A Study to Evaluate Tucatinib Plus Trastuzumab and Oxaliplatin-based Chemotherapy for HER2+ Gastrointestinal Cancers

Overview

About this study

The purpose of this study is to determine the recommended dose of tucatinib when combined with trastuzumab and modified FOLFOX7 (mFOLFOX7) in subjects with human epidermal growth factor receptor 2 (HER2)+ gastrointestinal cancers.

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:

  • Subjects must have unresectable or metastatic solid malignancy that is histologically or cytologically confirmed to be one of the tumor types listed below:
    • CRC;
    • Gastric adenocarcinoma;
    • Esophageal and GEJ adenocarcinoma;
    • Cholangiocarcinoma;
    • Gallbladder carcinoma.
  • Subjects must be receiving or must be candidates to receive an oxaliplatin-based regimen as part of their standard-of-care treatment.  If subject is receiving oxaliplatin at the time of enrollment, the oxaliplatin dose in their current regimen must be 85 mg/m^2 per 2-week cycle.
  • HER2+ disease, as determined by laboratory testing based on one of the following:
    • For colorectal, cholangiocarcinoma, and gallbladder carcinoma:
      • HER2 amplification or overexpression from fresh or archival tumor tissue utilizing one of the following Clinical Laboratory Improvement Amendments (CLIA) certified tests:
        • HER2 overexpression (3+ immunohistochemistry [IHC]) ̵ HER2 (ERBB2) amplification by in situ hybridization assay (fluorescence in situ hybridization [FISH] or chromogenic in situ hybridization signal ratio ≥ 2.0 or gene copy number >6) ̵ HER2 (ERBB2) amplification by next generation sequencing (NGS) assay;
        • HER2 amplification in a CLIA certified blood-based NGS assay.
      • Gastric, GEJ, and esophageal adenocarcinomas must use the following criteria:
        • HER2+ overexpression (IHC3+) by an FDA approved assay, from a newly obtained biopsy or surgical specimen, evaluated following the package insert’s interpretational manual for gastric adenocarcinoma. IHC2+ is eligible if the tumor is HER2 amplified by an FDA approved in situ hybridization assay.
  • Measurable or non-measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 as determined by the investigator.
  • Age 18 years or older.
  • An Eastern Cooperative Oncology Group Performance Status score of 0 or 1.
  • Life expectancy ≥ 3 months, in the opinion of the investigator.
  • Adequate hepatic function, as defined by:
    • 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 and alanine aminotransferase) ≤2.5× ULN (≤5× ULN if liver metastases are present).
  • Adequate baseline hematologic parameters as defined by:
    • Absolute neutrophil count ≥ 1.5×10³/µL;
    • Platelet count ≥ 100×10³/µL; subjects with stable platelet count from 75–100×10³/µL may be included with approval from the medical monitor;
    • Hemoglobin ≥ 8 g/dL.
  • 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 10. Estimated glomerular filtration rate (GFR):
    • Dose Cohort #1: ≥ 90 mL/min/1.73 m² using the Modification of Diet in Renal Disease equation as applicable.
    • Subjects with estimated GFR ≥60 to <90 mL/min/1.73 m² may be enrolled in subsequent dose cohorts with medical monitor approval.
  • International normalized ratio (INR) and partial thromboplastin time (PTT)/activated partial thromboplastin time (aPTT) ≤ 1.5× ULN, unless on medication known to alter INR and PTT/aPTT.
  • Left ventricular ejection fraction ≥ 50% as assessed by echocardiogram (ECHO) or multigated acquisition scan (MUGA) documented within 4 weeks prior to first dose of study treatment.
  • Subjects of childbearing potential, under the following conditions:
    • Must have a negative serum or urine pregnancy test (minimum sensitivity 25 mIU/mL or equivalent units of beta human chorionic gonadotropin) result within 7 days prior to the first dose of study treatment. Subjects with false positive results and documented verification that the subject is not pregnant are 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 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 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 study drug.
  • Subjects who can father children, under the following conditions:
    • 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 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 (as defined in Appendix C) starting at time of informed consent and continuing throughout the study and for at least 7 months after the final dose of 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 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:

  • History of allergic reactions to oxaliplatin, fluorouracil, leucovorin, trastuzumab, or compounds chemically or biologically similar to tucatinib, except for Grade 1 or 2 infusion related reactions to oxaliplatin or trastuzumab that were successfully managed, or known allergy to any of the excipients in the study drugs 2. Current treatment regimen with an oxaliplatin dose >85 mg/m2 per 2-week cycle or with an oxaliplatin dose 85 mg/m2 per 2-week cycle that was initiated more than 28 days prior to enrollment 3. Major surgery within 28 days prior to enrollment 4. Subjects with known active central nervous system metastasis (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) 5. Any toxicity related to prior cancer therapies that has not resolved to ≤ Grade 1, with the following exceptions: ● Alopecia; ● Clinically insignificant electrolyte abnormalities 6. 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 history of symptomatic congestive heart failure, left ventricular systolic dysfunction, or decrease in ejection fraction ● Severe dyspnea at rest (Common Terminology Criteria for Adverse Events [CTCAE] v5.0 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 7. Known myocardial infarction or unstable angina within 6 months prior to first dose of study treatment 8. 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 at least 12 weeks. 9. Presence of known chronic liver disease 10. Known dihydropyrimidine dehydrogenase deficiency 11. Known to be positive for human immunodeficiency virus 12. 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 13. Unable to swallow pills or requires enteral feeding or parenteral nutrition
  • Have used a strong CYP2C8 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. 15. Other medical, social, or psychosocial factors that, in the opinion of the investigator, could impact safety or compliance with study procedures 16. Any uncontrolled Grade 3 or higher (per National Cancer InstituteCTCAE v5.0) viral, bacterial, or fungal infection within 2 weeks prior to the first dose of study drug. Routine antimicrobial prophylaxis is permitted.

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

Tanios Bekaii-Saab, 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

Study Results Summary

Not yet available

Supplemental Study Information

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CLS-20487854

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