2025-524048-36-00招募中3 期
Paclitaxel plus ramucirumab and tislelizumab as switch maintenance versus continuation of chemotherapy and tislelizumab in patients with advanced HER2-negative and PD-L1 positive gastroesophageal adenocarcinoma: the ARMANI-2/ENGIC08 trial by GONO
适应症
干预措施
相关药物
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 入组人数
- 212
- 试验地点
- 42
- 主要终点
- PFS: time from randomization to first documented disease progression per RECIST v1.1 or death, whichever occurs first. Progressive disease is per Investigator assessment. Patients alive without progression at analysis are censored at date of last on-study tumor assessment documenting no progression. Patients with no post-baseline tumor assessments are censored at randomization.
研究概览
简要总结
To evaluate the efficacy, in terms of progression-free survival (PFS), of switch maintenance strategy with paclitaxel, ramucirumab and tislelizumab compared to the continuation of chemotherapy and tislelizumab. For the primary endpoint PFS will be locally assessed by the Investigators.
研究设计
- 分配方式
- Na
- 主要目的
- Screening
- 盲法
- None
入排标准
- 年龄范围
- 18 years 至 65+ years（18-64 Years, 65+ Years）
- 接受健康志愿者
- 否
入选标准
- •Able to provide written informed consent and can understand and agree to comply with the requirements of the study and the schedule of assessments.
- •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
- •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.
- •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.
- •ECOG Performance Status ≤
- •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)
排除标准
- •HER2-positive disease as determined by local standards.
- •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/mm
- •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.
- •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.
- •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
- •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.
- •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.
研究组 & 干预措施
Tislelizumab
Test
干预措施: Tislelizumab (Drug)
FLUOROURACIL, CISPLATIN
Comparator
干预措施: CISPLATIN (Drug)
PACLITAXEL
Auxiliary
干预措施: PACLITAXEL (Drug)
Cyramza 10 mg/ml concentrate for solution for infusion
Test
干预措施: Cyramza 10 mg/ml concentrate for solution for infusion (Drug)
FLUOROURACIL, CALCIUM FOLINATE, OXALIPLATIN
Comparator
干预措施: CALCIUM FOLINATE (Drug)
CAPECITABINE, OXALIPLATIN
Comparator
干预措施: OXALIPLATIN (Drug)
CAPECITABINE, OXALIPLATIN
Comparator
干预措施: CAPECITABINE (Drug)
FLUOROURACIL, CISPLATIN
Comparator
干预措施: FLUOROURACIL (Drug)
FLUOROURACIL, CALCIUM FOLINATE, OXALIPLATIN
Comparator
干预措施: FLUOROURACIL (Drug)
TISLELIZUMAB
Comparator
干预措施: TISLELIZUMAB (Drug)
FLUOROURACIL, CALCIUM FOLINATE, OXALIPLATIN
Comparator
干预措施: OXALIPLATIN (Drug)
OXALIPLATIN, CALCIUM FOLINATE, FLUOROURACIL
Auxiliary
干预措施: OXALIPLATIN (Drug)
OXALIPLATIN, CALCIUM FOLINATE, FLUOROURACIL
Auxiliary
干预措施: FLUOROURACIL (Drug)
OXALIPLATIN, CALCIUM FOLINATE, FLUOROURACIL
Auxiliary
干预措施: CALCIUM FOLINATE (Drug)
结局指标
主要结局
PFS: time from randomization to first documented disease progression per RECIST v1.1 or death, whichever occurs first. Progressive disease is per Investigator assessment. Patients alive without progression at analysis are censored at date of last on-study tumor assessment documenting no progression. Patients with no post-baseline tumor assessments are censored at randomization.
PFS: time from randomization to first documented disease progression per RECIST v1.1 or death, whichever occurs first. Progressive disease is per Investigator assessment. Patients alive without progression at analysis are censored at date of last on-study tumor assessment documenting no progression. Patients with no post-baseline tumor assessments are censored at randomization.
次要结局
- OS calculated from the date of randomization to the date of death due to any cause. Alive patients will be censored on the date of last contact.
- PFS-2 calculated from the date of randomization to the date of disease progression on any treatment given after first disease progression, or death from any cause.
- Best overall response rate (ORR) is the percentage of patients with RECIST-measurable disease who achieve a complete or partial response per RECIST v1.1 after randomization. Responses are based on investigator-reported measurements. Baseline is the pre-randomization restaging after the 12-week Induction phase. Post-randomization restaging occurs every 8 weeks. ORR is assessed in the ITT population.
- Disease control rate (DCR) is the percentage of patients achieving complete or partial response or stable disease per RECIST v1.1 during post-induction treatment. Clinical responses are based on investigator-reported measurements. Baseline is the pre-randomization restaging after the 12-week Induction phase. After randomization, restaging occurs every 8 weeks. DCR is assessed in the ITT population.
- Overall toxicity rate. OTR is defined as the percentage of patients experiencing any treatment- related adverse event, according to NCI-CTCAE v5.0 after randomization. OTR assessed will be assessed in the per protocol population
- Other safety endpoints will include, but are not limited to, the following: treatment-emergent adverse events (TEAEs), serious adverse events (SAEs).
- Health-related quality of life (HRQoL) will be assessed using PROs: EORTC QLQ-C30, EORTC QLQ-OG25, and EQ-5D. Responses will be collected after randomization and every 8 weeks until disease progression, death, consent withdrawal, or initiation of another anticancer treatment, whichever occurs first.
- HRQoL will be assessed using Patient Reported Outcomes (PROs), i.e., the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire 30- item core module (EORTC QLQ-C30; 15 dimensions), the EORTC QLQ-OG25, and the EuroQol EQ-5D questionnaires. Responses will be collected after enrollment and at the end of the Induction phase
- Proportion of patients who are not eligible for a subsequent treatment after discontinuation of first-line treatment (i.e., attrition rate). Attrition rate will be computed as the percentage of patients without additional anticancer treatments after first-line therapy.
- PFS and OS will be calculated from randomization based on the best ORR to Induction treatment. ORR is the percentage of patients with RECIST-measurable disease achieving complete or partial response per RECIST v1.1. Responses are based on investigator-reported measurements. Baseline is the screening before enrollment, and restaging occurs at the end of the Induction phase.
研究者
Filippo Pietrantonio
Scientific
Gruppo Oncologico Del Nord Ovest
研究点 (42)
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