Safety, Tolerability and Efficacy of Regorafenib in Combination With FOLFIRINOX in Patients With RAS-mutated Metastatic Colorectal Cancer: a Dose-escalation, Phase I/II Trial
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 13
- 试验地点
- 4
- 主要终点
- Number of Participants With Pre-specified Treatment-related Adverse Events
研究概览
简要总结
Safety, tolerability and efficacy of regorafenib in combination with FOLFIRINOX in patients with RAS-mutated metastatic colorectal cancer: a dose-escalation, phase I/II trial
详细描述
Colorectal cancer (CRC) is a major cause of morbidity and mortality globally. More than 50% of patients can be expected to develop metastatic disease, and most of these patients will require palliative systemic therapy. The primary goal for patients who present with technically resectable liver metastases is definitely cure, with R0 resection as the primary goal. Consequently, any patient with limited liver and/or lung metastases should be considered a candidate for potential secondary resection as there are no criteria that allow physicians to distinguish between those patients for whom purely palliative treatment and those or whom potentially curative treatment is appropriate. Although survival times are slightly shorter for patients who undergo conversion therapy followed by surgery than for patients with initially resectable metastatic disease, they are far better than if resection is not carried out at all. First-line therapy commonly involves the doublet regimens of 5-fluorouracil, folinic acid, and either oxaliplatin or irinotecan. The addition of targeted therapies, such as bevacizumab (a pure anti-angiogenic agent which binds circulating VEGF-A), cetuximab, and panitumumab, to FOLFOX (5FU, oxaliplatin) or FOLFIRI (5FU, irinotecan) may be helpful to some patients in improving tumor response and ultimately overall survival. The cytotoxic triplet FOLFOXIRI (5FU, oxaliplatin, irinotecan) with or without bevacizumab may be an option in selected fit and motivated patients when cytoreduction (tumour shrinkage) is needed to undergo conversion therapy.
RAS mutations are found in about 50% of mCRC tumors. These mutations exclude affected patients from epidermal growth factor receptor (EGFR)-directed therapy. Besides their negative predictive value, RAS mutations may also carry distinct prognostic information. Modest studied the prognosis by RAS status of a total of 1239 mCRC patients from five randomized trials studying 2-CT. Actually, PFS and OS were significantly influenced by molecular subgroups. Multivariate comparison of Progression-Free Survival (PFS) and Overall Survival (OS) in patients with mutant tumors versus patients with non-mutated tumors revealed a negative prognostic effect of RAS mutations. Interestingly, the negative prognostic role of these mutations was consistently observed across different treatment regimens (subgroups of irinotecan- and oxaliplatin-treated patients as well as in bevacizumab- and non-bevacizumab-treated patients). Median PFS and OS were 10.3 vs. 9.5 months and 26.9 vs. 21.1 months in RAS-wildtype (and BRAF-wildtype) and RAS-mut patients, respectively. The TRIBE consortium reported that a 3-CT (FOLFOXIRI) combined with bevacizumab provided a significantly longer PFS (the primary end-point of the study) than did the 2-CT FOLFIRI plus bevacizumab . In the subgroup of RAS- and BRAF-wild-type patients, those in the FOLFOXIRI plus bevacizumab group reported a median PFS of 13.7 months (95% CI, 10.1-18.1) compared with 12.2 months (95%CI, 9.5-14.4) in the FOLFIRI plus bevacizumab group (HR 0.85, 95%CI 0.55-1.3).
Later on, the same group reported that FOLFOXIRI plus bevacizumab provided a significantly longer overall survival than the FOLFIRI plus bevacizumab group (HR 0.80, 95%CI 0·65-0·98; p=0·03) . Looking at survival by RAS status, Cremolini reported that median OS was 37.1 months (95%CI, 29.7-42.7) in the RAS- and BRAF-wild-type subgroup compared with 25.6 months (95%CI, 22.4-28.6) in the RAS-mut subgroup (HR 1.49, 95%CI, 1.11-1·99). Interestingly, median PFS was 13.7 months (95% CI 10.1-18.1) in the RAS-wild-type subgroup treated with FOLFOXIRI plus bevacizumab, while PFS data were not given for the RAS-mut patients . However, for these RAS-mut patients, it was possible to estimate the median PFS (i.e. 9.4 months) from the Kaplan-Meier curve which was provided.
Regorafenib is a small-molecule inhibitor of multiple membrane-bound and intracellular kinases. Beyond its well-known antiangiogenic properties, regorafenib has also less-known anti-proliferative activities in human colon cancer cell lines. Interestingly, regorafenib potently inhibits growth of patient-derived CRC xenografts alone and in combination with irinotecan . Regorafenib is approved for refractory mCRC patients, for locally advanced, unresectable or metastatic GIST patients and for HCC patients previously treated with sorafenib. The recommended dose is 160 mg (40 mg × 4 tablets) orally, once daily for the first 21 days of each 28-day cycle. Two phase III trials demonstrated a significant overall survival benefit for regorafenib over placebo in patients with mCRC who progressed on standard therapies . Two phase II trials studied the safety and efficacy profile of regorafenib when combined to chemotherapy in patients with mCRC . In vitro data indicate that both regorafenib and its metabolite M-2 inhibit glucuronidation mediated by UGT1A1 ( uridine 5'diphospho-glucuronosyl transferase A1) and UGT1A9 (whereas M-5 only inhibits UGT1A1), hence triggering potential pharmacokinetic interactions. The study from Schultheis was designed to explore whether addition of regorafenib to FOLFOX or FOLFIRI could be feasible as a treatment of mCRC, in terms of safety and pharmacokinetic interactions of the various drug components of the regimen. Forty-five patients were treated every 2 weeks with 5-fluorouracil 400 mg/m² bolus then 2400 mg/m² over 46 h, folinic acid 400 mg/m², and either oxaliplatin 85 mg/m² or irinotecan 180 mg/m².
On days 4-10, patients received regorafenib 160 mg orally once daily. Drug-related adverse events resulted in dose modification, dose interruption, or permanent discontinuation of study treatment in 31 (69%) patients overall (18 [72%] FOLFOX and 13 [65%] FOLFIRI).
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Sequential
- 主要目的
- Other
- 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
- •Written informed consent for full study.
- •Documentation of tumor RAS mutation, wild-type homozygous, heterozygous status of UGT1A1 gene. The status of UGT1A1 gene will be performed by the laboratory chosen by the investigator
- •Serum uracile < 16 ng/ml
- •Measurable disease, defined as at least one unidimensional measurable lesion on a CT scan, according to RECIST version 1.
- •Eastern Cooperative Oncology Group (ECOG) performance status ≤
- •Life expectancy of at least 3 months.
- •Adequate bone marrow, renal and liver functions as evidenced by the following laboratory requirements within 7 days prior to study treatment initiation: Absolute neutrophil count (ANC) ≥ 1,500/ mm3 without biologic response modifiers such as granulocyte colony-stimulating factor (G-CSF), within 21 days before the start of study treatment, Platelet count ≥ 100 000/mm3 , without platelet transfusion within 21 days before the start of study treatment ,Hemoglobin (Hb) ≥ 9 g/dL, without blood transfusion or erythropoietin, within 21 days before the start of study treatment, Serum creatinine ≤ 1.5 x upper limit of normal(ULN) Serum calcium ≥ Lower limits of normal LLN and ≤ 1.2 x UNL ; Serum magnesium ≥ LLN and ≤ 1.2 x UNL ; Kalemia ≥ LLN, Glomerular filtration rate as assessed by the estimated glomerular filtration rate (eGFR) ≥ 50 mL/min per 1.73 m2 calculated by the Modification of Diet in Renal Disease (MDRD) abbreviated formula, Total bilirubin ≤ 1.5 x ULN, Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x ULN (≤ 5 x ULN for patients with liver involvement of their cancer), Alkaline phosphatase (ALP) ≤ 2.5 x ULN (≤ 5.0 x ULN for patients with liver involvement for their cancer and/or bone metastases).
- •Lipase ≤ 1.5 x ULN.
- •Adequate coagulation, as assessed by the following laboratory test results:
- •International normalized ratio (INR) ≤ 1.5 or prothrombin time (PT) ≤ 1.5 x ULN, Partial thromboplastin time (PTT) or activated PTT (aPTT) ≤ 1.5 x ULN, Note: Patients on stable dose (dose has not been changed in at least 28 days) of anticoagulation therapy will be allowed to participate if they have no sign of bleeding or clotting and INR / PT and PTT / aPTT test results are compatible with the acceptable benefit-risk ratio at the investigator's discretion. In such case, limits as noted would not apply.
- •For women of reproductive potential, negative serum beta human chorionic gonadotropin (β-HCG) pregnancy test obtained within 7 days before the start of study treatment. Women not of reproductive potential are female patients who are postmenopausal or permanently sterilized (e.g., tubal occlusion, hysterectomy, bilateral salpingectomy).
- •For women of childbearing potential and men, agreement to use an adequate contraception for the duration of study participation and up to 4 months following completion of therapy for women and 6 months for male patients. Females of childbearing potential who are sexually active with a non-sterilized male partner must use 2 methods of effective contraception. The investigator or a designated associate is requested to advise the patient on how to achieve an adequate birth control.
- •Adequate contraception is defined in the study as any medically recommended method (or combination of methods) as per standard of care.
- •Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests and other study procedures.
- •Affiliation to the Social Security System.
排除标准
- •Previous or concurrent cancer that is distinct in primary site or histology from colorectal cancer within 5 years prior to study inclusion, except for curatively treated cervical cancer in situ, non-melanoma skin cancer and superficial bladder tumors [Ta (noninvasive tumor), Tis (carcinoma in situ) and T1 (lamina propria invasion)].
- •Discovery of metastases within 6 months after the termination of adjuvant chemotherapy.
- •Previous treatment for metastatic disease. Radiotherapy within 28 days prior to first dose of treatment.
- •Active cardiac disease including any of the following:
- •Congestive heart failure New York Heart Association (NYHA) class 2, Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 months), Myocardial infarction less than 6 months before first dose of treatment, Cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers or digoxin are permitted).
- •ECG with a QT/QTc interval higher than 450 ms for men and higher than 470 ms for women Uncontrolled hypertension.
- •Uncontrolled hypertension. (Systolic blood pressure > 140 mmHg or diastolic pressure > 90 mmHg despite optimal medical management).
- •Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism within 6 months before start of treatment.
- •8;Persistent proteinuria of National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE V5) grade 3 (i.e. urinary protein ≥ 3.5 g/24 hrs) 9;Peripheral neuropathy > grade1 (NCI-CTCAE v5). 10.Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to first dose of Treatment.
- •11.Ongoing infection >grade 2 (NCI-CTCAE v5). 12.Known history of human immunodeficiency virus (HIV) infection. 13.Chronic hepatitis B or C infection (if hepatitis status cannot be obtained from medical records, re-testing is required).
- •14.Seizure disorder requiring medication. 15.Symptomatic metastatic brain or meningeal tumors. 16.Evidence or history of any bleeding diathesis, irrespective of severity. Any hemorrhage or bleeding event ≥ grade 3 (NCI-CTCAE v5) within 4 weeks prior to the start of study medication.
- •17.History of organ allograft. 18.Non-healing wound, ulcer, or bone fracture. 19.Dehydration Grade 1 NCI-CTCAE v5). 20.Substance abuse, medical, psychological, or social conditions that may interfere with the patient's participation in the study or evaluation of the study results.
- •21.Known hypersensitivity to any of the study drugs, study drug classes, or any constituent of the products.
- •22.Interstitial lung disease with ongoing signs and symptoms. 23.Concomitant intake of St. John's wort. 24.Live attenuated vaccines are prohibited 10 days before the treatment, during the treatment and 3 months after the termination of treatment 25.History of gastrointestinal fistula or perforation 26.Inability to swallow oral medication. 27.Any malabsorption condition. 28.Pregnant or breast-feeding subjects. 29.Any condition that, in the opinion of the investigator, would interfere with the evaluation of study treatment or interpretation of patient safety or study results.
- •30.Participation in another clinical study with an investigational product during the last 30 days before inclusion. 31.Patients who might be interconnected with or dependent on the sponsor site or the investigator.
- •32.Legal incapacity or limited legal capacity.
研究组 & 干预措施
Folfirinox-R
Folfirinox + regorafenib
干预措施: Folfirinox + regorafenib (Combination Product)
结局指标
主要结局
Number of Participants With Pre-specified Treatment-related Adverse Events
时间窗: At the end of cycle 1 to 3 (each cycle is 14 days)
The physician determines pre-specified treatment-related toxicities and grades them by using the Common Terminology Criteria for Adverse Events (NCI-CTC Version 5). 1 - Mild: 2 - Moderate: 3 - Severe: 4 - Life-threatening: 5 - Death. Th evaluation is realized during the first three cycles.
次要结局
- Progression-free Survival (PFS)(From baseline of patient until the first observed disease progression)
- Number of Patients With Disease Control(Up to 6 months, from baseline of patient to the point where the values are the lowest (nadir).)
- Number of Participants With Objective Response(Up to 6 months, from baseline of patient to the point where the values are the lowest (nadir).)
- Overall Survival (OS)(From baseline to date of patient death)
- The Median of Regression of Tumor Size(Up to 6 months, from baseline of patient to the point where the values are the lowest (nadir).)
- Maintenance Treatment With Regorafenib Alone(Up to 16 weeks (after 12 cycles of Folfirinox-R))
- Determination of Circulating Free DNA Concentration (Not Available)(Baseline, 8 weeks, 16 weeks etc. through the end of treatment)
- Resection (R) Rates (Not Available)(Approximately at 6 months)