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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.

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

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

Liposomal Irinotecan

5-fluorouracil

Hanneke WM van Laarhoven, MD, PhD, PhD

Lyda ter Hofstede-Ruiter

Y Van der Wouw

Miriam Wumkes

Linda van Zutphen

Geert Cirkel

Els Wink

H WM van Laarhoven, MD, PhD, PhD

Lyda ter Hofstede

H. WM van Laarhoven, MD, PhD, PhD

T van Voorthuizen

H Verheij

A ten Tije

Debbie Arens

A J Vulink

C. Haazer

P Quarles

Yorik Visser

Jan Creemers

Marjan Laven

H K van Halteren

C van Netten

M Beerepoot

A Eerens

Y v.d. Wouw

W Heuts

M O den Boer

Wendy Heuts

Helga Droogendijk

José Schellekens

N Haj Mohammad

E van Liempt

Jan M Prins, MD, PhD

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.

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.

Liposomal iRInotecan, Carboplatin or oXaliplatin for Esophagogastric Cancer

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

Percentage of stroma and tumor immune infiltrate in metastatic tumor tissue as predictor of response to treatment and survival.

Growth velocity of tumor organoids after treatment measured in days

Concentration circulating tumour DNA (ctDNA) as a marker of response to treatment

Composition of the fecal microbiome as a potential biomarker for response to treatment and toxicity

The cost effectiveness in terms of QUALYs associated with treatment of F-Nal-IRI, CapCar and CapOx

Expression of ADAM12 in metastatic tumor tissue

Number of participants with treatment-related Neurotoxicity according to CTCAE v4.0

To determine the overall survival of F-Nal-IRI, capecitabine/Carboplatin (CapCar) and capecitabine/oxaliplatin (CapOx)

To determine the response rate of F-Nal-IRI, CapCar and CapOx

To determine the adverse events of F-Nal-IRI, CapCar and CapOx according to NCI common toxicity criteria (CTC) version 4

Overall Quality of life ranging from 0-100 with 100 being best Quality of Life

The percentage of patients proceeding to subsequent lines of treatment after progression and describe the types of treatment.

Reasons for forgoing subsequent treatment after progression on first-line treatment

Servier

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

Principal Investigator

Stomach Neoplasms

Stomach Cancer

Docetaxel

Bevacizumab

Antineoplastic Agents, Immunological

Angiogenesis Inhibitors

Growth Inhibitors

Tubulin Modulators

Antimitotic Agents

Given intravenously once a week for 3 out of four weeks for a minimum of 8 weeks and maximum of a year and a half

Given intravenously once a week for every other week for a minimum of 8 weeks and a maximum of a year and a half

Peter Enzinger, MD

The purpose of this study is to determine what effects (good and bad) bevacizumab (Avastin) and docetaxel (Taxotere), used in combination, have on metastatic gastric and esophageal cancer.

Bevacizumab will be administered intravenously in an outpatient clinic once a week, every other week. Docetaxel will also be administered intravenously in the outpatient clinic once a week for three out of four weeks. Blood tests and vital signs will be performed weekly.

After the first eight weeks of therapy a CT scan will be performed to determine and assess the progress of the disease. If therapy is continued, radiological procedures will be performed at week 16 and every 8 weeks thereafter.

Treatment will be given for a minimum of 8 weeks, as long as the patient does not experience unacceptable side effects. Chemotherapy will continue for a year and a half as long as the cancer is responding and there are no unacceptable side effects.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Liposomal iRInotecan, Carboplatin or oXaliplatin for Esophagogastric Cancer	NCT03764553	Esophageal Canc...	Liposomal Irino... Carboplatin Capecitabine Oxaliplatin 5-fluorouracil Leucovorin	18 Years -	Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Avastin and Taxotere for Esophagogastric Cancer	NCT00137813	Esophageal Canc... Gastric Cancer	Docetaxel Bevacizumab	18 Years -	Dana-Farber Cancer Institute
Avastin and Taxotere for Esophagogastric Cancer	NCT00137813	Esophageal Canc... Gastric Cancer	Docetaxel Bevacizumab	18 Years -	Dana-Farber Cancer Institute
Liposomal iRInotecan, Carboplatin or oXaliplatin for Esophagogastric Cancer	NCT03764553	Esophageal Canc...	Liposomal Irino... Carboplatin Capecitabine Oxaliplatin 5-fluorouracil Leucovorin	18 Years -	Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Spots Global Cancer Trial Database for metastatic esophagogastric cancer