Tucatinib, Trastuzumab, Ramucirumab, and Paclitaxel Versus Paclitaxel and Ramucirumab in Previously Treated HER2+ Gastroesophageal Cancer
Trial Status: Active
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.
- Histologically or cytologically confirmed diagnosis of locally-advanced unresectable or metastatic HER2+ gastric or gastroesophageal junction adenocarcinoma (GEC)
- HER2+ disease at screening, as follows:
- Phase 2 paclitaxel dose optimization stage: HER2 amplification in a blood-based NGS assay performed at a central laboratory or centrally confirmed HER2 overexpression/amplification in a tumor biopsy obtained after progression of the most recent line of systemic therapy, evaluated following the package insert of FDA-approved tests for immunohistochemistry (IHC) and in situ hybridization (ISH) (IHC3+ or IHC2+/ISH+)
- Phase 2 dose expansion stage:
- Cohort 2A: HER2 amplification in a blood-based NGS assay performed at a central laboratory
- Cohort 2B: centrally confirmed HER2 overexpression/amplification in a tumor biopsy obtained after progression of the most recent line of systemic therapy, evaluated following the package insert of FDA-approved tests for IHC and ISH (IHC3+ or IHC2+/ISH+)
- 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
- Adequate baseline hematologic parameters and hepatic function
- 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, DS8201a, 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:
- 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
- Known myocardial infarction or unstable angina within 6 months prior to first dose of study treatment
- 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 or requires enteral feeding
- 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.
- History of malignancy other than GEC within 2 years prior to screening, with the exception of those with a negligible risk of metastasis or death (e.g., 5-year OS of ≥90%), such as adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, or Stage I uterine cancer.
- History of deep vein thrombosis, pulmonary embolism, or any other significant thromboembolism during the 3 months prior to enrollment or randomization.
- Therapeutic anticoagulation with warfarin, low-molecular weight heparin or similar agents. Subjects receiving prophylactic, low-dose anticoagulation therapy are eligible provided that the coagulation parameters defined in the inclusion criteria (INR ≤1.5 and PTT/aPTT ≤1.5 ULN) or (PT ≤1.5 ULN and PTT/aPTT ≤1.5 ULN) are met.
- Chronic therapy with nonsteroidal anti-inflammatory agents (NSAIDs, e.g., indomethacin, ibuprofen, naproxen, or similar agents) or other anti-platelet agents (e.g., clopidogrel, ticlopidine, dipyridamole, anagrelide). Aspirin use at doses up to 325 mg/day is permitted.
- Significant bleeding disorders, vasculitis, or had a significant bleeding episode from the gastrointestinal tract within 3 months prior to study entry.
- History of any arterial thrombotic event, including myocardial infarction, unstable angina, cerebrovascular accident, or transient ischemic attack, within 6 months prior to enrollment or randomization.
- History of gastrointestinal perforation and/or fistulae within 6 months prior to enrollment or randomization.
- Serious non-healing wound or peptic ulcer or bone fracture within 28 days prior to enrollment or randomization
- History of bowel obstruction, history or presence of inflammatory enteropathy or extensive intestinal resection (hemicolectomy or extensive small intestine resection with chronic diarrhea), Crohn's disease, ulcerative colitis or chronic diarrhea
- Active or uncontrolled clinically serious infection
- Known active central nervous system metastases. Irradiated or resected lesions are permitted, provided the lesions are fully treated and inactive, subject is asymptomatic, and no steroids have been administered for at least 30 days.
Mayo Clinic in Arizona
Banner University Medical Center - Tucson
UCLA / Jonsson Comprehensive Cancer Center
Contact: Ruth Gonzalez
University of Iowa / Holden Comprehensive Cancer Center
University of Kansas Cancer Center
Ohio State University Comprehensive Cancer Center
Trial Phase Phase II/III
Trial Type Treatment
- Primary ID SGNTUC-022
- Secondary IDs NCI-2020-06703
- Clinicaltrials.gov ID NCT04499924