Liposomal iRInotecan, Carboplatin or oXaliplatin for Esophagogastric Cancer

Esophageal Cancer Clinical Trial

— LyRICX  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03764553
• Other study ID #: 2018_256
• Status: Recruiting
• Phase: Phase 2
• Start date: May 1, 2019
• Est. completion date: August 1, 2024

Study information

• Verified date: December 2022
• Source: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
• Contact: Hanneke WM van Laarhoven, MD, PhD, PhD
• Phone: 31 20 5665955
• Email: h.vanlaarhoven[@]amc.nl
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 310
• Est. completion date: August 1, 2024
• Est. primary completion date: August 1, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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 (ß-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.

Related Conditions & MeSH terms

• Esophageal Cancer

Intervention

Drug:
• Liposomal Irinotecan
Iv liposomal irinotecan
• Carboplatin
IV Carboplatin
• Capecitabine
PO Capecitabine
• Oxaliplatin
IV Oxaliplatin
• 5-fluorouracil
IV 5-fluorouracil
• Leucovorin
IV Leucovorin

Locations

Country	Name	City	State
Netherlands	Jeroen Bosch Ziekenhuis	's-Hertogenbosch
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	Hagaziekenhuis	Den Haag
Netherlands	Catherina Ziekenhuis	Eindhoven
Netherlands	Admiraal de Ruijter Ziekenhuis	Goes
Netherlands	Treant zorggroep	Hoogeveen
Netherlands	Laurentius Ziekenhuis	Roermond
Netherlands	VieCurie	Roermond
Netherlands	Bravis ziekenhuis locatie Roosendaal	Roosendaal
Netherlands	UMCU	Utrecht
Netherlands	VieCuri	Venlo	Limburg

Sponsors (2)

Lead Sponsor	Collaborator
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)	Servier

Country where clinical trial is conducted

Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Tumor micro environment	Percentage of stroma and tumor immune infiltrate in metastatic tumor tissue as predictor of response to treatment and survival.	54 months
Other	Stromal markers in blood	Concentration of ADAM12 in blood	54 months
Other	Growth velocity of patient derived tumor organoids	Growth velocity of tumor organoids after treatment measured in days	54 months
Other	ctDNA	Concentration circulating tumour DNA (ctDNA) as a marker of response to treatment	54 months
Other	Fecal microbiome	Composition of the fecal microbiome as a potential biomarker for response to treatment and toxicity	54 months
Other	Costs associated with treatment of F-Nal-IRI, CapCar and CapOx	The cost effectiveness in terms of QUALYs associated with treatment of F-Nal-IRI, CapCar and CapOx	54 months
Other	Stromal Markers in tumor	Expression of ADAM12 in metastatic tumor tissue	54 months
Primary	Progression free survival	To compare the progression free survival	42 months
Primary	Number of participants with treatment-related Neurotoxicity	Number of participants with treatment-related Neurotoxicity according to CTCAE v4.0	42 months
Secondary	Overall survival	To determine the overall survival of F-Nal-IRI, capecitabine/Carboplatin (CapCar) and capecitabine/oxaliplatin (CapOx)	54 months
Secondary	response rate	To determine the response rate of F-Nal-IRI, CapCar and CapOx	42 months
Secondary	adverse events	To determine the adverse events of F-Nal-IRI, CapCar and CapOx according to NCI common toxicity criteria (CTC) version 4	42 months
Secondary	Quality of life (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ C30))	Overall Quality of life ranging from 0-100 with 100 being best Quality of Life	42 months
Secondary	percentage subsequent treatment lines	The percentage of patients proceeding to subsequent lines of treatment after progression and describe the types of treatment.	42 months
Secondary	the reasons for forgoing subsequent treatment	Reasons for forgoing subsequent treatment after progression on first-line treatment	42 months