Phase 2 Randomized Study of Liposomal Irinotecan, Carboplatin, and Oxaliplatin in First-Line Treatment of Metastatic or Locally Advanced Esophagogastric Cancer
- Trial ID
- 2023-509287-26-00
- Sponsor
- Amsterdam UMC Stichting
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to compare the **progression-free survival** (PFS 1) and neurotoxicity of first-line treatment regimens involving F-Nal-IRI, CapCar, and CapOx in patients with previously untreated metastatic or locally advanced esophagogastric cancer. This is clinically relevant as it aims to identify the most effective treatment with the least neurotoxic effects, potentially improving patient outcomes and quality of life.
Secondary objectives include:
- Determining the overall survival and response rate of F-Nal-IRI, CapCar, and CapOx.
- Assessing adverse events according to NCI CTCAE version 5.0.
- Evaluating patient-reported outcome measures for those treated with these regimens.
- Identifying the percentage of patients proceeding to subsequent lines of treatment after progression and describing the types of treatment.
- Determining reasons for forgoing subsequent treatment after progression on first-line treatment.
- Comparing the primary and secondary objectives for patients treated with and without nivolumab.
- Comparing progression-free survival after reintroduction of carboplatin, oxaliplatin, or Nal-IRI with progression-free survival after the start of second-line treatment.
Participants
The clinical trial involves participants diagnosed with **previously untreated metastatic or locally advanced esophagogastric cancer**. The study population includes both male and female adults aged 18 years and older. Participants are required to have a histologically confirmed diagnosis of metastatic or irresectable HER2 negative adenocarcinoma of the stomach or oesophagus, with HER2 positive patients eligible if trastuzumab treatment is contraindicated. The trial does not include a vulnerable population. Participants must have measurable disease as assessed by RECIST 1.1 and an ECOG performance status of 0-2. Adequate bone marrow and organ function are prerequisites, with specific laboratory values outlined for inclusion. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as diet and physical activity are not specified. The selection process ensures that participants have not received systemic therapy for irresectable or metastatic disease, although palliative radiotherapy is permissible under certain conditions. The trial population was selected based on these criteria to ensure a homogeneous group for evaluating the study's objectives.
Plans and Procedures
The clinical trial is designed as a **randomized**, phase II study to evaluate the efficacy and safety of various chemotherapeutic regimens in the first-line treatment of previously untreated metastatic or locally advanced esophagogastric cancer. The trial employs a **double-blind** methodology to ensure unbiased results, with participants randomly assigned to receive one of the investigational treatments. The primary objective is to compare progression-free survival and neurotoxicity among the treatment groups, with secondary endpoints including overall survival, quality of life, and response rate according to RECIST 1.1 criteria. The trial is expected to conclude by June 2026, with recruitment having commenced in July 2019.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically confirmed diagnosis, measurable disease, and adequate organ function. Following randomization, participants will attend regular follow-up visits to monitor treatment response and adverse events, as per NCI CTCAE version 5.0. The end-of-study visit will assess the final outcomes and gather data on any subsequent treatments. The expected duration of participant involvement is contingent upon the treatment arm, with a maximum treatment period ranging from 2 to 4 months, depending on the specific regimen.
Participants may be withdrawn from the study prematurely if they experience unacceptable toxicity, disease progression, or if they withdraw consent. Additionally, any psychological, familial, or geographical conditions that hinder compliance with the study protocol may also lead to early termination. The trial is conducted in accordance with ICH/GCP guidelines, ensuring ethical and scientific integrity throughout the study duration.
Treatment
The clinical trial involves the administration of several **experimental medications** for the treatment of esophagogastric cancer. The first medication is **Xeloda**, which contains the active substance **capecitabine**. It is provided in the form of 500 mg film-coated tablets. The route of administration is oral, with a maximum daily dose of 2000 mg/m² and a total maximum dose of 28000 mg/m² over a treatment period of up to 3 cycles. The pharmaceutical form is designed to ensure proper absorption and bioavailability of the active compound.
Another experimental medication used in the trial is **Onivyde**, a pegylated liposomal formulation containing **irinotecan**. It is supplied as a 4.3 mg/ml concentrate for dispersion for infusion. The administration route is intravenous, with a maximum daily dose of 70 mg/m² and a total maximum dose of 70 mg/m² over a treatment period of up to 2 cycles. The liposomal formulation is intended to enhance the delivery and efficacy of irinotecan.
**Carboplatin** is also utilized in the study, provided as a 10 mg/ml solution for intravenous infusion. The maximum daily and total dose is 750 mg, administered over a treatment period of up to 4 cycles. This formulation is designed for direct infusion, allowing for controlled delivery of the active substance.
**Oxaliplatin** is administered as a 5 mg/ml concentrate for solution for infusion. The route of administration is intravenous, with a maximum daily dose of 130 mg/m² and a total maximum dose of 130 mg/m² over a treatment period of up to 3 cycles. This formulation is intended to facilitate the controlled release of the active compound during infusion.
Lastly, **Fluorouracil** is provided as a 50 mg/ml solution for injection. It is administered intravenously, with a maximum daily dose of 12522 mg/m² and a total maximum dose of 2400 mg/m² over a treatment period of up to 2 cycles. The solution for injection is designed to ensure rapid and efficient delivery of the active substance.
Throughout the trial, participant compliance with dosing schedules is monitored to ensure adherence to the treatment protocol. The study does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatment. All medications are chemically synthesized and have been authorized for use in the trial by relevant regulatory bodies.
Efficacy
The efficacy of the clinical trial will be assessed primarily through the measurement of **progression-free survival** (PFS) and neurotoxicity. Progression-free survival 1 is defined as the time from the start of study treatment until the first moment of disease progression. Secondary endpoints include progression-free survival 2, quality of life, overall survival, response rate according to RECIST 1.1, adverse events according to NCI CTCAE version 5.0, and the percentage of patients proceeding to subsequent lines of treatment after progression. Additionally, the trial will evaluate reasons for forgoing subsequent treatment after progression and compare the primary and secondary objectives for patients treated with and without nivolumab.
Data collection will involve validated scales and laboratory tests to assess these parameters. The trial will utilize RECIST 1.1 criteria for measuring response rates and NCI CTCAE version 5.0 for adverse events. The schedule for measuring these endpoints will be aligned with the trial's progression, with specific timepoints for assessment not explicitly detailed. The trial aims to provide comprehensive data on the efficacy of the treatment regimens in patients with metastatic or irresectable adenocarcinoma of the stomach or esophagus.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Patients must provide written informed consent according to ICH/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 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 systemic therapy 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
- ECOG (WHO) performance status 0-2
- Patient has adequate bone marrow and organ function as defined by the following laboratory values: o Absolute Neutrophil Count (ANC) > 1.5 x 109 /L o Hemoglobin (Hgb) > 5.6 mmol/L o Platelets > 100 x 109 /L
- Serum total bilirubin within ≤ 1.5 x ULN (upper limit of normal); or total bilirubin < 3.0 x 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 (ALT) and aspartate aminotransferase (AST) < 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 pregnancy test (urine or serum; beta-human chorionic gonadotropin (β-hCG)) documented 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
- Any prior anti-cancer chemotherapy, biologic or investigational therapy for metastatic or irresectable stomach or oesophageal cancer
- Disease progression within six months after completion of (neo)adjuvant chemotherapy containing a fluoropyrimidine and/or platinum compound and/or irinotecan; progression on neoadjuvant or definitive chemoradiation with carboplatin AUC2 and paclitaxel 50 mg/m2 within this time frame is allowed.
- − All target lesions in a radiation field without documented disease progression
- 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 CYP3A-enzyme, CYP2C8, and/or strong 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 DPD inhibitors, including sorivudine or its chemically related analogues such as brivudine.
- Pre-existing motor or sensory neurotoxicity greater than CTCAE grade 1.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 The Netherlands | Not Recruiting | 01 Jul 2019 | — |
| Netherlands | — | — | 322 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Fluorouracil 50mg/ml Injection. | Test | INJECTION | INTRAVENOUS ADMINISTRATION | 12522 | 2 | PRD4730727 |
Carboplatin 10 mg/ml Intravenous Infusion | Test | INTRAVENOUS INFUSION | IV INFUSION | 750 | 4 | PRD1161259 |
OPDIVO 10 mg/mL concentrate for solution for infusion. | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 360 | 3 | PRD2941372 |
Onivyde pegylated liposomal 4.3 mg/ml concentrate for dispersion for infusion | Test | CONCENTRATE FOR DISPERSION FOR INFUSION | INTRAVENOUS ADMINISTRATION | 70 | 2 | PRD6811022 |
Xeloda 500 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL | 2000 | 3 | PRD9863936 |
Oxaliplatin 5mg/ml concentrate for Solution for Infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS ADMINISTRATION | 130 | 3 | PRD8604637 |