individual who qualifies and wants to participate in a trial will be enrolled. Contact the study team to discuss study eligibility and potential participation.

Inclusion Criteria:

  • Histologically or cytologically confirmed diagnosis of locally-advanced unresectable or metastatic HER2+ gastric or gastroesophageal junction adenocarcinoma.
  • 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 by IHC and ISH (IHC3+ or IHC2+/ISH+) assay of a tumor tissue sample, processed in a Clinical Laboratory Improvement Amendments (CLIA)- or International Organization for Standardization (ISO)‑accredited laboratory;
    • 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, processed in a CLIA- or ISO‑accredited laboratory;
    • Phase 3: HER2 amplification in a blood-based NGS assay performed at a central laboratory.
  • Can supply archival tumor tissue for central review; if an archival sample is not available, the subject may be eligible, following approval by the medical monitor.
  • History of prior treatment with a HER2-directed antibody.
  • Progressive disease during or after first-line therapy for locally-advanced unresectable or metastatic GEC 6.
  • Phase 2: Measurable disease according to RECIST version 1.1.
  • Phase 3: Measurable or non-measurable disease according to RECIST version 1.1 7.
  • Age ≥ 18 years, or considered an adult by local regulations, at time of consent.
  • 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.
  • Adequate hepatic function as defined by the following:
    • Total bilirubin ≤ 1.5 × upper limit of normal (ULN), except for subjects with known Gilbert’s disease, who may enroll if the conjugated bilirubin is ≤ 1.5 × ULN;
    • Transaminases (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]) ≤ 2.5 × ULN (≤ 5 × ULN if liver metastases are present).
  • Adequate baseline hematologic parameters as defined by:
    • Absolute neutrophil count ≥ 1.5 × 10^9 /L;
    • Platelet count ≥ 100 × 10^9 /L; subjects with stable platelet count from 75-100 × 10^9 /L may be included with approval from the Medical Monitor;
    • Hemoglobin ≥ 9 g/dL; subjects with hemoglobin ≥ 8-9 g/dL may be included with approval from the Medical Monitor;
    • In subjects transfused before study entry, transfusion must be ≥ 14 days prior to start of therapy to establish adequate hematologic parameters independent from transfusion support.
  • Estimated glomerular filtration rate (GFR) ≥ 50 mL/min/1.73 m² using the Modification of Diet in Renal Disease (MDRD) study equation as applicable.
  • International normalized ratio (INR) ≤ 1.5, and prothrombin time (PT) and partial thromboplastin time (PTT)/activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN if not receiving anticoagulation therapy. Subjects on full-dose anticoagulation must be on a stable dose of oral anticoagulant or low molecular weight heparin. If on warfarin, the subject must have an INR of ≤ 3 and have no active bleeding (within ≤ 14 days prior to enrollment or randomization, excluding trace hematuria) or pathological condition that carries a high risk of bleeding (i.e., tumor involving major vessels or known varices). Therapy for potential drug interactions with tucatinib and oral anticoagulants.
  • Left ventricular ejection fraction (LVEF) ≥ 50% as assessed by echocardiogram or multi-gated acquisition (MUGA) scan documented within 4 weeks prior to first dose of study treatment .
  • Urinary protein of ≤ 1+ on dipstick or routine urinalysis. If dipstick or routine analysis indicates proteinuria ≥ 2+, then either a 24-hour urine must be collected and must demonstrate < 1000 mg of protein in 24 hours or the urine protein/creatinine (UPC) ratio must be <1 to allow participation in study.
  • For subjects of childbearing potential, the following stipulations apply:
    • Must have a negative serum or urine pregnancy test (minimum sensitivity of 25 mIU/mL or equivalent units of beta human chorionic gonadotropin [β-hCG]) result within 7 days prior to the first dose of study treatment. A subject with a false positive result and documented verification that the subject is not pregnant is eligible for participation;
    • Must agree not to try to become pregnant during the study and for at least 7 months after the final dose of any study drug;
    • Must agree not to breastfeed or donate ova, starting at time of informed consent and continuing through 7 months after the final dose of any study drug;
    • If sexually active in a way that could lead to pregnancy, must consistently use 2 highly effective methods of birth control, starting at the time of informed consent and continuing throughout the study and for at least 7 months after the final dose of any study drug.
  • For subjects who can father children, the following stipulations apply:
    • Must agree not to donate sperm starting at time of informed consent and continuing throughout the study period and for at least 7 months after the final dose of any study drug;
    • If sexually active with a person of childbearing potential in a way that could lead to pregnancy, must consistently use 2 highly effective methods of birth control, starting at time of informed consent and continuing throughout the study and for at least 7 months after the final dose of any study drug;
    • If sexually active with a person who is pregnant or breastfeeding, must consistently use one of 2 contraception options, starting at time of informed consent and continuing throughout the study and for at least 7 months after the final dose of any study drug.
  • The subject must provide written informed consent.
  • Subject must be willing and able to comply with study procedures, laboratory tests, and other requirements of the study

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 trastuzumab emtansine (T-DM1), trastuzumab deruxtecan (T-DXd), or any other HER2-directed antibody-drug conjugate.
  • History of exposure to the following cumulative doses of anthracyclines:
    • Doxorubicin >360 mg/m²;
    • Epirubicin >720 mg/m²;
    • Mitoxantrone >120 mg/m²;
    • Idarubicin >90 mg/m²;
    • Liposomal doxorubicin (e.g., Doxil, Caelyx, Myocet) > 550 mg/m².
    • History of allergic reactions to paclitaxel, trastuzumab, ramucirumab, or compounds chemically or biologically similar to tucatinib, except for Grade 1 or 2 infusion-related reactions to trastuzumab or ramucirumab that were successfully managed, or known allergy to any of the excipients in the study drugs or placebos.
  • Phase 2 paclitaxel dose optimization stage only: history of prior partial or total gastrectomy
  • Treatment with any systemic anti-cancer therapy (including hormonal and biologic therapy), radiation, or an experimental agent, or participation in another interventional clinical trial ≤ 3 weeks prior to first dose of study treatment.
  • Major surgery within 28 days prior to enrollment or randomization, central venous access device placement within 7 days prior to enrollment or randomization, or planned major surgery following initiation of study treatment.
  • Any toxicity related to prior cancer therapies that has not resolved to ≤ Grade 1, with the following exceptions:
    • Anemia;
    • Alopecia;
    • Congestive heart failure (CHF), which must have been ≤ Grade 1 in severity at the time of occurrence, and must have resolved completely.
  • Clinically significant cardiopulmonary disease such as:
    • Ventricular arrhythmia requiring therapy;
    • Symptomatic hypertension or uncontrolled asymptomatic hypertension ≥ 150/≥90 mmHg despite standard medical management, as determined by the investigator;
    • Any symptomatic history of CHF, left ventricular systolic dysfunction or decrease in ejection fraction;
    • Severe dyspnea at rest (Common Terminology Criteria for Adverse Events [CTCAE] Grade 3 or above) due to complications of advanced malignancy or hypoxia requiring supplementary oxygen therapy, except when therapy is needed for obstructive sleep apnea.
  • Known to be positive for hepatitis B by surface antigen expression. Known to be positive for hepatitis C infection (positive by polymerase chain reaction). Subjects who have been treated for hepatitis C infection are permitted if they have documented sustained virologic response of 12 weeks.
  • Presence of known chronic liver disease.
  • Phase 2: Known to be positive for human immunodeficiency virus (HIV).
  • Phase 3: Subjects known to be positive for HIV are excluded if they meet any of the following criteria:
    • CD4+ T-cell count of < 350 cells/uL;
    • Detectable HIV viral load;
    • History of an opportunistic infection within the past 12 months;
    • On stable antiretroviral therapy for < 4 weeks.
  • Subjects who are pregnant, breastfeeding, or planning to become pregnant from time of informed consent until 7 months following the last dose of study drug.
  • Unable to swallow pills.
  • Have used a strong cytochrome P450 (CYP)2C8 inhibitor within 5 half-lives of the inhibitor, or have used a strong CYP2C8 or CYP3A4 inducer within 5 days prior to first dose of study treatment.
  • Other medical, social, or psychosocial factors that, in the opinion of the investigator, could impact safety or compliance with study procedures

Participating Mayo Clinic locations

Study statuses change often. Please contact the study team for the most up-to-date information regarding possible participation.

Mayo Clinic Location Status Contact

Scottsdale/Phoenix, Ariz.

Mayo Clinic principal investigator

Mohamad Sonbol, M.D.

Contact us for the latest status

Contact information:

Cancer Center Clinical Trials Referral Office

(855) 776-0015

More information

Publications

Publications are currently not available
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CLS-20504795

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