An Open Label, Single-Arm, Phase 1b/2 Study of the Safety and Efficacy of Combination Treatment With Lenalidomide, Bortezomib, Dexamethasone and Siltuximab (CNTO 328) in Subjects With Newly Diagnosed, Previously Untreated Multiple Myeloma Requiring Systemic Chemotherapy
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 14
- 试验地点
- 1
- 主要终点
- Maximum Tolerated Dose (MTD) of Siltuximab
研究概览
简要总结
The goal of this clinical research study is to find the highest tolerable dose of Siltuximab that can be given in combination with Velcade (bortezomib), Revlimid (lenalidomide), and dexamethasone to patients with MM. The safety of this drug combination will also be studied.
详细描述
The Study Drugs:
Siltuximab is designed to block IL-6, which is a protein that plays an important role in the survival of myeloma cancer cells. This may slow the growth of cancer cells or cause the cancer cells to die.
Bortezomib is designed to block a protein that plays a role in cell function and growth. This may cause cancer cells to die.
Lenalidomide is designed to kill the myeloma cells and may 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.
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
- •Multiple Myeloma Diagnosis: Subject was previously diagnosed with multiple myeloma by the International Myeloma Foundation 2003 Diagnostic Criteria: IMF Diagnostic Criteria: DIAGNOSTIC CRITERIA: ALL 3 REQUIRED
- •Monoclonal plasma cells in the bone marrow > 10% and/or presence of a biopsy-proven plasmacytoma
- •Monoclonal protein present in the serum and/or urine *
- •Myeloma-related organ dysfunction (1 or more) ** ; [C] Calcium elevation in the blood S. Calcium >10.5 mg/l or upper limit of normal ; [R] Renal insufficiency ; [A] Anemia Hemoglobin < 10 g/dl or 2 g < normal ; [B] Lytic bone lesions or osteoporosis ***
- •Continuation from Inclusion # 1: *If no monoclonal protein is detected (non-secretory disease), then > 30% monoclonal bone marrow plasma cells and/or a biopsy-proven plasmacytoma required ** A variety of other types of end organ dysfunctions can occasionally occur and lead to a need for therapy. Such dysfunction is sufficient to support classification of myeloma if proven to be myeloma related. *** If a solitary (biopsy-proven) plasmacytoma or osteoporosis alone (without fractures) are the sole defining criteria, then > 30% plasma cells are required in the bone marrow.
- •Patient must not have been previously treated with any prior systemic therapy for the treatment of multiple myeloma. Prior treatment of hypercalcemia or spinal cord compression with corticosteroids does not disqualify the patient (the dose should not exceed the equivalent of 160 mg of dexamethasone in a 2 week period). Bisphosphonates are 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. Patients who require concurrent radiotherapy should have start of the protocol therapy (Cycle 1 Day 1) deferred until the radiotherapy is completed and one week have passed since the last date of 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 milli-International unit (mIU)/mL 10 - 14 days prior to therapy and repeated again within 24 hours of prescribing 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. All patients must be counseled at a minimum of every 28 days about pregnancy precautions and risks of fetal exposure.
- •Age >/= 18 years at the time of signing Informed Consent.
- •All necessary baseline studies for determining eligibility must be obtained within 28 days prior to enrollment.
- •Subject has a Eastern Cooperative Oncology Group (ECOG) performance status of 0-
- •All study participants must be registered into the mandatory RevAssist program, and be willing and able to comply with the requirements of RevAssist.
- •Able to take aspirin (81 or 325 mg) daily as prophylactic anticoagulation (patients intolerant to ASA may use warfarin or low molecular weight heparin).
- •Subject must be able to adhere to the study visit schedule and other protocol requirements.
排除标准
- •Patient has >/=Grade 2 peripheral neuropathy on clinical examination within 14 days before enrollment.
- •Renal insufficiency (Creatinine Clearance <30 mL/min by Cockcroft -Gault formula).
- •Subjects with evidence of mucosal or internal bleeding and/or platelet refractory (i.e., unable to maintain a platelet count >/= 50,000 cells/mm^3).
- •Subjects with an absolute neutrophil count (ANC) < 1000 cells/mm^
- •Growth factors may not be used to meet ANC eligibility criteria.
- •Total bilirubin > 1.5 mg/dL
- •Subjects with a hemoglobin < 8.0 g/dL (Transfusion are permitted).
- •AST (SGOT and ALT (SGPT) >/= 2 x upper limit of normal (ULN)
- •Myocardial infarction within 6 months prior to enrollment 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 ECG abnormality at screening has to be documented by the investigator as not medically relevant.
- •Clinically relevant active infection requiring intravenous antibiotics
- •Serious co-morbid medical conditions such as uncontrolled chronic obstructive or chronic restrictive pulmonary disease, and cirrhosis.
- •Any condition, including laboratory abnormalities, that in the opinion of the Investigator places the subject at unacceptable risk if he/she were to participate in the study.
- •Female subject is pregnant or breast-feeding.
- •Serious medical or psychiatric illness likely to interfere with participation in this clinical study.
- •Uncontrolled diabetes mellitus (Fasting Blood Sugar > 400 mg/dl despite medical treatment)
- •Hypersensitivity to acyclovir or similar anti-viral drug
- •Known history of POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein (M-protein) and skin changes).
- •Patients with known history of HIV, Hep B and C.
- •Hypersensitivity to boron or mannitol, or compounds containing these components
- •Vaccinated with live, attenuated vaccines within 4 weeks of the first dose of study treatment
研究组 & 干预措施
Siltuximab + Bortezomib + Lenalidomide
Induction: Lenalidomide 25 mg orally Days 1-14; Bortezomib 1.3 mg/m2 intravenous Days 1, 4, 8 and 11; Dexamethasone 20 mg orally Days 1, 2, 4, 5, 8, 9, 11, 12. Siltuximab 11 mg/kg intravenous Day 1.
If delayed transplant, induction therapy continued up to 2 cycles beyond achieving a CR/nCR (minimum of 4 cycles of therapy and a maximum of 8 cycles of therapy) and then transition to maintenance regimen described below.
Maintenance therapy: Lenalidomide at last tolerated dose Day 1-21 every 28 days for up to 12 months and then may be reduced to 10 mg.
Siltuximab 11 mg/kg intravenous every 21 days, or maximum tolerated dose from induction therapy. Bortezomib at last tolerated dose Day 1 and Day 8 Dexamethasone at last tolerated dose or 20 mg weekly.
干预措施: Lenalidomide (Drug)
Siltuximab + Bortezomib + Lenalidomide
Induction: Lenalidomide 25 mg orally Days 1-14; Bortezomib 1.3 mg/m2 intravenous Days 1, 4, 8 and 11; Dexamethasone 20 mg orally Days 1, 2, 4, 5, 8, 9, 11, 12. Siltuximab 11 mg/kg intravenous Day 1.
If delayed transplant, induction therapy continued up to 2 cycles beyond achieving a CR/nCR (minimum of 4 cycles of therapy and a maximum of 8 cycles of therapy) and then transition to maintenance regimen described below.
Maintenance therapy: Lenalidomide at last tolerated dose Day 1-21 every 28 days for up to 12 months and then may be reduced to 10 mg.
Siltuximab 11 mg/kg intravenous every 21 days, or maximum tolerated dose from induction therapy. Bortezomib at last tolerated dose Day 1 and Day 8 Dexamethasone at last tolerated dose or 20 mg weekly.
干预措施: Bortezomib (Drug)
Siltuximab + Bortezomib + Lenalidomide
Induction: Lenalidomide 25 mg orally Days 1-14; Bortezomib 1.3 mg/m2 intravenous Days 1, 4, 8 and 11; Dexamethasone 20 mg orally Days 1, 2, 4, 5, 8, 9, 11, 12. Siltuximab 11 mg/kg intravenous Day 1.
If delayed transplant, induction therapy continued up to 2 cycles beyond achieving a CR/nCR (minimum of 4 cycles of therapy and a maximum of 8 cycles of therapy) and then transition to maintenance regimen described below.
Maintenance therapy: Lenalidomide at last tolerated dose Day 1-21 every 28 days for up to 12 months and then may be reduced to 10 mg.
Siltuximab 11 mg/kg intravenous every 21 days, or maximum tolerated dose from induction therapy. Bortezomib at last tolerated dose Day 1 and Day 8 Dexamethasone at last tolerated dose or 20 mg weekly.
干预措施: Siltuximab (Drug)
Siltuximab + Bortezomib + Lenalidomide
Induction: Lenalidomide 25 mg orally Days 1-14; Bortezomib 1.3 mg/m2 intravenous Days 1, 4, 8 and 11; Dexamethasone 20 mg orally Days 1, 2, 4, 5, 8, 9, 11, 12. Siltuximab 11 mg/kg intravenous Day 1.
If delayed transplant, induction therapy continued up to 2 cycles beyond achieving a CR/nCR (minimum of 4 cycles of therapy and a maximum of 8 cycles of therapy) and then transition to maintenance regimen described below.
Maintenance therapy: Lenalidomide at last tolerated dose Day 1-21 every 28 days for up to 12 months and then may be reduced to 10 mg.
Siltuximab 11 mg/kg intravenous every 21 days, or maximum tolerated dose from induction therapy. Bortezomib at last tolerated dose Day 1 and Day 8 Dexamethasone at last tolerated dose or 20 mg weekly.
干预措施: Dexamethasone (Drug)
Siltuximab + Bortezomib + Lenalidomide
Induction: Lenalidomide 25 mg orally Days 1-14; Bortezomib 1.3 mg/m2 intravenous Days 1, 4, 8 and 11; Dexamethasone 20 mg orally Days 1, 2, 4, 5, 8, 9, 11, 12. Siltuximab 11 mg/kg intravenous Day 1.
If delayed transplant, induction therapy continued up to 2 cycles beyond achieving a CR/nCR (minimum of 4 cycles of therapy and a maximum of 8 cycles of therapy) and then transition to maintenance regimen described below.
Maintenance therapy: Lenalidomide at last tolerated dose Day 1-21 every 28 days for up to 12 months and then may be reduced to 10 mg.
Siltuximab 11 mg/kg intravenous every 21 days, or maximum tolerated dose from induction therapy. Bortezomib at last tolerated dose Day 1 and Day 8 Dexamethasone at last tolerated dose or 20 mg weekly.
干预措施: Questionnaires (Behavioral)
结局指标
主要结局
Maximum Tolerated Dose (MTD) of Siltuximab
时间窗: 21 days
Maximum tolerated dose (MTD) defined as follows: At first dose level, if greater than 1 out of 3 patients or greater than 1 out of 6 patients experience dose limiting toxicity (DLT), the dose level exceeds the maximum tolerated dose (MTD). Dose limiting toxicity (DLT) defined as toxicities graded in severity according to the guidelines outlined in the NCI-Common Toxicity Criteria for Adverse Effects (CTCAE) version 4.0.
次要结局
- Number of Participants With Response(Evaluated after eight cycles of 21 days.)