Liposomal iRInotecan, Carboplatin or oXaliplatin for Esophagogastric Cancer

NCT ID: NCT03764553

Last Updated: 2025-07-01

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 320 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-05-01
• Study Completion Date: 2026-07-01

Brief Summary

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.

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 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.

With the addition of nivolumab in the second quarter of 2022, the capecitabine combinations are expected to have a PFS benefit over the Nal-IRI of 0.65 months (50% of the 1.7 months seen in the CM6495, because 50% of the capecitabine regimens will be treated with nivolumab)

If the difference in the percentage of patients experiencing neurotoxicity grade 2-4 stays within the 10-30% range, an increase of at least 3.65 months of PFS identifies the most preferable combination strategy; if the percentage is ≤10% and the PFS increase <3.65 months, but in favor of carboplatin, then the choice should be based on other grade 3-4 toxicities observed; otherwise, the strategy with the lowest level of neurotoxicity grade 2-4 is the most preferable one. At least 4.65 months PFS should be gained to compensate for a difference in neurotoxicity grade 2-4 within the >30 to 50% range.

The total number to be included will be 272. Patients will first be tested for PD-L1 and then will be conditionally randomized. Patients with a PD-L1 CPS <5 or a contraindication for nivolumab treatment, will be randomized to respectively the Nal-IRI plus 5FU, the capecitabine plus carboplatin and capecitabine plus oxaliplatin group following a 2:1:1 scheme. Patients with a PD-L1 CPS ≥5 will be randomized to the capecitabine plus carboplatin and capecitabine plus oxaliplatin group following a 2:1 scheme and will receive nivolumab in addition to chemotherapy treatment.

Taking into account 15% withdrawal of patients from the trial before start of study medication, we will include 320 patients.

Conditions

Esophageal Cancer

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

No addition of nivolumab is possible for this arm

Group Type: EXPERIMENTAL

Liposomal Irinotecan

Intervention Type: DRUG

Iv liposomal irinotecan

5-fluorouracil

Intervention Type: DRUG

IV 5-fluorouracil

Leucovorin

Intervention Type: DRUG

IV Leucovorin

Carboplatin and capecitabine

IV and PO Capecitabine 1000 mg/m2 and carboplatin area under the curve (AUC5), every three weeks.

In case of PD-L1 CPS ≥5 only: nivolumab, dose according to local standard, iv day 1

Group Type: EXPERIMENTAL

Carboplatin

Intervention Type: DRUG

IV Carboplatin

Capecitabine

Intervention Type: DRUG

PO Capecitabine

oxaliplatin and capecitabine

IV and PO Capecitabine 1000 mg/m2 and oxaliplatin 130 mg/m2, every three weeks.

In case of PD-L1 CPS ≥5 only: nivolumab, dose according to local standard, iv day 1

Group Type: EXPERIMENTAL

Capecitabine

Intervention Type: DRUG

PO Capecitabine

Oxaliplatin

Intervention Type: DRUG

IV Oxaliplatin

Interventions

Liposomal Irinotecan

Iv liposomal irinotecan

Intervention Type: DRUG

Carboplatin

IV Carboplatin

Intervention Type: DRUG

Capecitabine

PO Capecitabine

Intervention Type: DRUG

Oxaliplatin

IV Oxaliplatin

Intervention Type: DRUG

5-fluorouracil

IV 5-fluorouracil

Intervention Type: DRUG

Leucovorin

IV Leucovorin

Intervention Type: DRUG

Other Intervention Names

Xeloda

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Servier

INDUSTRY

Sponsor Role: collaborator

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

OTHER

Sponsor Role: lead

Responsible Party

Hanneke W. M. van Laarhoven

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Jan M Prins, MD, PhD

Role: STUDY_DIRECTOR

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

Locations

Jeroen Bosch Ziekenhuis

's-Hertogenbosch, , Netherlands

Ziekenhuisgroep Twente

Almelo, , Netherlands

Flevoziekenhuis

Almere Stad, , Netherlands

Meander MC

Amersfoort, , Netherlands

Academic Medical Center, Medical Oncology

Amsterdam, , Netherlands

Rijnstate Ziekenhuis

Arnhem, , Netherlands

Amphia Ziekenhuis

Breda, , Netherlands

Reinier de Graaf Gasthuis

Delft, , Netherlands

Nij Smellinghe

Drachten, , Netherlands

Ziekenhuis Gelderse Vallei

Ede, , Netherlands

Catherina Ziekenhuis

Eindhoven, , Netherlands

Treant Zorggroep

Emmen, , Netherlands

Zuyderland Medisch Centrum

Geleen, , Netherlands

Admiraal de Ruijter Ziekenhuis

Goes, , Netherlands

Sint Jansdal

Harderwijk, , Netherlands

Elkerliek ziekenhuis

Helmond, , Netherlands

Tergooi ziekenhuizen

Hilversum, , Netherlands

Spaarne Gasthuis

Hoofddorp, , Netherlands

Treant zorggroep

Hoogeveen, , Netherlands

Dijklander ziekenhuis

Hoorn, , Netherlands

Medisch Centrum Leeuwarden

Leeuwarden, , Netherlands

Leids Universitair Medisch Centrum

Leiden, , Netherlands

Sint Antonius Ziekenhuis

Nieuwegein, , Netherlands

Canisius Wilherlmina ziekenhuis

Nijmegen, , Netherlands

Radboud Universitair Medisch Centrum

Nijmegen, , Netherlands

VieCurie

Roermond, , Netherlands

Laurentius Ziekenhuis

Roermond, , Netherlands

Bravis ziekenhuis locatie Roosendaal

Roosendaal, , Netherlands

Ikazia ziekenhuis

Rotterdam, , Netherlands

Maasstadziekenhuis

Rotterdam, , Netherlands

Rivierenland Ziekenhuis

Rotterdam, , Netherlands

Haaglanden Medisch Centrum

The Hague, , Netherlands

UMCU

Utrecht, , Netherlands

Isala Klinieken

Zwolle, , Netherlands

Countries

Netherlands

Provided Documents

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

2018_256

Identifier Type: -

Identifier Source: org_study_id