A Phase II Study of the ALK Inhibitor, Ceritinib (LDK378), in Relapsed/Refractory ALK+ Hematologic Malignancies
试验速览
- 阶段
- 2 期
- 状态
- 撤回
- 发起方
- 试验地点
- 1
- 主要终点
- Overall Response Rate (ORR)
研究概览
简要总结
This is a phase II, single arm, unblinded study of ceritinib in patients with rel/ref hematologic malignancies. Up to 24 evaluable subjects will be enrolled with an interim analysis for efficacy after the first 9 subjects are enrolled. Any subject who takes at least one dose of study drug will be evaluable for safety. Only subjects who complete at least 1 cycle of study drug and have clear progression on physical exam or have had at least one restaging study will be considered evaluable for response. Each subject will receive the same dose of 750mg po daily at the study entry. Subjects with stable disease or better will be allowed to continue study drug until disease progression or until intolerable adverse events or patient or physician decision. Intrapatient dose reductions will be allowed for adverse events. This is a multicenter study with Duke as the lead site. Blood and tissue samples, will be collected and used for exploratory analysis.
详细描述
This is a phase II, single arm, unblinded study of ceritinib in patients with rel/ref hematologic malignancies. Up to 24 evaluable subjects will be enrolled with an interim analysis for efficacy after the first 9 subjects are enrolled. Any subject who takes at least on dose of study drug will be evaluable for safety. Only subjects who complete at least 1 cycle of study drug and have clear progression on physical exam or have had at least one restaging study will be considered evaluable for response. Each subject will receive the same dose of 750mg po daily at the study entry. Subjects with stable disease or better will be allowed to continue study drug until disease progression or until intolerable adverse events or patient or physician decision. Intrapatient dose reductions will be allowed for adverse events. Blood and tissue samples, will be collected and used for exploratory analysis.
Dose Level 0 (starting dose) 750mg/day Dose level -1 600mg/day Dose level -2 450mg/day
Baseline evaluations are to be conducted within 30 days prior to start of protocol therapy unless otherwise noted in the time to events table. Scans and x-rays must be performed within six weeks prior to the start of therapy. Bone marrow biopsy must be performed within twelve weeks prior to starting therapy. In the event that the patient's condition is deteriorating, laboratory evaluations should be repeated within 48 hours prior to initiation of the next cycle of therapy. All the labs have to be within the study eligibility range prior to the start of study treatment.
All visits should occur within 3 days before or after the scheduled day of the visit. An early or late visit will not shorten or extend the duration of that cycle - all cycles will be 28 days.
If study drug is held for any reason then the missed days should still be counted as a day in the cycle. However, if the study drug is on hold when a 28 day cycle ends, then day 1 of the next cycle and the necessary evaluations should not be started until drug is restarted. Therefore, the cycle during which a drug is held could potentially have more than 28 days.
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
- •Alk+R/R hematologic malignancy including but not limited to ALK+ALCL or ALK+LBCL > 1 prior standard cytotoxic regimen
- •ECOG performance status <2
- •Evidence of measurable or evaluable disease
- •Toxicities ≤ grade 2 due to prior therapies Exception: any grade alopecia
- •Platelets >75 x 109/L
- •ANC>1.5 x 109/L
- •AST/ALT<3.0 x ULN, except liver involvement by their lymphoma, include if AST/ALT<5 x ULN.
- •Total Bilirubin<1.5 x ULN, (includes gilbert's syndrome if total bilirubin <3.0 x ULN and direct bilirubin <1.5 x ULN)
- •Potassium, magnesium, total calcium and phosphorous > lower limits of normal
- •Calculated or measured CrCl> 30ml/min
- •Ability to provide written informed consent
- •Willing/able to comply with scheduled visits, treatment plans, laboratory tests and other procedures
- •Women/men of reproductive potential must agree to use effective birth control during study and for 3 months after receiving study drug.
- •Must have existing tissue available for correlative studies
排除标准
- •No chemotherapy, radiation or surgical resection of malignancy < 3 weeks before start of study drug
- •Prior therapy with other ALK inhibitor investigational agents except crizotinib
- •Active, uncontrolled, serious infection or medical or psychiatric illness likely to interfere with trial
- •Known HIV infection
- •Extensive disseminated bilateral interstitial fibrosis or interstitial lung disease, (history of pneumonitis, hypersensitivity pneumonitis, interstitial pneumonia, obliterative bronchiolitis or clinically significant radiation pneumonitis) i.e. affecting daily living or requiring ongoing therapeutic intervention.
- •Symptomatic CNS metastases and neurologically unstable or increasing doses of steroids < 2 weeks prior to study entry
- •Major surgery 4 weeks before initiating protocol therapy.
- •Hypersensitivity to microcrystalline cellulose, mannitol, crospovidone, colloidal silicon dioxide, magnesium stearate
- •Diagnosis or treatment for malignancy other than NHL < 3 years before Day 1 of protocol therapy. Exceptions:
- •Basal or squamous cell carcinoma of the skin
- •In situ malignancy - completely resected.
- •Prostate cancer treated with prostatectomy or radiotherapy > 2 years before Day 1 of protocol therapy and PSA is undetectable
- •In situ malignancy - completely resected
- •Current treatment with another investigational agent < 14 days before enrollment. Other non-treatment studies allowed if it won't interfere with study participation.
- •Myocardial infarction or unstable angina 6 months before enrollment or New York Hospital Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities.
- •o QTcF>450msec
- •Oral steroids > 4mg dexamethasone or equivalent/day excluding steroids used for adrenal insufficiency
- •Impaired GI function from significant small bowel resection or gastric bypass surgery or inability to swallow up to five ceritinib capsules daily
- •Ongoing GI adverse events > grade 2 (e.g. nausea, vomiting, or diarrhea) at start of study.
- •Receiving medications that meet one of the following criteria and that cannot be discontinued at least 1 week prior to start of treatment and for the duration of participation:
- •Medication with a significant known risk of prolonging the QT interval or inducing Torsades de Pointes http://www.azcert.org/medical-pros/drug-lists/drug-lists.cfm
- •Strong inhibitors or strong inducers of CYP3A4/5 http://medicine.iupui.edu/flockhart/table.htm or http://www.druginteractioninfo.org
- •Therapeutic doses of warfarin sodium (Coumadin) or coumadin-derived anti-coagulant.
- •Enzyme-inducing anticonvulsive agents
- •Herbal supplements
- •Pregnant or nursing (lactating) women
研究组 & 干预措施
Ceritinib for ALK + patients
all ALK + hematologic malignancies patients will receive ceritinib
干预措施: ceritinib (Drug)
结局指标
主要结局
Overall Response Rate (ORR)
时间窗: 5 years
ORR defined as CR + PR. Stable disease of at least 3 months will also be reported.
次要结局
- Progression Free Survival (PFS)(5 years)
研究者
Anne Beaven, MD
Assistant Professor of Medicine
Duke University