Pilot Study of Crizotinib in Relapsed ALK+ Lymphomas
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 12
- 试验地点
- 1
- 主要终点
- objective response rates (ORR) in subjects with ALK+ lymphomas resistant or refractory to standard cytotoxic treatment, according to RECIST 1.1 criteria.
研究概览
简要总结
The purpose of this study is to determine the response and the duration of it in patients affected by ALK+ lymphoma that are resistant or refractory to standard cytotoxic treatment that will be treated with crizotinib.
详细描述
Study Rationale
Crizotinib is a selective ATP-competitive small-molecule inhibitor of the c-Met/HGFR and ALK receptor tyrosine kinases and their oncogenic variants (eg. c-Met/HGFR mutations or NPM-ALK fusion protein). Consistent with this mechanism of action, Crizotinib inhibited phosphorylation of c-Met/HGFR and NPM-ALK and their kinase target dependent functions in tumour cells both in vitro and in vivo. This compound will be clinically evaluated in oncology indications in which c-Met/HGFR or NPM-ALK are dysregulated including, but not limited to renal, lung, gastric, brain, prostate, head, and neck cancers, multiple myeloma, and selected lymphomas. Crizotinib demonstrated preclinical antitumour activity, including marked cytoreduction, in several tumour models that expressed activated c-Met/HGFR or NPM-ALK, supporting the rationale for study in clinical trials. Collective PK/PD modelling and efficacy data demonstrated that:
- near complete inhibition (free plasma IC90) of c-Met/HGFR activity during the entire dosing interval was necessary to achieve robust antitumour effect, as it was demonstrated several years ago for imatinib;
- the target efficacious free plasma concentration range was determined to be 8.1 to 12.8 nM (3.7 to 5.8 ng/mL). The projected efficacious dose in humans is estimated to be 70 to 100 mg once daily.
Additional safety and efficacy data presented at the 2010 ASCO meeting (Tan et al., Bang et al.) confirmed these data: plasma concentrations exceeding efficacious levels were obtained in patients receiving at least 100 mg/day of crizotinib; in addition objective tumour regressions were observed in >50% of 82 advanced lung cancer patients whose tumours were positive for the EML4/ALK fusion. Therefore the treatment of ALK+ lymphomas with crizotinib represents a rational attempt at treating a human cancer through the inactivation of its oncogenic mechanism.
When administered to 11 patients affected by relapsed resistant ALK+ lymphomas, crizotinib obtained an Overall Response Rate (ORR) of 10/11 (91%) which included 9 Complete Responses (CR, 82%) and 1 Partial Response. Disease status at the latest follow-up (June 2013) is as follows: 4 CR (months 17+, 26+, 31+, 36+) and 3 deaths due to progression; 1 patient in CR after crizotinib who received alloBMT and 2 patients (treated post alloBMT) are still in CR but they stopped crizotinib; 1 patient is in CR under brentuximab. Progression Free Survival (PSF) and Overall Survival rates at 3 years are 63.6% and 72.7%. Crizotinib exerted a potent antitumor activity in advanced ALK+ lymphoma and produced durable responses in this population of heavily pre-treated patients. In addition this study demonstrated that PCR-based detection of the NPM-ALK fusion in the peripheral blood may be an effective method to monitor disease response and progression.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 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
- •Signed and dated Informed Consent approved by Local Ethical Committee before any protocol-specific screening procedures.
- •ALK+ Non-Hodgkin lymphoma diagnosed by IHC or FISH.
- •Refractory disease or relapse after at least one prior chemotherapy regimen (typically a minimum of 6 cycles of CHOP); presence of measurable disease by physical examination, CT or CT-PET scan.
- •Any prior chemotherapy or major surgeries must have been completed at least 14 days prior to initiation of study medication. This could not be respected if there is clear evidence of disease progression, manifested as growing pain attributable to the tumour, fever, growing tumour lesions, increasing LDH values.
- •Able to take oral therapy.
- •Female or male, 18 years of age or older.
- •ECOG performance status 0-
- •Adequate organ function as defined by the following criteria:
- •Serum aspartate transaminase (AST) and serum alanine transaminase (ALT) ≤ 2.5 x upper limit of normal (ULN) or AST and ALT ≤ 5 x ULN if liver function abnormalities are due to underlying malignancy
- •Total serum bilirubin 1.5 x ULN (except patients with documented Gilbert's syndrome
- •Creatinine ≤ 1.5 x ULN.
- •Adequate bone marrow function:
- •Absolute neutrophil count (ANC) ≥ 1000/µL
- •Platelets ≥ 50.000/µL
- •Hemoglobin ≥ 9.0 g/dL The hematological values will not be considered in case of bone marrow involvement.
- •Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures.
- •Female and male patients who are of childbearing potential must agree to use an effective form of contraception with their partners throughout participation in this study.
排除标准
- •Current treatment on another therapeutic clinical trial.
- •Prior therapy specifically directed against ALK.
- •Major surgery within 14 days prior first dose of crizotinib.
- •History of uncontrolled cardiac disease including: myocardial infarct, uncontrolled angina or hypertension, clinically significant ventricular arrhythmia, unexplained syncope.
- •Pregnancy or breastfeeding.
- •Use of drugs or foods that are known potent CYP3A4 inhibitors, including but not limited to amprenavir, atazanavir, clarithromycin, delavirdine, diltiazem, erythromycin, indinavir, itraconazole, ketoconazole, miconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin, verapamil, voriconazole, and grapefruit or grapefruit juice.
- •Use of drugs that are known potent CYP3A4 inducers, including but not limited to carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine, tipranavir, ritonavir, and St. John's wort.
- •Use of drugs that are CYP3A4 substrates with narrow therapeutic indices, including but not limited aripiprazole, ergotamine, halofantrine, pimozide, triazolam, astemizole*, cisapride*, and terfenadine* (* withdrawn from U.S. market).
- •Prior malignancy other than basal cell carcinoma.
- •Other severe acute or chronic medical or psychiatric conditions, or laboratory abnormalities that would impart, in the judgment of the investigator and/or sponsor, excess risk associated with study participation or study drug administration.
研究组 & 干预措施
crizotinib
250mg BID
干预措施: crizotinib (Drug)
结局指标
主要结局
objective response rates (ORR) in subjects with ALK+ lymphomas resistant or refractory to standard cytotoxic treatment, according to RECIST 1.1 criteria.
时间窗: the entire duration of the study (5 years)
Duration ORR
时间窗: the entire duration of the study (5 years)
次要结局
- Progression free survival (PFS) in ALK+ lymphoma patients treated with crizotinib, that are resistant or refractory to standard cytotoxic treatment.(the entire duration of the study (5 years))
- Number of patients with adverse events after crizotinib treatment(the entire duration of the study (5 years))
- Quality of Life (QoL) in this population of patients using the the EORTC - C30 Quality of Life questionnaire(the entire duration of the study (5 years))
- Overall survival (OS) in ALK+ lymphoma patients treated with crizotinib(the entire duration of the study (5 years))