Phase II Randomized Trial Evaluating Modified FOLFIRINOX and FOLFOX in the Treatment of Locally Advanced or Metastatic Small Bowel Adenocarcinoma
试验速览
- 阶段
- 2 期
- 状态
- 尚未招募
- 发起方
- 入组人数
- 86
- 试验地点
- 16
- 主要终点
- Median Progression-free survival (PFS)
研究概览
简要总结
Phase II randomized trial evaluating modified FOLFIRINOX and FOLFOX in the treatment of locally advanced or metastatic small bowel adenocarcinoma
详细描述
Background:
Small bowel adenocarcinoma (SBA) is rare malignant disease accounting for less than 5% of all gastrointestinal tumors [1]. At time of first diagnosis about 40% of patients have distant metastases and more than half of the patients with initially resected SBA and lymph node invasion will experience metastatic recurrence [2]. Tumor phenotype characterization indicates that SBA molecular alterations are similar to adenocarcinoma of the colorectum [3, 4].
Palliative chemotherapy in SBA was mainly evaluated within retrospective studies. Fluoropyrimidines in combination with platinum derivates, especially oxaliplatin, appear to be the most efficient treatment regimen [5, 6]. The median progression-free survival (PFS) ranges from 6.9 to 8.7 months. Two prospective phase II studies evaluated the efficacy of oxaliplatin in combination with 5-fluorouracil (5-FU) or the oral prodrug capecitabine reporting an objective response rate (ORR) of approximately 50% with a median PFS of 7.8 and 11.3 months, and a median overall survival (OS) of 15.2 and 20.4 months, respectively [7, 8]. Indeed, FOLFOX regimen (5-FU+ oxaliplatin) represents the standard of care chemotherapy used worldwide [9, 10]. Treatment with anti-Epidermal Growth Factor Receptor (EGFR) monoclonal antibody was evaluate in a pilot study that report no signal of efficacy [11]. The anti-Vascular Endothelial Growth Factor (VEGF) monoclonal antibody Bevacizumab was also evaluated in a phase II trial in combination with capecitabine and oxaliplatin [12] with comparable results observed in a previous phase II trial investigating the same chemotherapy regimen without bevacizumab [7, 8]. Moreover, a registry study suggests that there is no benefit of adding bevacizumab to chemotherapy in first-line treatment of SBA [13]. Thus, it seems that FOLFOX or CAPOX (capecitabine+ oxaliplatin) without the addition of a monoclonal antibody represents one of the best therapeutic options in first-line treatment of SBA.
In metastatic colorectal adenocarcinoma the triplet regimen consisting of 5-FU, folinic acid, oxaliplatin, and irinotecan demonstrated an improved efficacy compared to doublet regimen depending on molecular subtype [14]. The median PFS was better in patients receiving triplet regimen compared to doublet chemotherapy (9.8 months versus 6.9 months). Moreover, in metastatic pancreatic adenocarcinoma triplet chemotherapy with FOLFIRINOX represents the current standard of care due to a significantly improved PFS and OS compared to former standard treatment with gemcitabine [15].
In SBA, a phase II trial including a small number of patients evaluated the triplet chemotherapy with capecitabine, irinotecan, and oxaliplatin. The authors reported a moderate ORR of 37.5%, a median PFS of 8.9 months, and a median OS of 13.4 months [16]. The moderate efficacy might be a result of the unusual choice of capecitabine instead of infusional 5-FU as component of the triplet regimen.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients are eligible to be included in the trial only if all of the following criteria apply at time of enrollment:
- •Patient's signed informed consent.
- •Patient's age ≥18 years at the time of signing the informed consent.
- •Histologically confirmed small bowel adenocarcinoma.
- •Microsatellite stable tumor or proficient mismatch repair status of the SBA (immunohistochemistry and polymerase chain reaction are both allowed for characterization)
- •Predicted locally advanced irresectable by the local study team or presenting with distant metastases.
- •Patient did not receive antitumor treatment for locally advanced irresetable or metastatic disease.
- •Measurable lesion according to RECIST 1.
- •ECOG performance status 0-
- •In case of patient's age >70 years, ECOG has to be 0 or 1 at randomization
- •Adequate bone marrow, hepatic and renal organ function, defined by the following laboratory test results:
- •Absolute neutrophil count 1.5 x 109/L (1500/µL)
- •Hemoglobin ≥ 80 g/L (8 g/dL) with or without blood transfusion
- •Platelet count ≥ 100 x109/L (100000/µL) without transfusion
- •Total serum bilirubin of ≤ 1.5 x upper limit of normal (ULN)
- •Aspartate aminotransferase (AST/GOT) and alanine aminotransferase (ALT/GPT) ≤ 2.5 × ULN; if liver function abnormalities are due to underlying liver metastasis, AST and ALT ≤ 5 × ULN
- •Calculated glomerular filtration rate (GFR) according to Cockcroft-Gault formula or according to MDRD ≥ 50 mL/min or serum creatinine≤ 1.5x ULN
- •Patients without anticoagulation need to present with an INR< 1.5x ULN and aPTT <1.5x ULN. Patient with prophylactic or therapeutic anticoagulation are allowed into the trial.
- •Proficient fluorouracil metabolism as defined:
- •Prior treatment with 5-FU or capecitabine without unusal toxicity or
- •If tested, normal DPD deficiency test according to the standard of the study site or
- •If tested, in patients with DPD deficiency test with a CPIC activity score of 1.0-1.5 fluoropyrimidine dosage should be reduced by 50%
- •For women of childbearing potential (WOCBP): negative pregnancy test within 14 days before randomization and agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods with a failure rate of < 1% per year during the treatment period and for at least 6 months after the last dose of study treatment.
- •A woman is considered to be of childbearing potential if she is post-menarcheal, has not reached a postmenopausal state (≥12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus). Examples of contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation, male partner's sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices.
- •For men with female partners of childbearing potential: men must remain abstinent or use a condom plus an additional contraceptive method that together result in a failure rate of < 1% per year during the treatment period and for 6 months after the last dose of study treatment. Men must refrain from donating sperm during this same period.
- •Men with pregnant female partners must remain abstinent or use a condom during the treatment period and for 6 months after the last dose of study medication to avoid exposing the embryo.
排除标准
- •Patients are excluded from this trial if any of the following criteria apply at time of enrollment:
- •Adenocarcinoma of the ampulla of Vateri
- •Ileus or directly imminent ileus as assessed by the local study team. Patients with treated and resolved ileus are allowed into the trial.
- •Previous chemotherapy for metastatic or irresectable disease.
- •New York Heart Association Class III or greater heart failure by clinical judgement.
- •Myocardial infarction within 6 months prior to randomization; percutaneous transluminal coronary angioplasty (PTCA) with or without stenting within 6 months prior to randomization.
- •Unstable angina pectoris.
- •Unstable cardiac arrhythmia >grade 2 NCI CTCAE despite anti-arrhythmic therapy.
- •Ongoing toxicities >grade 2 NCI CTCAE, in particular peripheral neuropathy.
- •Active uncontrolled infection by investigator's perspective.
- •Severe chronic non-healing wounds, ulcerous lesions or untreated bone fracture.
- •Known hypersensitivity to 5-FU, leucovorin, capecitabine, irinotecan or oxaliplatin or to any of the other excipients listed in section 6.1 of the corresponding SmPC.
- •Recent or concomitant treatment with brivudine.
- •Peripheral sensitive neuropathy with functional impairment (> grade 1 acc. to CTCAE version 6.0 (see appendix 2)).
- •Simultaneous application of Johannis herbs preparations.
- •Pernicious or other megaloblastic anaemia caused by vitamin B12 deficiency.
- •Major surgical procedure, open biopsy, or significant traumatic injury within 21 days prior to randomization that may interfere with systemic therapy as judged by the investigator.
- •Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug, may affect the interpretation of the results, or may render the patient at high risk from treatment complications.
- •Medical history of malignant disease other than SBA with the following exceptions:
- •patients who have been disease-free for at least three years before randomization 18.
- •patients with adequately treated and completely resected basal cell or squamous cell skin cancer, in situ cervical, breast or prostate cancer, stage I uterine cancer 18.
- •patients with any treated or untreated malignant disease that is associated with a 5-year survival prognosis of ≥ 80% and does not require active therapy at randomization
- •Known alcohol or drug abuse.
- •Pregnant or breastfeeding females.
- •Participation in a clinical trial or experimental drug treatment within 28 days prior to potential inclusion in the clinical trial or within a period of 5 half-lives of the substances administered in a clinical trial or during an experimental drug treatment prior to potential inclusion in the clinical trial, depending on which period is longest, or simultaneous participation in another clinical trial while taking part in this clinical trial.
- •Patients dependent on Sponsor, investigator or study site.
- •Patient committed to an institution by virtue of an order issued either by the judicial or the administrative authorities.
- •Limited legal capacity. Inability to undergo the medical follow-up of the trial for geographical, social or psychological reasons.
研究组 & 干预措施
Treatment arm A: mFOLFIRINOX every two weeks
- oxaliplatin 85 mg/m² 2 hours intravenously
- irinotecan 150 mg/m² 60-90 minutes intravenously
- leucovorin 400 mg/m² 2 hours intravenously
- 5-fluorouracil 2400 mg/m² 46 hours continuous intravenous infusion
干预措施: mFOLFIRINOX versus FOLFOX chemotherapy (Drug)
Treatment arm B: FOLFOX every two weeks
- oxaliplatin 85 mg/m² 2 hours intravenously
- leucovorin 400 mg/m² 2 hours intravenously
- 5-fluorouracil 400 mg/m² intravenous bolus injection
- 5-fluorouracil 2400 mg/m² 46 hours continuous intravenous infusion
干预措施: mFOLFIRINOX versus FOLFOX chemotherapy (Drug)
结局指标
主要结局
Median Progression-free survival (PFS)
时间窗: 84 months
Progression-free survival (PFS)-, defined as time from the date of randomization to the date of first radiological disease progression according to RECIST version 1.1 or the date of death from any cause.
次要结局
- Median Overall survival (OS)(84 months)
- Objective response rate (ORR)(84 months)
- Patient Safety(84 months)
- Quality of life (QoL)(84 months)
研究者
Annika Kurreck
PD Dr. med.
Charite University, Berlin, Germany