Study to Determine the Efficacy of Regorafenib in Metastatic Colorectal Cancer Patients and to Discover Biomarkers
A Phase II Exploratory Study to Identify Biomarkers Predictive of Clinical Response to Regorafenib in Patients With Metastatic Colorectal Cancer Who Have Failed First-line Therapy
In recent years, anti-angiogenic agents have been incorporated into clinical practice for the treatment of metastatic CRC, leading to improvements in progression-free survival and overall survival. Regorafenib is an oral multi-kinase inhibitor that targets angiogenic and oncogenic kinases. Although structurally similar to another multi-kinase inhibitor, sorafenib, it appears to be pharmacologically more potent and possesses broader antiangiogenic properties.
Both sorafenib and regorafenib target BRAF wild-type and BRAF V600E mutant but the inhibition of p38 MAP kinase is a peculiar characteristic of regorafenib. A Phase I study of regorafenib as a single agent in patients with heavily pretreated CRC showed promising clinical activity with a disease control rate (PR + SD) of 59% in evaluable patients. In the Phase III trial (CORRECT), which was a randomized double-blind, placebo-controlled study comparing either regorafenib plus best supportive care (BSC) or placebo plus BSC, it was shown that regorafenib significantly increased overall survival (OS), progression-free survival (PFS) and disease control rate (DCR), independently of KRAS status. A major interest, given the data presented in the CORRECT trial, is to determine predictive biomarkers to indicate patients likely to benefit, or to be resistant to this anti-angiogenic compound.
This study aims to determine the efficacy of regorafenib as single-agent treatment for the treatment of second-line metastatic colorectal cancer and to identify predictive biomarkers in the actual metastatic tumors to be treated. In the case of metastatic CRC patients, liver lesions are frequently the most common site of metastatic deposit and these lesions can be biopsied to assess putative biomarkers. Patients will be asked to undergo a biopsy of a metastatic lesion prior to treatment, and an optional liver biopsy at the time of relapse. Using several high-throughput discovery platforms, biomarkers will be identified in the metastatic tumor specimens and in blood samples collected throughout the treatment. This will allow us to evaluate putative biomarkers and monitor tumor biomarker dynamics using serial blood collection.
The objectives of this trial are to help identify the patient subgroup most likely to be responsive or resistant to regorafenib, so that future treatment with regorafenib can be directed to the more responsive but as yet identified patient population.
調査の概要
研究の種類
入学 (実際)
段階
- フェーズ2
連絡先と場所
研究場所
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Montreal、カナダ、H1T 2M4
- Hopital Maisonneuve-Rosemont
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New Brunswick
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Moncton、New Brunswick、カナダ、E1C 6Z8
- The Moncton Hospital (Horizon Health Network)
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Quebec
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Montreal、Quebec、カナダ、H3T 1E2
- Jewish General Hospital
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Montreal、Quebec、カナダ、H3T 1M5
- St-Mary's Hospital Centre
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Montréal、Quebec、カナダ、H4A 3J1
- McGill University Health Centre
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参加基準
適格基準
就学可能な年齢
健康ボランティアの受け入れ
受講資格のある性別
説明
Inclusion Criteria:
- Signed informed consent.
- Age ≥18 years.
- Histological documentation of adenocarcinoma of the colon or rectum, with at least one liver metastatic site available for biopsy.
- Metastatic disease not suitable for upfront curative-intent surgery.
- Patients must have received one (and no more than one) prior treatment regimen for metastatic CRC.
- Measurable disease according to RECIST v.1.1.
- ECOG status ≤1.
- Life expectancy ≥ 3 months.
- Women of childbearing potential and men must agree to use adequate contraception since signing of the informed consent form until at least 3 months after the last study drug administration.
Adequate bone-marrow, liver, and renal function:
- Total bilirubin ≤1.5 × ULN
- ALT and AST ≤5 × ULN (since liver involvement of their cancer)
- Alkaline phosphatase limit ≤5 × ULN, since liver involvement of their cancer
- Amylase and lipase ≤1.5 × ULN
- Serum creatinine ≤1.5 × ULN
- INR and PTT ≤1.5 × ULN.
- Platelet count ≥100 x 10^9/L, hemoglobin ≥90 g/L, absolute neutrophil count (ANC) >1.5 x 10^9/L
Exclusion Criteria:
- Previous treatment with regorafenib.
- Previous or concurrent cancer that is distinct in primary site or histology from colorectal cancer within 5 years before randomization, EXCEPT for curatively treated cervical cancer in situ, non-melanoma skin cancer and superficial bladder tumours.
- Extended field radiotherapy within 4 weeks or limited field radiotherapy within 2 weeks prior to registration. Patients must have recovered from all therapy-related toxicities. The site of irradiation should have evidence of progressive disease (new lesions or increase in lesion size) if this is the only site of disease.
- Major surgical procedure or significant traumatic injury within 28 days before starting the study treatment.
- Female patients that are pregnant or breast-feeding.
- Congestive heart failure ≥ Class 2 according to the NYHA.
- 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
- Phaeochromocytoma
- Pleural effusion or ascites that causes respiratory compromise.
- Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism within the 3 months before starting the study treatment.
- Ongoing uncontrolled infection > Grade 2 per CTCAE v. 4.0.
- Known history of HIV infection.
- Active hepatitis B or C, or chronic hepatitis B or C requiring antiviral therapy.
- Seizure disorder requiring medication.
- Any history of or currently known brain metastases (patients with stable brain metastases ≥ 3 months may be eligible for the study).
- History of organ allograft.
- Evidence or history of severe bleeding diathesis.
- Non-healing wound, ulcer, or bone fracture.
- Renal failure requiring haemodialysis or peritoneal dialysis
- Dehydration ≥ 2 per CTCAE v. 4.0.
- Substance abuse or medical, psychological, or social conditions that may interfere with the patient's participation in the study or evaluation of the study results.
- Known hypersensitivity to regorafenib, regorafenib class of drugs, or excipients in the formulation.
- Any illness or medical conditions that are unstable or could jeopardize the safety of the patient in the opinion of the investigator.
- Interstitial lung disease with ongoing signs and symptoms at the time of informed consent.
- Persistent proteinuria ≥ Grade 3 per CTCAE v. 4.0 (i.e. >3.5g/24 hours).
- Inability to swallow oral medications.
- Any malabsorption condition.
- Unresolved toxicity > Grade 1, attributed to any prior therapy/procedure, excluding alopecia and oxaliplatin neurotoxicity ≤ Grade 2, per CTCAE v. 4.0.
研究計画
研究はどのように設計されていますか？
デザインの詳細
- 主な目的：処理
- 割り当て：なし
- 介入モデル：単一グループの割り当て
- マスキング：なし（オープンラベル）
武器と介入
参加者グループ / アーム |
介入・治療 |
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実験的：Regorafenib
Single-agent regorafenib
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The dose of regorafenib given will be 160 mg once a day (od) oral (po), using a 21 days on / 7 days off treatment schedule.
This equates to four (4) tablets once a day for three (3) weeks.
The patient should take the dose at the same time each day, with a full glass of water, and following a light meal.
A "light meal"consists of less than 30% fat and around 300-550 calories.
他の名前：
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この研究は何を測定していますか？
主要な結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
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A biomarker (in blood or tissue) that may be predictive of level of response to regorafenib
時間枠：4 years
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A biopsy from a liver metastasis will be taken at baseline for discovery of biomarkers that correlate with response to regorafenib.
Genomic material (DNA and RNA) will be isolated from all biopsies.
Those that pass quality control (high quality DNA, RNA and >60% tumor content) will be considered evaluable.
Batched analysis will be performed at the end of the study with the evaluable samples for multiplex biomarker discovery.
Patient's biomarker status at baseline will be correlated with treatment effect on PFS and response (including response rate and disease control rate) to explore which biological targets may be particularly important in defining the appropriate treatment population for regorafenib.
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4 years
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二次結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
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Number of participants with adverse events
時間枠：Up to 3 years
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Assessment of safety profile of regorafenib in treated patients : report of Adverse Events according to the The NCI's Common Toxicity Criteria version 4.0
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Up to 3 years
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Progression free survival (PFS) time
時間枠：Time from registration to progressive disease (up to 3 years)
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The time from the date of registration until the date of radiological disease progression assessed by RECIST 1.1 or until death due to any cause, even in the absence of radiological progression.
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Time from registration to progressive disease (up to 3 years)
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Objective Response Rate (RR)
時間枠：Up to 3 years
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Determination of the objective response rate (ORR: CR (complete response) +PR (partial response) +SD (stable disease)) of treated patients according to RECIST 1.1 criteria.
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Up to 3 years
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協力者と研究者
スポンサー
捜査官
- 主任研究者：Gerald Batist, MD、Jewish General Hospital
- 主任研究者：Petr Kavan, MD, PhD、McGill University Health Centre/Research Institute of the McGill University Health Centre
研究記録日
主要日程の研究
研究開始 (実際)
一次修了 (予想される)
研究の完了 (予想される)
試験登録日
最初に提出
QC基準を満たした最初の提出物
最初の投稿 (見積もり)
学習記録の更新
投稿された最後の更新 (実際)
QC基準を満たした最後の更新が送信されました
最終確認日
詳しくは
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