Oxaliplatin and Liposomal Irinotecan (Plus Trastuzumab for HER2-positive Disease) in Advanced Esophageal and Gastric Adenocarcinoma

  • STATUS
    Recruiting
  • End date
    Dec 13, 2026
  • participants needed
    52
  • sponsor
    University of Wisconsin, Madison
Updated on 13 May 2022
combinations
hysterectomy
systemic therapy
measurable disease
anticoagulants
fluorouracil
oophorectomy
international normalized ratio
combination chemotherapy
oxaliplatin
neutrophil count
HER2
irinotecan
blood transfusion
trastuzumab
aptt
thromboplastin
adenocarcinoma

Summary

This is an open label, phase II, multi-site trial evaluating the efficacy and safety of the combination of 5-FU, oxaliplatin, nal-IRI, and immunotherapy (plus trastuzumab for HER2-positive tumors) as first-line therapy for participants with advanced Esophageal and Gastric Adenocarcinoma (EGA). The investigators hypothesize that this drug combination will be better tolerated than current first-line chemotherapy combinations for this disease.

Description

This is an open label, phase II, multi-site trial evaluating the efficacy and safety of the combination of 5-FU, oxaliplatin, nal-IRI, and immunotherapy (plus trastuzumab for HER2-positive tumors) as first-line therapy for participants with advanced Esophageal and Gastric Adenocarcinoma (EGA).

Participants will be enrolled into one of four cohorts. Participants in Cohort 1 (HER-2 negative) will receive 5-FU, oxaliplatin and nal-IRI. Cohort 3 (HER-2 negative) will use nivolumab in addition to 5-FU, oxaliplatin and nal-IRI. Participants in Cohort 2 (HER-2 positive) will receive trastuzumab in addition to 5-FU, oxaliplatin and nal-IRI. Cohort 4 (HER-2 positive) will also include pembrolizumab in addition to trastuzumab, 5-FU, oxaliplatin and nal-IRI.

Chemotherapy doses will be the same for all cohorts and will follow similar modifications for toxicities. Agents will be administered as per institutional standards when similar regimens (such as FOLFIRINOX, FOLFOX, and trastuzumab) are used.

Cohort 1 (HER2-negative tumors): Up to 13 evaluable participants will be accrued to Cohort 1.

Cohort 2 (HER2-positive tumors): Up to a total of 6 subjects will be enrolled to evaluate the safety and tolerability of the proposed 5-Fluorouracil, Oxaliplatin and liposomal Irinotecan combination in HER2-positive subjects.

Cohort 3 (HER-2 negative tumors):12 participants will be enrolled during stage 1. If at most 5 objective responses per RECIST 1.1 are observed, then further enrollment will be halted. Otherwise, 15 additional participants will be enrolled for a total number of 27.

Cohort 4 (HER-2 positive tumors): treated with oxaliplatin, Nal-IRI and trastuzumab in combination with pembrolizumab. A total of up to 6 subjects will be accrued to evaluate safety and tolerability.

Details
Condition Esophageal Adenocarcinoma, Gastric Adenocarcinoma
Treatment Trastuzumab, Pembrolizumab, Oxaliplatin, 5-FU, nal-IRI, Nivolumab
Clinical Study IdentifierNCT04150640
SponsorUniversity of Wisconsin, Madison
Last Modified on13 May 2022

Eligibility

Yes No Not Sure

Inclusion Criteria

Written informed consent and HIPAA authorization for release of personal health information
NOTE: HIPAA authorization may be included in the informed consent or obtained
separately
Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2
Histological or cytological confirmed locally advanced or metastatic EGA. Known HER2 status prior to treatment initiation required. Known PDL1 CPS status prior to treatment initiation
Measurable disease according to RECIST v1.1
No prior lines of systemic therapy for advanced disease
Participants who had received neoadjuvant or adjuvant therapy or definitive chemoradiation will be allowed to participate if recurrence occurred 6 months or longer from the completion of all prior treatments
Demonstrate adequate organ function as defined below; all screening labs to be obtained within 14 days prior to registration
Absolute Neutrophil Count (ANC) ≥1,500 /μl without the use of hematopoietic growth factors
Hemoglobin (Hgb) ≥8 g/dL (blood transfusions are permitted for participants with hemoglobin levels below 8 g/dL)
Platelets ≥100,000 /μl
Serum creatinine ≤1.5 X upper limit of normal (ULN) OR Measured or calculated creatinine clearance (GFR can also be used in place of creatinine or CrCl). CrCl calculation using the Cockcroft-Gault formula. ≥50 mL/min for participants with creatinine levels > 1.5 X institutional ULN
Bilirubin within normal range for the institution (biliary drainage is allowed for biliary obstruction)
Aspartate aminotransferase (AST) ≤ 2.5 X ULN OR ≤ 5 X ULN for subjects with liver metastases
Alanine aminotransferase (ALT) ≤ 2.5 X ULN OR ≤ 5 X ULN for subjects with liver metastases
Albumin >3.0 g/dL
International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants
Activated Partial Thromboplastin Time (aPTT) ≤1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants
Women of childbearing potential should have a negative urine or serum pregnancy test
within 14 days of study registration. NOTE: Women are considered of child
Women of childbearing potential and males must be willing to abstain from heterosexual activity or to use a form of effective method of contraception from the time of informed consent until 30 days after treatment discontinuation
As determined by the enrolling physician or protocol designee, ability of the subject to understand and comply with study procedures for the entire length of the study
bearing potential unless they are surgically sterile (have undergone a
hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are
naturally postmenopausal for at least 12 consecutive months

Exclusion Criteria

Known hypersensitivity to 5-FU, oxaliplatin or other platinum agents, or any of the components of nal-IRI and other liposomal products
Known dihydropyrimidine dehydrogenase (DPD) deficiency (testing not required prior to enrollment)
Other active malignancy requiring treatment within the last 2 years. Exceptions include subjects with non-melanoma skin cancer, non-invasive/in situ cancer or low-risk prostate cancer requiring hormonal therapy only
Major surgery within 28 days or minor surgery within 14 days of the start of the study treatment, except for tumor biopsy or placement of central infusion device (port placement)
Radiotherapy less than 7 days prior to the start of the study treatment
Active infection requiring systemic therapy
Current therapy with other investigational agents or participation in another clinical study (supportive care and nontherapeutic trial participation allowed if not receiving an investigational drug). Participants may participate in prescreening for other therapeutic trials (prescreening of biologic sample for specific mutations, receptors, etc.)
Pregnant or breastfeeding
Known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis, which is excluded regardless of clinical stability
Severe arterial thromboembolic events (myocardial infarction, unstable angina pectoris, stroke) less than 6 months before inclusion
Participants who receive nivolumab or pembrolizumab in addition to chemotherapy should not have any contraindications to immune checkpoint inhibitors and should not have received immunotherapy agents for the treatment of EGA prior to study enrollment
NYHA Class III or IV congestive heart failure, ventricular arrhythmias or uncontrolled blood pressure
Participants must not have active autoimmune disease that has required systemic treatment in the past 2 years. Participants are permitted to receive immunotherapy l if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger (precipitating event)
Known history of Human Immunodeficiency Virus (HIV)
Participants must not have a condition requiring systemic treatment with either corticosteroids (>10 mg/day prednisone equivalents) or other immunosuppressive medications within 14 days of study immunotherapy administration. Inhaled or topical steroids and adrenal replacement doses (≤10 mg/day prednisone equivalent) are permitted. Participants with prior immune mediated adverse events related to immunotherapy that resulted in permanent treatment discontinuation with these agents
Psychological, familial, or sociological condition potentially hampering compliance
with the study protocol and follow-up schedule
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