Switch Maintenance with Paclitaxel, Ramucirumab and Tislelizumab vs Continued Chemotherapy plus Tislelizumab in HER2‑negative, PD‑L1‑positive Gastroesophageal Adenocarcinoma
- Trial ID
- 2025-524048-36-00
- Protocol
- ARMANI-2/ENGIC08
- Sponsor
- Fondazione GONO G.I.
Trial statistics
Diseases & Conditions
Objectives
The primary objective is to compare the efficacy of a switch‑maintenance regimen of paclitaxel, ramucirumab and tislelizumab with continuation of chemotherapy plus tislelizumab, using investigator‑assessed progression‑free survival as the endpoint; this endpoint indicates the duration patients remain free from disease progression, a critical measure of clinical benefit in advanced HER2‑negative and PD‑L1‑positive gastroesophageal adenocarcinoma.
Secondary objectives are to:
- Evaluate overall survival and progression‑free survival in predefined patient subgroups.
- Assess progression‑free survival 2 (PFS2) and overall survival, with PFS2 locally evaluated.
- Determine tumor activity of the switch‑maintenance strategy versus continued chemotherapy.
- Characterize the safety profile of the switch‑maintenance regimen compared with continued chemotherapy.
- Measure the impact on patients’ health‑related quality of life.
- Evaluate the effect of induction‑phase chemotherapy on health‑related quality of life.
- Determine the attrition rate, defined as the proportion of patients unable to receive subsequent therapy after discontinuation of first‑line treatment.
- Investigate the prognostic and predictive significance of the best local response to induction therapy on subsequent efficacy of the switch‑maintenance regimen.
Participants
The trial enrolled adult men and women with histologically confirmed gastroesophageal adenocarcinoma that was HER2‑negative and PD‑L1 positive, either locally advanced unresectable or metastatic. Participants were required to be at least 18 years old, have an ECOG performance status of 0–1, and possess adequate organ function as defined by specific laboratory thresholds. Both sexes were included, with appropriate contraceptive measures mandated for individuals of childbearing potential, and women of childbearing potential needed a negative pregnancy test. Eligible patients had no prior therapy for metastatic disease, although prior neoadjuvant, adjuvant, or peri‑operative treatment was allowed if recurrence occurred more than six months after the last dose. The sponsor did not provide the total number of participants.
Plans and Procedures
The ARMANI‑2/ENGIC08 trial is a phase III, randomized, parallel‑group, controlled study evaluating a switch‑maintenance regimen of paclitaxel + ramucirumab + tislelizumab versus continuation of chemotherapy + tislelizumab in patients with advanced gastroesophageal adenocarcinoma that is HER2‑negative and PD‑L1 positive. After obtaining written informed consent, eligible participants undergo a screening visit to confirm inclusion criteria, baseline laboratory values, and tumor assessment. All subjects receive a 12‑week induction phase of standard chemotherapy; at the end of induction, patients are randomized 1:1 to the two treatment arms. Post‑randomization, study visits occur every 8 weeks and include physical examination, performance‑status assessment, laboratory safety tests, administration of the assigned study drugs, and radiologic tumor evaluation per RECIST v1.1. The primary endpoint, investigator‑assessed progression‑free survival, is measured from randomization to documented disease progression or death. Secondary assessments (overall survival, response rates, safety, and health‑related quality of life) are collected at the same 8‑week intervals. Participants remain in the trial until disease progression, death, withdrawal of consent, unacceptable toxicity, or a decision by the investigator to discontinue therapy. The overall study recruitment period is scheduled from 30 April 2026 to 23 August 2030, with individual patient involvement lasting from screening through the end‑of‑study visit at disease progression or study termination.
Treatment
Paclitaxel is supplied for intravenous infusion at a dose of 80 mg/m² per administration.
ramucirumab is provided as a solution for infusion and administered intravenously at 8 mg/kg.
Tislelizumab is administered as a concentrate for solution for infusion by intravenous infusion at a dose of 200 mg per administration.
Oxaliplatin is given by intravenous infusion at doses of 85 mg/m² (background regimen) or 130 mg/m² (comparator regimen).
Capecitabine is taken orally at 2000 mg/m² per dose.
Fluorouracil is administered by intravenous infusion at 800 mg/m² (background) and by intravenous bolus injection/infusion at 1652 mg/m² (comparator).
Cisplatin is delivered by intravenous infusion at 80 mg/m² per dose.
Calcium folinate is infused intravenously at 200 mg/m² per administration.
All study drugs are administered according to the protocol‑defined schedule, typically on day 1 of each treatment cycle. Dosing adjustments are permitted based on observed toxicities. Participant compliance is monitored through drug accountability logs and infusion records.
Efficacy
Efficacy will be evaluated primarily by progression‑free survival, defined as the time from randomization to the first documented disease progression according to RECIST v1.1 or death, whichever occurs first, as assessed locally by investigators. Patients without progression at the time of analysis will be censored at the date of the last on‑study tumor assessment showing no progression; those with no post‑baseline assessments will be censored at randomization.
Secondary efficacy parameters include overall survival (date of randomization to death from any cause, with censoring at last contact for survivors), PFS‑2 (date of randomization to progression on any subsequent treatment after first progression or death), best overall response rate (percentage of patients achieving complete or partial response per RECIST v1.1), disease control rate (percentage achieving complete response, partial response, or stable disease per RECIST v1.1), and overall toxicity rate (percentage experiencing any treatment‑related adverse event per NCI‑CTCAE v5.0). Health‑related quality of life will be captured using the EORTC QLQ‑C30, EORTC QLQ‑OG25, and EQ‑5D questionnaires.
Tumor assessments will be performed at baseline after the 12‑week induction phase and subsequently every 8 weeks after randomization. Responses for ORR and DCR will be based on investigator‑reported measurements. HRQoL questionnaires will be administered after randomization and every 8 weeks until disease progression, death, withdrawal of consent, or initiation of another anticancer therapy. All efficacy analyses will use the intention‑to‑treat population unless otherwise specified.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Able to provide written informed consent and can understand and agree to comply with the requirements of the study and the schedule of assessments.
- Age ≥ 18 years on the day of signing the informed consent form
- Diagnosis of histologically confirmed gastroesophageal adenocarcinoma, either locally advanced unresectable or metastatic.
- Locally assessed HER2-negative status and PD-L1 TAP score ≥5%.
- No prior treatment for metastatic disease. Patients who received prior neoadjuvant, adjuvant or perioperative therapy and had disease recurrence beyond 6 months from the last dose are eligible.
- Measurable and/or non-measurable evaluable disease according to RECIST v1.1. Note: The target lesion(s) selected have not been previously treated with local therapy OR The target lesion(s) selected that are within the field of prior local therapy have subsequently progressed as defined by RECIST v1.1.
- ECOG Performance Status ≤ 1.
- Life expectancy of at least 12 weeks in the opinion of the Investigator.
- Adequate organ function as indicated by the following laboratory values during screening: a. Patients must not have required a blood transfusion or growth factor support ≤ 14 days before sample collection at screening for the following i. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L ii. Platelets ≥ 100 x 109/L iii. Hemoglobin ≥ 90 g/L b. Serum creatinine ≤ 1.5 x ULN (upper limit of normal) or estimated Glomerular Filtration Rate ≥ 60 mL/min/1.73 sqm (Appendix 6). c. Serum total bilirubin ≤ 1.5 x ULN (total bilirubin must be < 3 x ULN for patients with Gilberts syndrome) d. AST and/or ALT ≤ 2.5 x ULN, or ≤ 5 x ULN in case of liver metastases e. 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)
- The patient’s urinary protein is ≤ 1+ on dipstick or routine urinalysis. If urine dipstick or routine analysis indicates proteinuria ≥ 2+, then 24-hour urine must be collected and must demonstrate < 1000 mg of protein in 24 hours to allow participation in the study.
- Women of childbearing potential must have a negative blood pregnancy test at the baseline visit. For this trial, women of childbearing potential are defined as all women after puberty, unless they are postmenopausal for at least 12 months, are surgically sterile, or are sexually inactive. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of amenorrhea, a single FSH measurement is insufficient.
- Male subjects with female partners of childbearing potential and female subjects of childbearing potential must be willing to use adequate contraception as approved be the Investigator (barrier contraceptive measure or oral contraception), as outlined in Section 7, starting with the screening visit and ≥ 120 days after the last treatment dose of tislelizumab or ≥ 180 days after the last dose of chemotherapy or ≥ 90 days after the last dose of ramucirumab. Note: abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.
- Women must not be breastfeeding.
- Archival tumor tissue (primary or metastatic) and blood samples are required for exploratory research at enrollmen
Exclusion Criteria
- HER2-positive disease as determined by local standards.
- Active leptomeningeal disease or uncontrolled brain metastasis. Patients with equivocal findings or with confirmed brain metastases are eligible for enrollment provided that they are asymptomatic and radiologically stable without the need for corticosteroid treatment for ≥ 4 weeks before the first study treatment. Note: Patients with a history of treated and, at the time of screening, asymptomatic CNS metastases are eligible, provided they meet all the following: a. Brain imaging at screening shows no evidence of interim progression. b. Have measurable or evaluable disease outside the CNS. c. No ongoing requirement for corticosteroids as therapy for CNS disease; anticonvulsants at a stable dose are allowed. d. No stereotactic radiation or whole-brain radiation within 14 days prior to the first study treatment.
- Active autoimmune diseases or history of autoimmune diseases that may relapse. Note: Patients with the following diseases are not excluded and may proceed to further screening: a. Controlled type I diabetes b. Hypothyroidism (provided it is managed with hormone replacement therapy only) c. Controlled celiac disease d. Skin diseases not requiring systemic treatment (e.g., vitiligo, psoriasis, alopecia) e. Any other disease that is not expected to recur in the absence of external triggering factors.
- Any active malignancy ≤ 3 years before enrollment except for the specific cancer under investigation in this study and any locally recurring cancer that has been treated curatively (e.g., resected basal or squamous cell skin cancer, superficial bladder cancer, carcinoma in situ of the cervix or breast).
- Any condition that requires systemic treatment with either corticosteroids (>10 mg daily of prednisone or equivalent) or other immunosuppressive medications (including but not limited to cyclophosphamide, azathioprine, methotrexate, thalidomide, anti-TNFα agents, or mTOR inhibitors) ≤14 days prior to the first study treatment. Note: Patients who are currently or have previously been on any of the following steroid regimens are not excluded: a. Adrenal replacement steroid (dose ≤ 10 mg daily of prednisone or equivalent). b. Topical, ocular, intra-articular, intranasal, or inhaled corticosteroid with minimal systemic absorption. c. Short course (≤ 7 days) of corticosteroid prescribed prophylactically (e.g., for contrast dye allergy) or for the treatment of a non-autoimmune condition (e.g., delayed-type hypersensitivity reaction caused by contact allergen)
- Uncontrolled diabetes or grade >1 laboratory test abnormalities in potassium, sodium, or corrected calcium despite standard medical management or grade ≥3 hypoalbuminemia ≤14 days before enrollment.
- 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.
- History of interstitial lung disease, non-infectious pneumonitis or uncontrolled diseases (including pulmonary fibrosis, acute lung diseases, etc), presence of severe dyspnea at rest, or requirement for supplementary oxygen therapy
- Severe chronic or active infections requiring systemic antibacterial, antifungal or antiviral therapy, including tuberculosis infection, etc. a. Severe infections within 4 weeks before the first study treatment including, but not limited, to hospitalization for complications of infection, bacteremia, or severe pneumonia. b. Received therapeutic oral or intravenous antibiotics within 2 weeks before the first study treatment.
- Known active HIV infection. Note: Patients with HIV infection may be enrolled if all the subsequent conditions are met: a. Undetectable viral RNA, CD4+ count ≥ 350 cells/mm3. b. No history of acquired immune deficiency syndrome-defining opportunistic infection within the past 12 months. c. Stable for at least 4 weeks on the same anti-HIV medications (meaning there are no expected further changes in that time to the number or type of antiretroviral drugs in the regimen). If an HIV infection meets the above criteria, monitoring of viral RNA load and CD4+ count is recommended.
- Acute or chronic hepatitis B. Subjects who are hepatitis B surface antigen (HBsAg) positive are eligible if they have hepatitis B virus (HBV) - DNA less than 500 IU/mL or 2,500 copies/mL (inactive carriers). Note: Subjects with detectable HBsAg or detectable HBV-DNA should be managed per institutional or local guidelines. Subjects beginning antiviral agents at Screening should be treated for >2 weeks prior to enrollment.
- Acute or chronic hepatitis C. Patients who are positive for hepatitis C virus (HCV) antibodies and with no history of curative viral treatment are eligible if they documented to be HCV-RNA negative; subjects who have completed curative viral therapy ≥12 weeks prior to enrollment and are documented to HCV-RNA negative are eligible.
- Any major surgical procedure requiring general anesthesia ≤ 28 days before the first study treatment.
- Prior allogeneic stem cell transplantation or organ transplantation.
- Evidence of bleeding diathesis or coagulopathy.
- Significant bleeding episodes from the gastrointestinal tract, gastrointestinal perforation and/or fistulae within 3 months prior to the first study treatment.
- Serious or non-healing wound or peptic ulcer or bone fracture within 3 months prior to the first study treatment.
- Ongoing chronic therapy with nonsteroidal anti-inflammatory agents (NSAIDs such as indomethacin, ibuprofen, naproxen, or similar agents) or other anti-platelet agents (e.g., clopidogrel, ticlopidine, dipyridamole, anagrelide). Aspirin use at doses up to 325 mg/day is permitted.
- Any of the following cardiovascular risk factors: a. Cardiac chest pain, defined as moderate pain that limits instrumental activities of daily living, ≤ 28 days before the first study treatment. b. Any grade 3 or higher venous thromboembolic event (e.g., pulmonary embolism) ≤ 28 days prior to the first study treatment. c. Significant vascular disease (such as aortic aneurysm requiring surgical repair or recent arterial thrombosis) ≤ 6 months before the first study treatment. d. Any history of acute myocardial infarction ≤ 6 months before the first study treatment. e. Any history of heart failure meeting New York Heart Association (NYHA) Classification III or IV (Appendix 5) ≤ 6 months before the first study treatment. f. Any event of ventricular arrhythmia grade ≥2 in severity ≤ 6 months before the first study treatment. g. QTc > 470 msec. h. Any history of cerebrovascular accident ≤ 6 months before the first study treatment. i. Uncontrolled hypertension: systolic pressure ≥ 160 mmHg or diastolic pressure ≥ 100 mmHg despite anti-hypertension medications ≤ 28 days before the first study treatment.
- Known hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins.
- Complete dihydropyrimidine dehydrogenase (DPYD) deficiency (i.e., presence of c1679GG, c1905+1AA, c2846TT DPYD polymorphisms). Patients with partial DPYD deficiency may receive a reduced dose of fluoropyrimidine as detailed in Table 18. Uracilemia may be tested as a surrogate for DPYD enzyme deficiency instead of polymorphism testing (German Sites only). Patients with uracilemia ≥ 16 ng/ml are not eligible.
- Known allergy or hypersensitivity to any components used in the ramucirumab and tislelizumab DP preparation. Subjects have no contraindications to fluoropyrimidine, cisplatin, oxaliplatin or paclitaxel as per local prescribing information. Subjects with contraindication for cisplatin may receive oxaliplatin and vice versa.
- Has received any chemotherapy, immunotherapy (e.g., interleukin, interferon, thymosin) or any investigational therapy within 14 days or 5 half-lives (whichever is shorter) of the first study drug administration.
- Extended field radiation within 4 weeks prior to enrollment or limited field radiation within 2 weeks prior to enrollment.
- Has received any herbal medicine used to control cancer within 14 days of the first study drug administration.
- Was administered a live vaccine ≤ 4 weeks before receipt of first dose of study drug. Note: Seasonal vaccines for influenza are generally inactivated vaccines and are allowed. Intranasal live vaccines and are not allowed.
- Underlying medical conditions (including laboratory abnormalities) or alcohol or drug abuse or dependence that, will be unfavorable for the administration of study drug or affect the explanation of drug toxicity or AEs or result in insufficient or might impair compliance with study conduct.
- Concurrent participation in another therapeutic clinical study.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Germany | Not Yet Recruiting | 30 Apr 2026 | 40 |
 Italy | Not Yet Recruiting | 30 Apr 2026 | 122 |
 Spain | Not Yet Recruiting | 30 Apr 2026 | 50 |
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 |
|---|---|---|---|---|---|---|
OXALIPLATIN | Other | — | INTRAVENOUS INFUSION | 85 | 12 | SUB09490MIG |
FLUOROURACIL | Other | — | INTRAVENOUS BOLUS INJECTION/IV INFUSION | 1652 | 12 | SUB07721MIG |
TISLELIZUMAB | Other | — | INTRAVENOUS INFUSION | 200 | 12 | SUB193656 |
CALCIUM FOLINATE | Comparator | — | INTRAVENOUS INFUSION | 200 | 104 | SUB06052MIG |
CAPECITABINE | Comparator | — | ORAL | 2000 | 104 | SUB12474MIG |
CALCIUM FOLINATE | Other | — | INTRAVENOUS INFUSION | 200 | 12 | SUB06052MIG |
FLUOROURACIL | Comparator | — | INTRAVENOUS BOLUS INJECTION/IV INFUSION | 1652 | 104 | SUB07721MIG |
TISLELIZUMAB | Comparator | — | INTRAVENOUS INFUSION | 200 | 104 | SUB193656 |
CISPLATIN | Other | — | INTRAVENOUS INFUSION | 80 | 12 | SUB07483MIG |
Cyramza 10 mg/ml concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS INFUSION | 8 | 104 | PRD1961195 |