Phase I Study of Panobinostat Plus ICE Chemotherapy Followed by a Randomized Phase-II Study of ICE Compared With Panobinostat Plus ICE for Patients With Relapsed and Refractory Classical Hodgkin Lymphoma
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 62
- 试验地点
- 1
- 主要终点
- Number of Participants With Complete Remission (CR)
研究概览
简要总结
Objectives:
Primary objective:
- Phase-I: To determine the maximal tolerated dose (MTD) of panobinostat (LBH589) + Ifosfamide + Mesna, Carboplatin and Etoposide (ICE) combination
- Randomized Phase-II: To estimate the complete response (CR) rate in patients with relapsed and refractory classical Hodgkins Lymphoma (HL) receiving ICE versus PANOBINOSTAT plus ICE therapy
Secondary Objectives:
- To assess the safety and tolerability of the novel combination of PANOBINOSTAT (LBH589) plus ICE versus ICE in patients with relapsed and refractory HL
- To estimate the overall response rate (CR + partial response PR)
- To estimate the success rate of stem cell collection in patients eligible for stem cell transplant
- To estimate the percentage of patients who subsequently undergo autologous stem cell transplantation (ASCT)
- To estimate the event free survival (EFS) at 1 year after randomization
- To determine pretreatment expression level of histone deacetylases (HDAC1), HDAC2, and pSTAT3 and Signal transducer and activator of transcription protein (pSTAT6) by Immunohistochemistry (IHC) and correlate the results with treatment response
详细描述
Phase I:
The Study Drugs:
Panobinostat is designed to block the function of enzymes that are found inside cancer cells. These enzymes trigger cells to grow and multiply out of control. By blocking these enzymes, it may slow down the growth of or kill cancer cells.
Ifosfamide is designed to slow or stop the growth of cancer cells.
Carboplatin is designed to interfere with the growth of cancer cells by stopping cell division, which may cause the cells to die.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 16 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Histologically confirmed classical Hodgkin lymphoma (nodular sclerosis, mixed cellularity, or lymphocyte-rich classical HL).
- •Patients must have failed (relapsed or refractory) front-line standard anthracycline-containing regimen, such as ABVD, Stanford V, or BEACOPP.
- •Bidimensionally measurable disease with at least 1 lesion >/= 2.0 cm in a single dimension
- •Acceptable hematologic status:Hemoglobin >/= 9.0 g/dL, Absolute neutrophil count >/= 1500 cells/mm3, Platelet count >/= 100,000 cells/mm3
- •Normal serum K+, Mg+, PO4, and total Ca++ (pre-treatment abnormal values may be therapeutically corrected before starting therapy and must be documented as normal or if abnormal values persist must be documented as clinically insignificant). Albumin should be >/= 3
- •Pre-study World Health Organization (WHO) performance status of 0, 1, or 2
- •Age >/= 16 years
- •Voluntary signed Institutional Review Board (IRB) approved consent informed before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care.
- •Patients of reproductive potential (female of child bearing potential has not been postmenopausal for at least 12 consecutive months or not surgically sterile; male of child bearing potential has not been surgically sterile)must follow accepted birth control methods (e.g. barrier method) during treatment.
- •Clinically euthyroid. Note: Patients are permitted to receive thyroid hormone supplements to treat underlying hypothyroidism.
- •Baseline Multiple Gated Acquisition (MUGA) or ECHO must demonstrate left ventricular ejection fraction (LVEF) >/= 50%.
排除标准
- •Lymphocyte predominant histology
- •More than one prior chemotherapy regimens.
- •Prior therapy with other HDAC inhibitors, including valproic acid
- •Prior therapy with heat shock protein (HSP)-90 inhibitors
- •Prior stem cell transplant
- •Abnormal liver function: Bilirubin > 2.0 mg/dL (26 µmol/L), Alkaline phosphatase > 2 x upper limits of normal (ULN), aspartate aminotransferase AST (SGOT) and/or alanine aminotransferase ALT > 2 x ULN
- •Serum creatinine >1.5 mg/dl
- •Presence of Central Nervous System (CNS) involvement with Hodgkin lymphoma
- •Presence of Human immunodeficiency virus (HIV) infection or acquired immune deficiency syndrome (AIDS).
- •Another primary malignancy (other than squamous cell and basal cell carcinoma of the skin, in situ carcinoma of the cervix, or treated prostate cancer with a stable Prostate Specific Antigen PSA) for which the patient has not been disease free for at least 3 years.
- •Serious nonmalignant disease (e.g., congestive heart failure, hydronephrosis); active uncontrolled bacterial, viral, or fungal infections; or other conditions which would compromise protocol objectives in the opinion of the investigator
- •Impaired cardiac function or clinically significant cardiac diseases, including any one of the following:History or presence of sustained ventricular tachyarrhythmia, Any history of ventricular fibrillation or torsade de pointes, Bradycardia defined as HR< 50 bpm, Patients with pacemakers are eligible if HR >/= 50 bpm, Screening ECG with a corrected QT interval (QTc) > 450 msec, Right bundle branch block + left anterior hemiblock (bifascicular block), Patients with myocardial infarction or unstable angina </= 6 months prior to starting study drug, Other clinically significant heart disease (e.g., congestive heart failure (CHF) New York Heart Association class III or IV , uncontrolled hypertension, history of labile hypertension, or history of poor compliance with an antihypertensive regimen)
- •Female subject is pregnant or breast-feeding. Confirmation that the subject is not pregnant must be established by a negative serum Beta-human chorionic gonadotropin (Beta-hCG) pregnancy test result obtained during screening, unless the female has recently (within 8 weeks) undergone egg harvest, which would result in the (Beta-hCG) test to be elevated without pregnancy. Pregnancy testing is not required for post-menopausal or surgically sterilized women.
- •Patient has received other investigational drugs within 14 days before enrollment or who have not recovered from side effects of those therapies.
- •Serious medical or psychiatric illness likely to interfere with participation in this clinical study.
- •Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of panobinostat
- •Patients with diarrhea > Common Terminology Criteria for Adverse Events Version 4 (CTCAE V.4) grade 2
- •Patients using medications that have a relative risk of prolonging the QT interval or inducing torsade de pointes if treatment cannot be discontinued or switched to a different medication prior to starting study drug.
- •Patients who have received either immunotherapy within </= 8 weeks; chemotherapy within </= 3 weeks; or radiation therapy to > 30% of marrow-bearing bone within </= 2 weeks prior to starting study treatment; or who have not yet recovered from side effects of such therapies.
- •Patients who have undergone major surgery </= 4 weeks prior to starting study drug or who have not recovered from side effects of such therapy.
研究组 & 干预措施
Panobinostat MTD + ICE
Phase 1: Escalating Panobinostat dose with routine ICE Chemotherapy
干预措施: Panobinostat (Drug)
Panobinostat MTD + ICE
Phase 1: Escalating Panobinostat dose with routine ICE Chemotherapy
干预措施: Ifosfamide (Drug)
Panobinostat MTD + ICE
Phase 1: Escalating Panobinostat dose with routine ICE Chemotherapy
干预措施: Mesna (Drug)
Panobinostat MTD + ICE
Phase 1: Escalating Panobinostat dose with routine ICE Chemotherapy
干预措施: Carboplatin (Drug)
Panobinostat MTD + ICE
Phase 1: Escalating Panobinostat dose with routine ICE Chemotherapy
干预措施: Etoposide (Drug)
ICE Chemotherapy
Phase 2: Routine ICE Chemotherapy (Ifosfamide, Carboplatin, + Etoposide)
干预措施: Ifosfamide (Drug)
ICE Chemotherapy
Phase 2: Routine ICE Chemotherapy (Ifosfamide, Carboplatin, + Etoposide)
干预措施: Mesna (Drug)
ICE Chemotherapy
Phase 2: Routine ICE Chemotherapy (Ifosfamide, Carboplatin, + Etoposide)
干预措施: Carboplatin (Drug)
ICE Chemotherapy
Phase 2: Routine ICE Chemotherapy (Ifosfamide, Carboplatin, + Etoposide)
干预措施: Etoposide (Drug)
ICE Chemotherapy
Phase 2: Routine ICE Chemotherapy (Ifosfamide, Carboplatin, + Etoposide)
干预措施: Pegfilgrastim (Drug)
Panobinostat + ICE
Phase 2: Panobinostat with ICE Chemotherapy
干预措施: Panobinostat (Drug)
Panobinostat + ICE
Phase 2: Panobinostat with ICE Chemotherapy
干预措施: Ifosfamide (Drug)
Panobinostat + ICE
Phase 2: Panobinostat with ICE Chemotherapy
干预措施: Mesna (Drug)
Panobinostat + ICE
Phase 2: Panobinostat with ICE Chemotherapy
干预措施: Carboplatin (Drug)
Panobinostat + ICE
Phase 2: Panobinostat with ICE Chemotherapy
干预措施: Etoposide (Drug)
Panobinostat + ICE
Phase 2: Panobinostat with ICE Chemotherapy
干预措施: Pegfilgrastim (Drug)
结局指标
主要结局
Number of Participants With Complete Remission (CR)
时间窗: Assessed after 3 cycles of ICE (2 months)
Will be assessed by Kaplan-Meier methods.
Maximum Tolerated Dose (MTD) of Panobinostat + ICE
时间窗: From first dose of panobinostat (or chemotherapy, in the arm of ICE alone) until 30 days after last dose, up to 6 years
Maximum Tolerated Dose (MTD) of Panobinostat + ICE
次要结局
- Percentage of Participants With Failure Free Survival (FFS)(16 months)