Phase I/Ib Trial of the Efficacy and Safety of Combination Therapy of Lenalidomide/Bortezomib/Dexamethasone and Panobinostat in Transplant Eligible Patients With Newly Diagnosed Multiple Myeloma (MM)

M.D. Anderson Cancer Center1 个研究点分布在 1 个国家目标入组 77 人开始时间: 2013年2月18日最近更新: 2019年3月4日

适应症

干预措施

试验速览

阶段: 1 期
状态: 已完成
发起方: M.D. Anderson Cancer Center
入组人数: 77
试验地点: 1
主要终点: Maximum Tolerated Dose (MTD) of Panobinostat with Bortezomib, Lenalidomide, and Dexamethasone

研究概览研究设计入排标准研究组 & 干预措施结局指标研究者研究点记录与标识符相似试验

研究概览

简要总结

The goal of this clinical research study is to find the highest tolerable dose of the drug panobinostat that can be given in combination with the drugs Velcade (bortezomib), Revlimid (lenalidomide), and Decadron (dexamethasone) to patients with MM. The safety of this drug combination will also be studied.

Panobinostat is designed to cause chemical changes in different groups of proteins that are attached to DNA (the genetic material of cells), which may slow the growth of cancer cells or cause the cancer cells to die.

Bortezomib is designed to block a protein that causes cells to grow. This may cause cancer cells to die.

Lenalidomide is designed to change the body's immune system. It may also interfere with the development of tiny blood vessels that help support tumor growth. This may slow the growth of cancer cells.

Dexamethasone is a corticosteroid that is similar to a natural hormone made by your body. Dexamethasone is often given to MM patients in combination with other chemotherapy to treat cancer.

详细描述

Study Groups:

If you are found to be eligible to take part in this study, you will be assigned to a dose level of panobinostat based on when you join this study.

If you are enrolled in the first portion of Part A, up to 4 dose levels of panobinostat will be tested. Three (3) to 6 participants will be enrolled at each dose level. The first group of participants will receive the lowest dose level. Each new group will receive a higher dose than the group before it, if no intolerable side effects were seen. This will continue until the highest tolerable dose of panobinostat is found.

If you are enrolled in the second portion of Part A, you will receive panobinostat at the recommended dose from the first portion of Part A.

If you are enrolled in the first portion of Part B, up to 3 dose levels of panobinostat will be tested. Three (3) to 6 participants will be enrolled at each dose level. The first group of participants will receive the lowest dose level. Each new group will receive a higher dose than the group before it, if no intolerable side effects were seen. This will continue until the highest tolerable dose of panobinostat is found.

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

•Clonal bone marrow plasma cells >/=10% or biopsy-proven bony or extramedullary plasmacytoma and any one or more of the following myeloma defining events: Myeloma defining events: Evidence of end organ damage that can be attributed to the underlying plasma cell proliferative disorder, specifically: Hypercalcaemia: serum calcium >0.25 mmol/L (>1 mg/dL) higher than the upper limit of normal or >2.75 mmol/L (>11 mg/dL) Renal insufficiency: creatinine clearance <40 mL per min† or serum creatinine >177 μmol/L (>2 mg/dL)Anaemia: haemoglobin value of >20 g/L below the lower limit of normal, or a haemoglobin value <100 g/L Bone lesions: one or more osteolytic lesions on skeletal radiography, CT, or PET-CT Any one or more of the following biomarkers of malignancy: Clonal bone marrow plasma cell percentage ≥60% Involved:uninvolved serum free light chain ratio§ ≥100>1 focal lesions on MRI studies.
•Continue of Inclusion Criteria 1: If bone marrow has less than 10% clonal plasma cells, more than one bone lesion is required to distinguish from solitary plasmacytoma with minimal marrow involvement. Patient must not have been previously treated with any prior systemic therapy for the treatment of active multiple myeloma. o Prior treatment of hypercalcemia or spinal cord compression with corticosteroids does not disqualify the patient (the dose should not exceed the equivalent of 320 mg of dexamethasone in a 2 week period). o Bisphosphonates are permitted. Prior Therapy for smoldering myeloma is permitted.
•Patients treated with local radiotherapy with or without concomitant exposure to steroids, for pain control or management of cord/nerve root compression, are eligible. One week must have lapsed since last date of radiotherapy, which is recommended to be a limited field and from start of protocol therapy. . Patients who require concurrent radiotherapy should have entry to the protocol deferred until the radiotherapy is completed and one week have passed since the last date of therapy and from start of protocol therapy. .
•Voluntary written informed consent 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.
•Females of childbearing potential (FCBP)† must have a negative serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL 10-14 days prior to therapy and repeated again within 24 hours of starting lenalidomide and must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME, at least 28 days before she starts taking lenalidomide. FCBP must also agree to ongoing pregnancy testing. Men must agree to use a latex condom during sexual contact with a FCBP even if they have had a successful vasectomy.
•Age > / = 18 years at the time of signing Informed Consent.
•Patients must meet the following laboratory criteria: absolute neutrophil count (ANC) >/= 1.5 x 10^9/L (growth factors not permitted to make eligible) , Hemoglobin >/= 9 g/dl (transfusion permitted) , Platelets >/= 100 x 10^9/L , Aspartate transaminase (AST) and Alanine transaminase (ALT) </= 2.5 x upper limits of normal (ULN) , Serum bilirubin </= 1.5 x ULN
•Baseline Multi Gated Acquisition Scan (MUGA) or echocardiogram (ECHO) must demonstrate LVEF >/= 50%
•All study participants must be registered into the mandatory RevAssist® program, and be willing and able to comply with the requirements of RevAssist®.
•Eastern Cooperative Oncology Group (ECOG) Performance Status of </= 2
•Able to take aspirin (81 or 325 mg) daily as prophylactic anticoagulation (patients intolerant to ASA may use warfarin or low molecular weight heparin).

排除标准

•Patient has >/=Grade 2 peripheral neuropathy on clinical examination within 28 days of signing consent.
•Renal insufficiency Creatinine > 2.5 mg/dl
•Myocardial infarction within 6 months prior to signing consent or has New York Heart 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. Prior to study entry, any Electrocardiograph (ECG) abnormality at screening has to be documented by the investigator as not medically relevant.
•Patients who will need valproic acid for any medical condition during the study or within 5 days prior to first panobinostat treatment.
•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 heart rate (HR) >/= 50 bpm. Screening ECG with a QTcF > 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)
•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 (CTCAE version 4) grade 2 at the time of signing consent
•Other concurrent severe and/or uncontrolled medical conditions (e.g., uncontrolled diabetes or active or uncontrolled infection) including abnormal laboratory values, that could cause unacceptable safety risks or compromise compliance with the protocol
•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
•Female subject is pregnant or breast-feeding.
•Hypersensitivity to acyclovir or similar anti-viral drug
•Hypersensitivity to boron or mannitol, or compounds containing these components

研究组 & 干预措施

Panobinostat + Bortezomib + Lenalidomide + Dexamethasone

Experimental

Induction Starting Doses: Lenalidomide 25 mg orally daily on days 1-14; Bortezomib 1.3 mg/m^2 intravenous (IV) daily on days 1, 4, 8 and 11; Dexamethasone 20 mg orally daily on days 1, 2, 4, 5, 8, 9, 11, 12 and Panobinostat orally 10 mg on days 1, 3, 5, 8, 10 and 12. Induction therapy consists of 21 day cycle in Part A and 28 day cycle in Part B.