Liposomal iRInotecan, Carboplatin or oXaliplatin for Esophagogastric Cancer (LyRICX)

December 15, 2022 updated by: H.W.M. van Laarhoven, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Liposomal iRInotecan, Carboplatin or oXaliplatin in the First Line Treatment of Esophagogastric Cancer: a Randomized Phase 2 Study

This is a multi-center, open label, randomized phase II trial for patients with previously untreated metastatic or locally advanced esophagogastric cancer, using a pick the winner design to identify the best combination therapy in terms of progression free survival and neurotoxicity.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

The sample size to identify the best combination therapy is based on the following decision making strategy. With less or even zero neurotoxicity grade 2-4 (defined as worst toxicity), the Nal-IRI plus 5FU/LV (Fluorouracil/leucovorin)combination is expected to outperform the standard combination capecitabine plus oxaliplatin and may also outperform capecitabine plus carboplatin. To compensate for a higher neurotoxicity grade 2-4 level, the capecitabine combinations should demonstrate increased progression free survival (PFS) according to the next schedule.

Table 1. Decision making strategy

Difference in % neurotoxicity grade 2-4 Compensating Increase in PFS >10 - 30% + 3 months >30 - 50% + 4 months

The total number to be included will be 269. Patients will be randomized to respectively the Nal-IRI plus 5FU, the capecitabine plus carboplatin and capecitabine plus oxaliplatin group following a 2:2:1 scheme until 49 patients have been included in the capecitabine plus oxaliplatin group and following a 1:1:0 scheme 10 afterwards for the remaining patients. Taking into account 15% withdrawal of patients from the trial before start of study medication, the investigators will include 310 patients.

Study Type

Interventional

Enrollment (Anticipated)

310

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

  • Name: Lyda ter Hofstede-Ruiter
  • Phone Number: 31 20 5665955
  • Email: l.ruiter@amc.nl

Study Locations

  • Netherlands
      • 's-Hertogenbosch, Netherlands, 5223 GZ
        • Recruiting
        • Jeroen Bosch Ziekenhuis
        • Contact:
        • Contact:
      • Amersfoort, Netherlands
      • Amsterdam, Netherlands, 1100 DD
        • Recruiting
        • Academic Medical Center, Medical Oncology
      • Arnhem, Netherlands, 6815 AD
      • Breda, Netherlands, 4818 CK
        • Recruiting
        • Amphia Ziekenhuis
        • Contact:
        • Contact:
      • Delft, Netherlands, 2625 AD
        • Recruiting
        • Reinier de Graaf Gasthuis
        • Contact:
        • Contact:
      • Den Haag, Netherlands, 2545 AA
      • Eindhoven, Netherlands
      • Goes, Netherlands, 4460 AA
        • Recruiting
        • Admiraal de Ruijter Ziekenhuis
        • Contact:
        • Contact:
      • Hoogeveen, Netherlands, 7909 AA
      • Roermond, Netherlands, 6043 CV
      • Roermond, Netherlands
      • Roosendaal, Netherlands, 4708 AE
      • Utrecht, Netherlands, 3508 GA
    • Limburg
      • Venlo, Limburg, Netherlands, 5912 BL
        • Recruiting
        • VieCuri
        • Contact:
          • Y Van der Wouw

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Patients must provide written informed consent according to International Conference on Harmonization (ICH)/Guideline for Good Clinical practice (GCP), and national/local regulations prior to any screening procedures.
  • Male or female adult patients (> 18 years).
  • Patients with histologically confirmed diagnosis of metastatic or irresectable human epidermal growth (HER2) negative adenocarcinoma of the stomach or oesophagus; patients with HER2 positive disease are eligible when treatment with trastuzumab is contraindicated. If histology cannot be obtained, cytology is acceptable to prove metastatic disease.
  • Patients with metastatic or irresectable adenocarcinoma of the stomach or oesophagus not pre-treated with chemotherapy or radiotherapy for irresectable or metastatic disease. Palliative radiotherapy on the primary tumor or a metastatic lesion is allowed if other untreated lesions eligible for evaluation are present.
  • Measurable disease as assessed by RECIST 1.1
  • Eastern Cooperative Oncology Group (ECOG) (WHO) performance status 0-2

  • Patient has adequate bone marrow and organ function as defined by the following laboratory values:

    • Absolute Neutrophil Count (ANC) > 1.5 x 109 /L
    • Hemoglobin (Hgb) > 5.6 mmol/L
    • Platelets > 100 x 109 /L
  • Serum total bilirubin within ≤ 1.5 x ULN (upper limit of normal); or total bilirubin < 3.0 x upper limit of normal (ULN) with direct bilirubin within normal range in patients with well documented Gilbert's syndrome; biliary drainage is allowed for biliary obstruction
  • Serum creatinine < 1.5 x ULN or creatinine clearance >30 mL/min/1.73 m2
  • Alanine aminotransferase (AST) and aspartate aminotransferase (ALT) < 2.5x ULN within normal range or < 5.0 x ULN if liver metastases are present
  • If a female patient is of child-bearing potential, as evidenced by regular menstrual periods, she must have a negative serum pregnancy test, beta-human chorionic gonadotropin (β-hCG) documented 72 hours prior to the first administration of study drug. If sexually active, the patient must agree to use contraception considered adequate and appropriate by the Investigator during the period of administration of study drug and after the end of treatment as recommended.
  • Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial.

Exclusion Criteria:

  • Prior systemic treatment for metastatic or irresectable stomach or oesophageal cancer.
  • Evidence of disease progression within six months after completion of adjuvant or neoadjuvant treatment (whichever is last) containing a fluoropyrimidine and/or platinum compound and/or irinotecan; progression on neoadjuvant chemoradiation with carboplatin area under the curve (AUC2) and paclitaxel 50 mg/m2 within this time frame is allowed.
  • All target lesions in a radiation field without documented disease progression. 11
  • Patient has known brain metastases, unless previously treated and well-controlled for at least 3 months (defined as clinically stable, no edema, no steroids and stable in 2 scans at least 4 weeks apart).
  • Past or current malignancy other than entry diagnosis interfering with prognosis of metastatic esophagogastric cancer.
  • Known uncontrollable hypersensitivity or contraindications to any of the components of liposomal irinotecan (Nal-IRI) other liposomal irinotecan formulations, irinotecan, fluoropyrimidines, leucovorin, oxaliplatin, carboplatin. Patients with previous dose reductions or delays are eligible.
  • Complete dihydropyrimidine dehydrogenase deficiency .
  • Patient has active, uncontrolled bacterial, viral or fungal infection(s) requiring systemic therapy.
  • Patient has known past or active infection with human immunodeficiency virus (HIV), hepatitis B or hepatitis C.
  • Signs of interstitial lung disease (ILD)
  • Patient has any other concurrent severe and/or uncontrolled medical condition that would, in the investigator's judgment contraindicate patient participation in the clinical study.
  • Use of other investigational drugs within 30 days of enrollment.
  • Patient is enrolled in any other clinical protocol or investigational trial that will interfere with the primary endpoint.
  • Patients who in the investigators' opinion may be unwilling, unable or unlikely to comply with requirements of the study protocol.
  • Current use or any use in last two weeks of strong cytochrome P4503A (CYP3A-enzyme), CYP2C8, and/or strong UDP glucuronosyltransferase (UGT1A) inhibitors/inhibitors
  • Breast feeding, known pregnancy, positive serum pregnancy test or unwillingness to use a reliable method of birth control, during therapy and for 3 months following the last dose of study treatment.
  • Treatment within 4 weeks with dihydropyrimidine dehydrogenase (DPD) inhibitors, including sorivudine or its chemically related analogues such as brivudine.
  • Pre-existing motor or sensory neurotoxicity greater than WHO grade 1.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: RANDOMIZED
  • Interventional Model: PARALLEL
  • Masking: NONE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
EXPERIMENTAL: Liposomal irinotecan, leucovorin and 5FU
IV Nal-IRI 80 mg/m² (expressed as irinotecan hydrochloride (HCl) salt), folinic acid 400 mg/m², fluorouracil 2400 mg/m² over 46 h, every 2 weeks.
Drug: Liposomal Irinotecan
Iv liposomal irinotecan
Drug: 5-fluorouracil
IV 5-fluorouracil
Drug: Leucovorin
IV Leucovorin
EXPERIMENTAL: Carboplatin and capecitabine
IV and PO Capecitabine 1000 mg/m2 and carboplatin area under the curve (AUC5), every three weeks.
Drug: Carboplatin
IV Carboplatin
Drug: Capecitabine
PO Capecitabine
Other Names:
  • Xeloda
EXPERIMENTAL: oxaliplatin and capecitabine
IV and PO Capecitabine 1000 mg/m2 and oxaliplatin 130 mg/m2, every three weeks.
Drug: Capecitabine
PO Capecitabine
Other Names:
  • Xeloda
Drug: Oxaliplatin
IV Oxaliplatin

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Progression free survival
Time Frame: 42 months
To compare the progression free survival
42 months
Number of participants with treatment-related Neurotoxicity
Time Frame: 42 months
Number of participants with treatment-related Neurotoxicity according to CTCAE v4.0
42 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Overall survival
Time Frame: 54 months
To determine the overall survival of F-Nal-IRI, capecitabine/Carboplatin (CapCar) and capecitabine/oxaliplatin (CapOx)
54 months
response rate
Time Frame: 42 months
To determine the response rate of F-Nal-IRI, CapCar and CapOx
42 months
adverse events
Time Frame: 42 months
To determine the adverse events of F-Nal-IRI, CapCar and CapOx according to NCI common toxicity criteria (CTC) version 4
42 months
Quality of life (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ C30))
Time Frame: 42 months
Overall Quality of life ranging from 0-100 with 100 being best Quality of Life
42 months
percentage subsequent treatment lines
Time Frame: 42 months
The percentage of patients proceeding to subsequent lines of treatment after progression and describe the types of treatment.
42 months
the reasons for forgoing subsequent treatment
Time Frame: 42 months
Reasons for forgoing subsequent treatment after progression on first-line treatment
42 months

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Tumor micro environment
Time Frame: 54 months
Percentage of stroma and tumor immune infiltrate in metastatic tumor tissue as predictor of response to treatment and survival.
54 months
Stromal markers in blood
Time Frame: 54 months
Concentration of ADAM12 in blood
54 months
Growth velocity of patient derived tumor organoids
Time Frame: 54 months
Growth velocity of tumor organoids after treatment measured in days
54 months
ctDNA
Time Frame: 54 months
Concentration circulating tumour DNA (ctDNA) as a marker of response to treatment
54 months
Fecal microbiome
Time Frame: 54 months
Composition of the fecal microbiome as a potential biomarker for response to treatment and toxicity
54 months
Costs associated with treatment of F-Nal-IRI, CapCar and CapOx
Time Frame: 54 months
The cost effectiveness in terms of QUALYs associated with treatment of F-Nal-IRI, CapCar and CapOx
54 months
Stromal Markers in tumor
Time Frame: 54 months
Expression of ADAM12 in metastatic tumor tissue
54 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Collaborators

Servier

Investigators

  • Study Director: Jan M Prins, MD, PhD, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

May 1, 2019

Primary Completion (ANTICIPATED)

August 1, 2024

Study Completion (ANTICIPATED)

August 1, 2024

Study Registration Dates

First Submitted

October 29, 2018

First Submitted That Met QC Criteria

December 3, 2018

First Posted (ACTUAL)

December 5, 2018

Study Record Updates

Last Update Posted (ACTUAL)

December 16, 2022

Last Update Submitted That Met QC Criteria

December 15, 2022

Last Verified

December 1, 2022

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2018_256

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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