Induction Regorafenib in Combination With Metronomic Cyclophosphamide, Capecitabine, and Low-dose Aspirin Followed by Chemotherapy in Second Line Metastatic Colorectal Cancer Carcinoma An Open-label Randomized Phase II-III Study
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 446
- 试验地点
- 16
- 主要终点
- best objective response during treatment period (phase II)
研究概览
简要总结
This study evaluates the interest of regorafenib in combination of metronomic chemotherapies and low-dose aspirin as a 2 months induction therapy before chemotherapy initiation in the second-line metastatic colorectal carcinoma
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 with histologically proven metastatic colorectal cancer in progression after a first line of chemotherapy +/- targeted therapy
- •Patients must have been treated for their metastatic disease with one of the following regimens as first-line therapy:
- •FOLFOX (Oxaliplatine, 5-Fluoro-uracil)
- •FOLFIRI (Irinotecan, 5-Fluoro-uracil)
- •FOLFIRINOX (Irinotecan, oxaplipatin, 5-Fluoro-uracil) or FOLFOXIRI (irinotecan, oxaliplatin, 5-Fluoro-uracil)
- •FOLFOX and anti-VEGFA (bevacizumab only)
- •FOLFIRI and anti-VEGFA (bevacizumab only)
- •FOLFIRINOX or FOLFOXIRI and anti-VEGFA (bevacizumab only)
- •FOLFOX and anti-EGFR (Epiderman Growth Factor Recepto)
- •FOLFIRI and anti-EGFR
- •FOLFIRINOX or FOLFOXIRI and anti-EGFR
- •Of note, a chemotherapy prescribed for metastases occurring within six months after the end of an adjuvant chemotherapy are considered as a second line of therapy.
- •Patients should have a history of resistance to first line chemotherapy defined by:
- •Disease progression during the first line of their metastatic disease, less than 3 months after the last exposition to chemotherapy (even a chemotherapy regimen mentioned above or a 5-Fluoro-uracil-based maintenance therapy).
- •Disease relapse within 6 months after the end of an adjuvant FOLFOX based chemotherapy.
- •Disease relapse within 6 months after the surgical resection of metastases following a first line of chemotherapy.
- •Life expectancy of at least 3 months
- •Female or male with age ≥18 years old
- •Performance status Eastern Cooperative Oncology Group World Health Organization (ECOG-WHO) ≤1 (Appendix 1),
- •Measurable disease defined according to RECIST v1.1 (scanner or MRI)
- •Molecular status: patients eligible should have microsatellite-stable (MSS) status, absence of BRAF V600E (B(Raf gene, val600-to-glu) mutation and a known RAS (Retrovirus Associated Sequences) status.
- •Adequate bone marrow, liver and renal functions.
- •Haemoglobin ≥ 9 g/dL; absolute neutrophil count (ANC) ≥ 1.5 x 109/L; platelets ≥ 100 x 109/L
- •Total serum bilirubin ≤ 1.5 times upper normal value (ULN), serum alkaline phosphatase < 5 times ULN, aminotransferases (AST/ALT) ≤ 3 × ULN in absence of hepatic metastasis or ≤ 5 if presence of hepatic lesions
- •Cockcroft glomerular filtration rate > 50 ml/min
- •Proteinuria <2+ (dipstick urinalysis) or ≤1g/24hour
- •No contraindication to Iodine contrast media injection during CT
- •For female patients of childbearing potential, negative pregnancy test within 14 days before starting the study drug through at 210 days after the last dose of regorafenib. Men and women are required to use adequate birth control during the study (when applicable),
- •Signed and dated informed consent,
- •Ability to comply with the study protocol, in the Investigator's judgment.
- •Registration in a national health care system (CMU included).
排除标准
- •Diagnosis of additional malignancy within 2 years prior to the inclusion (exception of curatively treated basal cell carcinoma of the skin and/or curatively resected in situ cervical and/or bladder cancer),
- •Current participation in a study of an investigational agent. Patients might be included at least 21 days following the last investigational agent administration.
- •Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before inclusion in the trial;
- •Patient under judicial protection (curators, autorship) and/or deprived of freedom,
- •Planned surgical procedure within the first month of treatment or any procedure that might change the timing of regorafenib administration during the first month of treatment,
- •Previous exposure to regorafenib,
- •Previous exposure to other anti-angiogenic treatment than bevacizumab,
- •Complete deficit in dihydropyrimidine dehydrogenase (DPD),
- •Major surgical procedure, open biopsy or significant traumatic injury within 28 days before start of study medication,
- •Pregnant or breast-feeding subjects,
- •Congestive Heart Failure ≥ New York Heart Association (NYHA) class 2, unstable angina (anginal symptomatology at rest),
- •Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 months),
- •Myocardial infarction less than 6 months before start of study drug,
- •Cardiac arrhythmias requiring anti-arrhythmic therapy (beta-blockers or digoxin are permitted),
- •Uncontrolled hypertension (Systolic blood pressure >150 mmHg and/or diastolic pressure >100 mmHg despite optimal medical management), or history of hypertensive crisis, or hypertensive encephalopathy
- •Pleural effusion or ascites that causes respiratory compromise (≥ CTCAE grade 2 dyspnea),
- •Ongoing infection >grade 2 CTCAE V5 (Appendix 6 ),
- •Known History of human immunodeficiency virus (HIV) infection,
- •Active hepatitis B or C or chronic hepatitis B or C requiring treatment with antiviral therapy,
- •Subjects with seizure disorder requiring medication,
- •History of organ allograft,
- •Subjects with evidence or history of any bleeding diathesis, irrespective of severity,
- •Any haemorrhage or bleeding event ≥ CTCAE Grade 3 within 4 weeks prior to the start of study medication,
- •Serious, Non-healing wound, active ulcer or untreated bone fracture,
- •History of abdominal fistula, GI perforation, intra-abdominal abscess or active GI bleeding within 6 months prior to inclusion,
- •Dehydration CTCAE v4 grade ≥1,
- •Known hypersensitivity to any of the study drugs, study drug classes or excipient in the formulation,
- •Interstitial lung disease with ongoing signs or symptoms,
- •Persistent proteinuria of CTCAE Grade 3 (>3.5 g/24 hours),
- •Subject unable to swallow oral medications,
- •Any malabsorption condition, unresolved toxicity higher than CTCAE (V4) Grade 1 attributed to any prior therapy/procedure excluding alopecia, hypothyroidism and oxaliplatin induced neuropathy ≤ Grade 2,
- •Systemic anticancer therapy including cytotoxic therapy, signal transduction inhibitors, immunotherapy, and hormonal therapy during this trial or within 3 weeks,
- •Treatment with any other investigational medicinal product within 28 days prior to study entry, EXCEPT for ASPIRIN,
- •Co-administration of drugs potentially interacting with regorafenib i.e. CYP3A4 or UGT1A9 (UDP-glucuronosyltransferase 1-9) inducers/inhibitors.
研究组 & 干预措施
Experimental
Regorafenib + metronomic Capecitabine + metronomic Cyclophosphamide + low-dose Aspirin followed by second line of chemotherapy (Bevacizumab + FOLFOX or FOLFIRI)
干预措施: quality of life questionnaires (Other)
Experimental
Regorafenib + metronomic Capecitabine + metronomic Cyclophosphamide + low-dose Aspirin followed by second line of chemotherapy (Bevacizumab + FOLFOX or FOLFIRI)
干预措施: Blood sample (Procedure)
Experimental
Regorafenib + metronomic Capecitabine + metronomic Cyclophosphamide + low-dose Aspirin followed by second line of chemotherapy (Bevacizumab + FOLFOX or FOLFIRI)
干预措施: Regorafenib (Drug)
Experimental
Regorafenib + metronomic Capecitabine + metronomic Cyclophosphamide + low-dose Aspirin followed by second line of chemotherapy (Bevacizumab + FOLFOX or FOLFIRI)
干预措施: Metronomic chemotherapies (Drug)
Experimental
Regorafenib + metronomic Capecitabine + metronomic Cyclophosphamide + low-dose Aspirin followed by second line of chemotherapy (Bevacizumab + FOLFOX or FOLFIRI)
干预措施: Aspirin (Drug)
Experimental
Regorafenib + metronomic Capecitabine + metronomic Cyclophosphamide + low-dose Aspirin followed by second line of chemotherapy (Bevacizumab + FOLFOX or FOLFIRI)
干预措施: Bevacizumab (Drug)
Experimental
Regorafenib + metronomic Capecitabine + metronomic Cyclophosphamide + low-dose Aspirin followed by second line of chemotherapy (Bevacizumab + FOLFOX or FOLFIRI)
干预措施: FOLFIRI or FOLFOX (Drug)
Control
Second line of chemotherapy (Bevacizumab + FOLFOX or FOLFIRI)
干预措施: quality of life questionnaires (Other)
Control
Second line of chemotherapy (Bevacizumab + FOLFOX or FOLFIRI)
干预措施: Blood sample (Procedure)
Control
Second line of chemotherapy (Bevacizumab + FOLFOX or FOLFIRI)
干预措施: Bevacizumab (Drug)
Control
Second line of chemotherapy (Bevacizumab + FOLFOX or FOLFIRI)
干预措施: FOLFIRI or FOLFOX (Drug)
结局指标
主要结局
best objective response during treatment period (phase II)
时间窗: during treatment period (from first treatment administration and disease progression, an average of 14 months
the best response rate evaluated with RECIST v1.1 criteria per an independent radiologist committee during the treatment period defined as the number of with complete response (CR) or partial response (PR) as best response divided by the total number of patients evaluable. Patients for whom best overall tumor response is not CR or PR will be considered non-responders.
overall survival (OS) (phase III)
时间窗: through study completion, an average of 64 months
Overall survival is defined as the time from the randomization to death from any cause.
次要结局
未报告次要终点