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P2 5-FU, Oxaliplatin & Liposomal Irinotecan (Nal-IRI) in 1st Line Advanced Esophageal & Gastric

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ClinicalTrials.gov Identifier: NCT04150640
Recruitment Status : Recruiting
First Posted : November 5, 2019
Last Update Posted : August 5, 2020
Sponsor:
Collaborator:
Ipsen
Information provided by (Responsible Party):
University of Wisconsin, Madison

Brief Summary:
This is an open label, phase II, multi-site trial evaluating the efficacy and safety of the combination of 5-FU, oxaliplatin and nal-IRI (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.

Condition or disease Intervention/treatment Phase
Esophageal Adenocarcinoma Gastric Adenocarcinoma Drug: Nal-IRI Drug: Oxaliplatin Drug: 5-FU Drug: Trastuzumab Phase 2

Detailed Description:

This is an open label, phase II, multi-site trial evaluating the efficacy and safety of the combination of 5-FU, oxaliplatin and nal-IRI (plus trastuzumab for HER2-positive tumors) as first-line therapy for participants with advanced Esophageal and Gastric Adenocarcinoma (EGA). Participants in Cohort 1 will receive 5-FU, oxaliplatin and nal-IRI. Participants in Cohort 2 will receive trastuzumab in addition to 5-FU, oxaliplatin and nal-IRI. Chemotherapy doses will be the same for both cohorts and will follow the same dose modifications for toxicities. Nal-IRI will be administered first. 5-FU and Oxaliplatin and trastuzumab will be administered after nal-IRA as per institutional standards when similar regimens (such as FOLFIRINOX) are administered.

Cohort 1 (HER2-negative tumors): Initially, 13 evaluable participants will be accrued to Cohort 1. If at most 5 objective responses are observed among the 13 subjects, then the study will be terminated early due to an unacceptably low response rate. Otherwise, an additional 15 evaluable participants will be enrolled in the second stage for a total of 28 evaluable subjects.

Cohort 2 (HER2-positive tumors): 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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 34 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase 2 Trial of 5-Fluorouracil, Oxaliplatin and Liposomal Irinotecan (Plus Trastuzumab for HER2-positive Disease) During 1st Line Treatment of Advanced Esophageal and Gastric Adenocarcinoma
Actual Study Start Date : July 13, 2020
Estimated Primary Completion Date : December 2022
Estimated Study Completion Date : December 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Cohort 1: HER2 Negative
Participants in Cohort 1 (HER2-negative) will be treated with nal-IRI (50 mg/m^2 - intravenously over 90 min), 5-FU (2400 mg/m^2 over 46 hrs), and oxaliplatin (60 mg/m^2). Each cycle is 28 days. Participants will receive treatments on day 1 and 15 of each cycle.
Drug: Nal-IRI
chemotherapy drug
Other Name: liposomal irinotecan

Drug: Oxaliplatin
chemotherapy drug

Drug: 5-FU
chemotherapy drug
Other Name: Fluorouracil

Experimental: Cohort 2: HER2 Positive
Participants in Cohort 2 (HER2-positive)will be treated with nal-IRI (50 mg/m^2 - intravenously over 90 min), trastuzumab (6 mg/kg C1D1, then 4 mg/kg on each subsequent treatment days), 5-FU (2400 mg/m^2 over 46 hrs), and oxaliplatin (60 mg/m^2). Each cycle is 28 days. Participants will receive treatments on day 1 and 15 of each cycle.
Drug: Nal-IRI
chemotherapy drug
Other Name: liposomal irinotecan

Drug: Oxaliplatin
chemotherapy drug

Drug: 5-FU
chemotherapy drug
Other Name: Fluorouracil

Drug: Trastuzumab
chemotherapy drug




Primary Outcome Measures :
  1. Cohort 1: Objective Response Rate (ORR) [ Time Frame: up to 1 year ]
    ORR will be calculated by combining the number of participants who achieve complete response and partial response per RECIST 1.1 criteria, from the start of treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the start of treatment). An ORR of 40% or less for proposed combination of 5-Fluorouracil, Oxaliplatin and nal-IRI during 1st line treatment of advanced esophageal and gastric adenocarcinoma in HER2-negative subjects will be considered as unacceptably low. The number and frequencies of objectives responses will be summarized in tabular format. The ORR will be reported along with the corresponding one-sided 90% confidence intervals.

  2. Cohort 2: Incidence of Adverse Events [ Time Frame: up to 1 year ]
    The primary objective of cohort 2 (HER2-positive EGA) is to evaluate safety and tolerability of the studied drug combination. Toxicities and adverse events will be summarized by type and severity in tabular format.


Secondary Outcome Measures :
  1. Progression Free Survival (PFS) [ Time Frame: up to 2 years ]
    PFS will be defined from the date study enrollment to the date of progression event or death. If a participant does not experience a progression event at the end of the follow-up period, then the PFS will be censored at the last assessment date. PFS will be analyzed using the Kaplan-Meier method. Median PFS will be reported along with the corresponding 90% confidence interval which will be constructed using the nonparametric Brookmeyer-Crooley method.

  2. Disease Control Rate (DCR) [ Time Frame: up to 1 year ]
    The DCR is the proportion of all participants with stable disease (SD) for 8 weeks, or partial response (PR), or complete response (CR) according to RECIST 1.1, from the start of treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the start of treatment).DCR will be reported along with the corresponding 90% confidence intervals which will be constructed using the Wilson score method.

  3. Progression Free Survival at 6 months [ Time Frame: up to 6 months ]
    PFS will be defined from the date study enrollment to the date of progression event or death. If a participant does not experience a progression event at the end of the follow-up period, then the PFS will be censored at the last assessment date. PFS will be analyzed using the Kaplan-Meier method. Median PFS will be reported along with the corresponding 90% confidence interval which will be constructed using the nonparametric Brookmeyer-Crooley method.

  4. Progression Free Survival at 12 months [ Time Frame: up to 1 year ]
    PFS will be defined from the date study enrollment to the date of progression event or death. If a participant does not experience a progression event at the end of the follow-up period, then the PFS will be censored at the last assessment date. PFS will be analyzed using the Kaplan-Meier method. Median PFS will be reported along with the corresponding 90% confidence interval which will be constructed using the nonparametric Brookmeyer-Crooley method.

  5. Cohort 1: Incidence of Adverse Events [ Time Frame: up to 1 year ]
    Toxicities and adverse events will be summarized in tabular format, stratified by type and severity

  6. Cohort 2: Overall Response Rate [ Time Frame: up to 1 year ]
    ORR will be calculated by combining the number of participants who achieve complete response and partial response per RECIST 1.1 criteria, from the start of treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the start of treatment).



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.
  • 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 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
  • 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.

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.
  • Current therapy with other investigational agents or participation in another clinical study.
  • 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
  • Psychological, familial, or sociological condition potentially hampering compliance with the study protocol and follow-up schedule.
  • Active infection requiring systemic therapy.
  • 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.
  • NYHA Class III or IV congestive heart failure, ventricular arrhythmias or uncontrolled blood pressure.
  • Known history of Human Immunodeficiency Virus (HIV).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04150640


Contacts
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Contact: Cancer Connect (800) 622-8922 clinicaltrials@cancer.wisc.edu

Locations
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United States, Wisconsin
University of Wisconsin Carbone Cancer Center Recruiting
Madison, Wisconsin, United States, 53792
Contact: Cancer Connect    800-622-8922    clinicaltrials@cancer.wisc.edu   
Principal Investigator: Nataliya Uboha, MD, PhD         
Sponsors and Collaborators
University of Wisconsin, Madison
Ipsen
Investigators
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Principal Investigator: Nataliya Uboha, MD, PhD University of Wisconsin, Madison
Additional Information:
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Responsible Party: University of Wisconsin, Madison
ClinicalTrials.gov Identifier: NCT04150640    
Other Study ID Numbers: UW19029
A534260 ( Other Identifier: UW Madison )
SMPH/MEDICINE/HEM-ONC ( Other Identifier: UW Madison )
2019-0632 ( Other Identifier: Institutional Review Board )
NCI-2019-07966 ( Registry Identifier: NCI Trial ID )
Protocol Version 2/27/2020 ( Other Identifier: UW Madison )
First Posted: November 5, 2019    Key Record Dates
Last Update Posted: August 5, 2020
Last Verified: August 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Additional relevant MeSH terms:
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Adenocarcinoma
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Fluorouracil
Oxaliplatin
Irinotecan
Trastuzumab
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antimetabolites, Antineoplastic
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Topoisomerase I Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Antineoplastic Agents, Immunological