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
Carboplatin,Etoposide,Ifosfamide,LBH589 "B" (oral) ,Panobinostat
The goal of this clinical research study is to learn if the combination of the drugs ifosfamide, carboplatin, and etoposide (a routine chemotherapy called ICE) and panobinostat can help to control relapsed or refractory Hodgkin's lymphoma. The safety of this drug combination will also be studied.
Disease Group: Lymphoma
Treatment Agent: Carboplatin,Etoposide,Ifosfamide,LBH589 "B" (oral) ,Panobinostat
Treatment Location: Only at MDACC
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
IRB Review and Approval Date: 01/31/2011
Recruitment Status: Not Accepting
Projected Accrual: N/A
1) Histologically confirmed classical Hodgkin lymphoma (nodular
sclerosis, mixed cellularity, or lymphocyte-rich classical HL).
2) Patients must have failed (relapsed or refractory) front-line standard anthracycline-containing regimen, such as ABVD, Stanford V, or BEACOPP.
3) Bidimensionally measurable disease with at least 1 lesion >/= 2.0 cm in a single dimension
4) Acceptable hematologic status:Hemoglobin >/= 9.0 g/dL, Absolute neutrophil count >/= 1500 cells/mm3, Platelet count >/= 100,000 cells/mm3
5) 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
6) Pre-study World Health Organization (WHO) performance status of 0, 1, or 2
7) Age >/= 16 years
8) Voluntary signed 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.
9) 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.
10) Clinically euthyroid. Note: Patients are permitted to receive thyroid hormone supplements to treat underlying hypothyroidism.
11) Baseline Multiple Gated Acquisition (MUGA) or ECHO must demonstrate left ventricular ejection fraction (LVEF) >/= 50%.
1) Lymphocyte predominant histology
2) More than one prior chemotherapy regimens.
3) Prior therapy with other HDAC inhibitors, including valproic acid
4) Prior therapy with heat shock protein (HSP)-90 inhibitors
5) Prior stem cell transplant
6) 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
7) Serum creatinine >1.5 mg/dl
8) Presence of Central Nervous System (CNS) involvement with Hodgkin lymphoma
9) Presence of Human immunodeficiency virus (HIV) infection or acquired immune deficiency syndrome (AIDS).
10) 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.
11) 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
12) 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 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., CHF NY Heart Association class III or IV , uncontrolled hypertension, history of labile hypertension, or history of poor compliance with an antihypertensive regimen)
13) 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.
14) Patient has received other investigational drugs within 14 days before enrollment or who have not recovered from side effects of those therapies.
15) Serious medical or psychiatric illness likely to interfere with participation in this clinical study.
16) Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of panobinostat
17) Patients with diarrhea > Common Terminology Criteria for Adverse Events Version 4 (CTCAE V.4) grade 2
18) 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.
19) 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.
20) Patients who have undergone major surgery </= 4 weeks prior to starting study drug or who have not recovered from side effects of such therapy
Information and next steps
Phase I/Phase II
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