Clinical trial NCT03764553: Liposomal iRInotecan, Carboplatin or oXaliplatin for Esophagogastric Cancer
Official title: Liposomal iRInotecan, Carboplatin or oXaliplatin in the First Line Treatment of Esophagogastric Cancer: a Randomized Phase 2 Study
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Esophageal Cancer
Keywords: palliative chemotherapy
metastatic esophagogastric cancer
Efficacy
toxicity
Lead sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Sponsor class: OTHER
Collaborators: name: Servier
First posted: 2018-12-05
Enrollment: 320
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: phase 2 study
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Progression free survival
timeFrame: 42 months
measure: Number of participants with treatment-related Neurotoxicity
timeFrame: 42 months
Secondary outcomes:
measure: Overall survival
timeFrame: 54 months
measure: response rate
timeFrame: 42 months
measure: adverse events
timeFrame: 42 months
measure: Quality of life (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ C30))
timeFrame: 42 months
measure: percentage subsequent treatment lines
timeFrame: 42 months
measure: the reasons for forgoing subsequent treatment
timeFrame: 42 months
Other outcomes:
measure: Tumor micro environment
timeFrame: 54 months
measure: Stromal markers in blood
timeFrame: 54 months
measure: Growth velocity of patient derived tumor organoids
timeFrame: 54 months
measure: ctDNA
timeFrame: 54 months
measure: Fecal microbiome
timeFrame: 54 months
measure: Costs associated with treatment of F-Nal-IRI, CapCar and CapOx
timeFrame: 54 months
measure: Stromal Markers in tumor
timeFrame: 54 months
Locations:
city: 's-Hertogenbosch
country: Netherlands
facility: Jeroen Bosch Ziekenhuis
city: Almelo
country: Netherlands
facility: Ziekenhuisgroep Twente
city: Almere
country: Netherlands
facility: Flevoziekenhuis
city: Amersfoort
country: Netherlands
facility: Meander MC
city: Amsterdam
country: Netherlands
facility: Academic Medical Center, Medical Oncology
city: Arnhem
country: Netherlands
facility: Rijnstate Ziekenhuis
city: Breda
country: Netherlands
facility: Amphia Ziekenhuis
city: Delft
country: Netherlands
facility: Reinier de Graaf Gasthuis
city: Den Haag
country: Netherlands
facility: Hagaziekenhuis
city: Den Haag
country: Netherlands
facility: Haaglanden Medisch Centrum
city: Drachten
country: Netherlands
facility: Nij Smellinghe
city: Ede
country: Netherlands
facility: Ziekenhuis Gelderse Vallei
city: Eindhoven
country: Netherlands
facility: Catherina Ziekenhuis
city: Emmen
country: Netherlands
facility: Treant Zorggroep
city: Geleen
country: Netherlands
facility: Zuyderland Medisch Centrum
city: Goes
country: Netherlands
facility: Admiraal de Ruijter Ziekenhuis
city: Harderwijk
country: Netherlands
facility: Sint Jansdal
city: Helmond
country: Netherlands
facility: Elkerliek ziekenhuis
city: Hilversum
country: Netherlands
facility: Tergooi ziekenhuizen
city: Hoofddorp
country: Netherlands
facility: Spaarne Gasthuis
city: Hoogeveen
country: Netherlands
facility: Treant zorggroep
city: Hoorn
country: Netherlands
facility: Dijklander ziekenhuis
city: Leeuwarden
country: Netherlands
facility: Medisch Centrum Leeuwarden
city: Leiden
country: Netherlands
facility: Leids Universitair Medisch Centrum
city: Nieuwegein
country: Netherlands
facility: Sint Antonius Ziekenhuis
city: Nijmegen
country: Netherlands
facility: Canisius Wilherlmina ziekenhuis
city: Nijmegen
country: Netherlands
facility: Radboud Universitair Medisch Centrum
city: Roermond
country: Netherlands
facility: VieCurie
city: Roermond
country: Netherlands
facility: Laurentius Ziekenhuis
city: Roosendaal
country: Netherlands
facility: Bravis ziekenhuis locatie Roosendaal
city: Rotterdam
country: Netherlands
facility: Ikazia ziekenhuis
city: Rotterdam
country: Netherlands
facility: Maasstadziekenhuis
city: Rotterdam
country: Netherlands
facility: Rivierenland Ziekenhuis
city: Utrecht
country: Netherlands
facility: UMCU
city: Zwolle
country: Netherlands
facility: Isala Klinieken
Study officials:
affiliation: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
name: Jan M Prins, MD, PhD
role: STUDY_DIRECTOR
References: