Clinical Trials /

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

NCT04150640

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). The investigators hypothesize that this drug combination will be better tolerated than current first-line chemotherapy combinations for this disease.

Related Conditions:
  • Esophageal Adenocarcinoma
  • Gastric Adenocarcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: UW19029
  • SECONDARY ID: A534260
  • SECONDARY ID: SMPH/MEDICINE/MEDICINE*H
  • NCT ID: NCT04150640

Conditions

  • Esophageal Adenocarcinoma
  • Gastric Adenocarcinoma

Interventions

DrugSynonymsArms
Nal-IRIliposomal irinotecanCohort 1: HER2 Negative
OxaliplatinCohort 1: HER2 Negative
5-FUFluorouracilCohort 1: HER2 Negative
TrastuzumabCohort 2: HER2 Positive

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
Cohort 1: HER2 NegativeExperimentalParticipants in Cohort 1 (HER2-negative) will be treated with nal-IRI (60 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.
  • Nal-IRI
  • Oxaliplatin
  • 5-FU
Cohort 2: HER2 PositiveExperimentalParticipants in Cohort 2 (HER2-positive)will be treated with nal-IRI (60 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.
  • Nal-IRI
  • Oxaliplatin
  • 5-FU
  • Trastuzumab

Eligibility 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).
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Cohort 1: Objective Response Rate (ORR)
Time Frame:up to 1 year
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:Progression Free Survival (PFS)
Time Frame:up to 2 years
Safety Issue:
Description: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.
Measure:Disease Control Rate (DCR)
Time Frame:up to 1 year
Safety Issue:
Description: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.
Measure:Progression Free Survival at 6 months
Time Frame:up to 6 months
Safety Issue:
Description: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.
Measure:Progression Free Survival at 12 months
Time Frame:up to 1 year
Safety Issue:
Description: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.
Measure:Cohort 1: Incidence of Adverse Events
Time Frame:up to 1 year
Safety Issue:
Description:Toxicities and adverse events will be summarized in tabular format, stratified by type and severity
Measure:Cohort 2: Overall Response Rate
Time Frame:up to 1 year
Safety Issue:
Description: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).

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:University of Wisconsin, Madison

Last Updated