Comparison of Ramucirumab with Irinotecan, Leucovorin, and 5-FU Versus Ramucirumab with Paclitaxel in Advanced or Metastatic Gastric Adenocarcinoma
- Trial ID
- 2024-512934-14-00
- Protocol
- RAMIRIS
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to compare **overall survival** (OS) in patients with locally advanced, inoperable, or metastatic esophagogastric adenocarcinoma receiving FOLFIRI with **ramucirumab** versus paclitaxel with ramucirumab as second-line therapy. This comparison is crucial for determining the most effective treatment regimen for patients who have failed prior taxane-containing therapy. OS is defined as the time from randomization to death from any cause, providing a direct measure of treatment efficacy in prolonging life.
Secondary objectives include:
- Comparing the treatment arms in terms of **disease control rate** (DCR), defined as the proportion of patients with complete or partial remission or stable disease according to RECIST 1.1.
- Evaluating **progression-free survival** (PFS), defined as the time from randomization to disease progression or death from any cause.
- Assessing **quality of life** (QoL) as measured by EORTC-QLQ-C30 during treatment and follow-up until 30 days after the end of treatment or until progression or the start of new anticancer therapy.
Participants
The clinical trial involves participants diagnosed with **advanced or metastatic adenocarcinoma** of the stomach or gastroesophageal junction, who have not responded to prior palliative chemotherapy. The study population includes both male and female subjects aged 18 years and older. Participants are required to have a histologically confirmed diagnosis of gastric adenocarcinoma, including adenocarcinoma of the esophagogastric junction, with metastatic or locally advanced disease that is not suitable for potentially curative resection. The trial population was selected based on their ability to comply with scheduled assessments and manage toxicities, as well as their adequate hematological, hepatic, and renal functions. Participants must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 and a life expectancy greater than 12 weeks. The trial does not specify the total number of participants, as this information was not provided by the sponsor. Lifestyle considerations such as diet, physical activity, or habits are not detailed in the available data. The study includes a vulnerable population, and both genders are eligible to participate without any specific gender distribution requirements.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy of **ramucirumab** in combination with either **irinotecan hydrochloride trihydrate**, **leucovorin**, and **fluorouracil** or **paclitaxel** in patients with advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction who have failed one prior line of palliative chemotherapy. This is a randomized, double-blind, controlled trial with a phase II/III design. The trial aims to compare overall survival and objective overall response rate between the two treatment groups. The trial is expected to conclude by October 31, 2025, with recruitment having started on May 10, 2017.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, histological confirmation of gastric adenocarcinoma, and adequate organ function. Follow-up visits will be scheduled to monitor treatment response and manage any adverse events. The end-of-study visit will evaluate the overall outcomes and gather final data. The expected length of participant involvement is up to 12 months, with conditions for early termination including disease progression, unacceptable toxicity, or withdrawal of consent.
Key elements of the research methodology include the use of **RECIST 1.1** criteria for assessing response rates and Kaplan-Meier analysis for overall survival. The trial will also assess secondary endpoints such as progression-free survival, tumor control rate, safety, tolerability, and quality of life. Participants are required to provide informed consent and comply with scheduled assessments and management of toxicities. The trial is not categorized as low intervention and is conducted under strict regulatory compliance to ensure the safety and well-being of participants.
Treatment
The clinical trial involves the administration of several experimental medications, each with specific pharmaceutical forms, dosages, and administration routes. **Cyramza** (ramucirumab) is provided as a 10 mg/ml concentrate for solution for infusion. It is administered intravenously with a maximum daily dose of 8 mg/kg and a total maximum dose of 208 mg/kg over a treatment period of 12 months. The active substance, ramucirumab, is a protein-based therapeutic agent.
**Irinotecan Aurobindo** and **Irinotecan Kabi** are both formulations of irinotecan hydrochloride trihydrate, available as a 20 mg/ml concentrate for solution for infusion. These are administered intravenously with a maximum daily dose of 180 mg/kg and a total maximum dose of 4680 mg/kg over 12 months. The active substance is chemically derived.
**Paclitaxel Accord**, **Paclitaxel Aurobindo**, and **Paclitaxel Ribosepharm** are formulations of paclitaxel, each provided as a 6 mg/ml concentrate for solution for infusion. These are administered intravenously with a maximum daily dose of 80 mg/kg and a total maximum dose of 3120 mg/kg over 12 months. The active substance is chemically derived.
**Leucovorin** (calcium folinate pentahydrate) and **Calciumfolinat Sandoz** (folinic acid) are provided as a 10 mg/ml solution for injection/infusion. These are administered intravenously with a maximum daily dose of 400 mg/kg and a total maximum dose of 10400 mg/kg over 12 months. The active substances are chemically derived.
**Fluorouracil Accord**, **Fluorouracile Teva**, and **5-FU medac** are formulations of fluorouracil, provided as solutions for injection/infusion. These are administered intravenously with a maximum daily dose of 400 mg/kg and a total maximum dose of 10400 mg/kg over 12 months. The active substance is chemically derived.
**SANIFOLIN** is a formulation of calcium folinate, provided as a powder for solution for injection. It is administered intravenously with a maximum daily dose of 400 mg/kg and a total maximum dose of 10400 mg/kg over 12 months. The active substance is chemically derived.
All medications are administered intravenously, and participant compliance is monitored throughout the trial. The trial aims to compare the overall survival and objective overall response rate in patients with advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction, who have failed one prior line of palliative chemotherapy.
Efficacy
The efficacy of the clinical trial will be assessed using co-primary endpoints, which include **Overall Survival (OS)** and **Objective Overall Response Rate (ORR)**. Overall Survival is defined as the time from randomization to death from any cause and will be assessed according to the Kaplan-Meier method. The Objective Overall Response Rate is defined as the proportion of patients achieving complete or partial remission, evaluated according to RECIST 1.1 criteria.
Secondary endpoints will include comparisons between treatment arms regarding progression-free survival, objective response rate (complete response + partial response), tumor control rate (complete response, partial response, stable disease), safety and tolerability according to NCI-CTCAE V 4.03, and quality of life assessments during treatment and follow-up.
The trial will involve patients with advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction who have failed one prior line of palliative chemotherapy. The trial aims to compare the efficacy of FOLFIRI with **ramucirumab** versus **paclitaxel** with ramucirumab as second-line therapy. The efficacy assessments will be conducted in the intent-to-treat population.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Signed written informed consent
- Male or female* ≥ 18 years of age; Patients in reproductive age must be willing to use adequate contraception (that results in a failure rate of <1% per year) during the study and for 3 months after the end of ramucirumab treatment (appropriate contraception is defined as surgical sterilization (e.g. bilateral tubal ligation, vasectomy), hormonal contraception (including oral contraceptive pills (combination of estrogen and progesterone), vaginal ring, injectables, implants, intrauterine devices (IUDs) and intrauterine hormone-releasing system (IUS)), nonhormonal IUDs and complete abstinence). Female patients with childbearing potential need to have a negative pregnancy test within 7 days before study start. * There are no data that indicate special gender distribution. Therefore, patients will be enrolled in the study gender-independently.
- Histologically proven gastric adenocarcinoma including adenocarcinoma of the esophagogastric junction
- Metastatic or locally advanced disease, not amenable to potentially curative resection
- Phase II only: Documented objective radiological or clinical disease progression during or within 6 months of the last dose of first-line platinum and fluoropyrimidine doublet with or without anthracycline or docetaxel. Neoadjuvant/adjuvant treatment is not counted unless progression occurs <6 months after completion of the treatment. In these cases neoadjuvant/adjuvant treatment is counted as one line. OR Phase III only: Radiological or clinical disease progression during or after the last dose of a first-line platinum, fluoropyrimidine-containing therapy. Patients must also have received a taxane with the first-line or during their adjuvant or neoadjuvant therapy or both. Neoadjuvant/adjuvant platinum containing therapy is permitted and is counted as first-line therapy if progression occurs <12 months after completion of the treatment. If progression occurred ≥ 12 months after completion of neoadjuvant/adjuvant therapy, the therapy is not counted as a treatment line. At decision of the investigator, different regimens can be considered as one line of prior treatment, in case these were administrated as a sequential or alternating therapy.
- Measurable or non-measurable but evaluable disease
- ECOG performance status 0-1
- Life expectancy > 12 weeks
- Adequate hematological, hepatic and renal functions: • Absolute neutrophil count (ANC) ≥ 1.5 x 109/L • Platelets ≥ 100 x 109/L • Hemoglobin ≥9 g/dL (5.58 mmol/L) • Total bilirubin ≤ 1.5 times the upper normal limit (UNL) • AST (SGOT) and ALT (SGPT) ≤ 3.0 x UNL in absence of liver metastases, or ≤ 5 x UNL in presence of liver metastases; AP ≤ 5 x UNL • Serum creatinine ≤ 1.5 x upper limit of normal, or creatinine clearance (measured via 24-hour urine collection) ≥40 mL/minute (that is, if serum creatinine is >1.5 times the ULN, a 24-hour urine collection to calculate creatinine clearance must be performed) • Urinary protein ≤1+ on dipstick or routine urinalysis (UA; if urine dipstick or routine analysis is ≥2+, a 24-hour urine collection for protein must demonstrate <1000 mg of protein in 24 hours to allow participation in this protocol) • Adequate coagulation function as defined by International Normalized Ratio (INR) ≤ 1.5, and a partial thromboplastin time (PTT) ≤ 5 seconds above the ULN (unless receiving anticoagulation therapy). Patients receiving warfarin/ phenprocoumon must be switched to low molecular weight heparin and have achieved stable coagulation profile prior to first dose of protocol therapy.
- Ability to comply with scheduled assessments and with management of toxicities
Exclusion Criteria
- Other tumor type than adenocarcinoma (e.g. leiomyosarcoma, lymphoma) or a second cancer except in patients with squamous or basal cell carcinoma of the skin or carcinoma in situ of the cervix that has been effectively treated. Patients curatively treated and disease-free for at least 5 years will be discussed with the sponsor before inclusion
- Squamous gastric cancer
- Concurrent chronic systemic immune therapy, chemotherapy, or hormone therapy not indicated in the study protocol
- Phase II only: Previous therapy with paclitaxel or FOLFIRI; Phase III only: Previous therapy with FOLFIRI
- Current treatment with any anti-cancer therapy ≤ 2 weeks prior to study treatment start unless rapidly progressing disease is measured
- Concurrent treatment with any other anti-cancer therapy
- Previous exposure to a VEGF or VEGFR inhibitor or any antiangiogenic agent, or prior enrolment in this study
- Patient has undergone major surgery within 28 days prior to first dose of protocol therapy, or minor surgery/subcutaneous venous access device placement within 7 days prior to first dose of protocol therapy. The patient has elective or planned major surgery to be performed during the course of the clinical trial
- Grade 3-4 GI bleeding within 3 months prior to enrollment
- History of deep vein thrombosis (DVT), pulmonary embolism (PE), or any other significant thromboembolism (venous port or catheter thrombosis or superficial venous thrombosis are not considered “significant”) during the 3 months prior to first dose of protocol therapy
- Cirrhosis at a level of Child-Pugh B (or worse) or cirrhosis (any degree) and a history of hepatic encephalopathy or clinically meaningful ascites resulting from cirrhosis. Clinically meaningful ascites is defined as ascites from cirrhosis requiring diuretics or paracentesis.
- The patient has uncontrolled known brain or leptomeningeal metastases
- Known allergic/ hypersensitivity reaction to any of the components of the treatment
- Contraindications to the use of atropine
- Other serious illness or medical conditions within the last 12 months prior to study drug administration
- Any arterial thromboembolic events, including but not limited to myocardial infarction, transient ischemic attack, cerebrovascular accident, or unstable angina, within 6 months prior to first dose of protocol
- The patient has uncontrolled or poorly-controlled hypertension (>160 mmHg systolic or > 100 mmHg diastolic for >4 weeks) despite standard medical management
- Active uncontrolled infection
- Current history of chronic diarrhea
- Active disseminated intravascular coagulation
- Any other serious concomitant disease or medical condition that in the judgment of the investigator renders the subject at high risk of treatment complication or reduced the probability of assessing clinical effect
- Known Dihydropyrimidine dehydrogenase (DPD) deficiency
- Prior history of GI perforation/fistula (within 6 months of first dose of protocol therapy) or risk factors for perforation.
- Serious or nonhealing wound, ulcer, or bone fracture within 28 days prior to first dose of protocol therapy
- The patient is receiving chronic antiplatelet therapy, including aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs, including ibuprofen, naproxen, and others), dipyridamole or clopidogrel, or similar agents. Once-daily aspirin use (maximum dose 325 mg/day) is permitted
- Concurrent treatment with other experimental drugs or participation in another clinical trial with any investigational drug within 30 days prior to treatment start or at the same time as this study
- Lack of resolution of all toxic effects (excluding alopecia) of prior chemotherapy, prior radiotherapy or surgical procedure to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grade < 1. Note: Neuropathy due to prior chemotherapy is allowed if not > NCI Grade II according to CTCAE version 4.03
- Subject pregnant or breast feeding, or planning to become pregnant within 3 months after the end of treatment
- Subject (male or female) is not willing to use highly effective methods of contraception (per CTFG-Guideline) during treatment and for 3 months (male or female) after the end of treatment
- Patients known to have a HER 2 positive Cancer who have not been treated already with a HER 2 targeting agent.
- Patients with a psychiatric illness or patients imprisoned or working in the institution of the treating physician
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Not Recruiting | 10 May 2017 | 14 |
 Germany | Not Recruiting | 10 May 2017 | 292 |
 Italy | Not Recruiting | 10 May 2017 | 13 |
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 |
|---|---|---|---|---|---|---|
Irinotecan Kabi 20 mg/ml Konzentrat zur Herstellung einer Infusionslösung | Test | KONZENTRAT ZUR HERSTELLUNG EINER INFUSIONSLÖSUNG | CONCENTRATE FOR SOLUTION FOR INFUSION | 180 | 12 | PRD409036 |
5-FU medac 50 mg/ml, Injektionslösung | Test | INJEKTIONSLÖSUNG | INTRAVENOUS USE | 400 | 12 | PRD536079 |
Calciumfolinat Sandoz 10 mg/ml – Injektions-/Infusionslösung | Test | INJEKTIONS-/INFUSIONSLÖSUNG | INTRAVENOUS USE | 400 | 12 | PRD4733835 |
SANIFOLIN polvere per soluzione iniettabile | Test | POLVERE PER SOLUZIONE INIETTABILE | INTRAVENOUS USE | 400 | 12 | PRD460205 |
Irinotecan Kabi 20 mg/ml Konzentrat zur Herstellung einer Infusionslösung | Test | KONZENTRAT ZUR HERSTELLUNG EINER INFUSIONSLÖSUNG | CONCENTRATE FOR SOLUTION FOR INFUSION | 180 | 12 | PRD409038 |
Paclitaxel Aurobindo 6 mg/ml concentrato per soluzione per infusione | Test | CONCENTRATO PER SOLUZIONE PER INFUSIONE | INTRAVENOUS USE | 80 | 12 | PRD9998136 |
Paclitaxel Accord 6 mg/ml Konzentrat zur Herstellung einer Infusionslösung | Test | KONZENTRAT ZUR HERSTELLUNG EINER INFUSIONSLÖSUNG | INTRAVENOUS USE | 80 | 12 | PRD2002521 |
Leucovorin 10 mg/ml Lösung zur Injektion/ Infusion | Test | LÖSUNG ZUR INJEKTION/ INFUSION | INTRAVENOUS USE | 400 | 12 | PRD4259228 |
Cyramza 10 mg/ml concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 8 | 12 | PRD2386703 |
Paclitaxel Ribosepharm 6 mg/ml Konzentrat zur Herstellung einer Infusionslösung | Test | KONZENTRAT ZUR HERSTELLUNG EINER INFUSIONSLÖSUNG | INTRAVENOUS USE | 80 | 12 | PRD6701803 |