A Prospective, Multicenter, Non-comparative, Open-label, Phase II Study to Evaluate the Effects of Daratumumab Monotherapy on Bone Parameters in Patients With Relapsed and /or Refractory Multiple Myeloma Who Have Received at Least 2 Prior Lines of Therapy, Including Lenalidomide and a Proteasome Inhibitor
试验速览
- 阶段
- 2 期
- 发起方
- 入组人数
- 57
- 试验地点
- 1
- 主要终点
- changes in bone resorption marker, C-telopeptide of collagen type 1 (CTX), after 4 months of daratumumab monotherapy
研究概览
简要总结
The purpose of this study is to evaluate the effects of daratumumab monotherapy on bone disease in patients with relapsed/refractory MM who have received at least 2 prior lines of therapy, including lenalidomide and a PI.
详细描述
This is a prospective, multicenter, non-comparative, open-label Phase II study. Daratumumab will be administered according to approved label. Approximately 57 subjects located in Greece will be enrolled in the study.
Patients shall receive treatment until disease progression, physician decision, unacceptable toxicity, withdrawal of consent, or death (whichever occurs first). Survival status and data of subsequent anti-myeloma treatment will be collected post-treatment.
Primary and secondary variables related to bone disease markers will be evaluated every other cycle of therapy. Disease evaluations will occur monthly and consist mainly of measurements of myeloma proteins. Other parameters may include bone marrow examinations, skeletal surveys, assessment of extramedullary plasmacytomas, and measurements of serum calcium corrected for albumin, and β2- microglobulin and albumin. Assessment of myeloma response and disease progression will be conducted in accordance with the modified IMWG response criteria
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
- •Males and females at least 18 years of age.
- •Voluntary written informed consent.
- •Subject must have documented relapsed or refractory multiple myeloma as defined by the criteria below:
- •a. Measurable disease as defined by any of the following:
- •Serum monoclonal paraprotein (M-protein) level ≥ 1.0 g/dL (except for IgA subtype: ≥ 0.5 g/dL) or urine M-protein level ≥ 200 mg/24 hours; or
- •Light chain multiple myeloma for subjects without measurable disease in the serum or urine by SPEP/UPEP: Serum immunoglobulin free light chain ≥ 10 mg/dL and abnormal serum immunoglobulin kappa lambda free-light-chain ratio.
- •Prior treatment with at least two lines of therapy including lenalidomide and a PI for MM (induction followed by any planned high dose therapy or consolidation or maintenance would be considered as one regimen).
- •Documented evidence of progressive disease as defined by the IMWG 2014 on or after the last regimen.
- •Karnofsky Performance Status score of ≥
- •All of the following laboratory test results during screening:
- •Absolute neutrophil count (ANC) of ≥1.0 x 109/L.
- •Platelet count of ≥ 75 x 109/L in patients in whom <50% of bone marrow nucleated cells are plasma cells and ≥50 x 109/L in patients in whom more than 50% of bone marrow nucleated cells are plasma cells.
- •Hemoglobin value (> 7.5 g/dL).
- •Alanine aminotransferase level ≤2.5 times the upper limit of normal (ULN).
- •Adequate renal function (CrCl ≥ 30 mL/min by CKD-EPI).
- •Willingness and ability to participate in study procedures.
- •Reproductive Status:
- •Women of childbearing potential (WOCBP) must have two negative serum or urine pregnancy tests, one 10-14 days prior to start of the study drug and one within 24 hours prior to the start of study drug.
- •Women must not be breastfeeding.
- •WOCBP must agree to follow instructions for effective methods of contraception for 4 weeks before the start of treatment with study drugs, for the duration of treatment with study drugs, and for 3 months after cessation of study treatment.
- •Male patients must use a latex or synthetic condom during any sexual contact with females of reproductive potential, even if they have undergone a successful vasectomy. They must also agree to follow instructions for methods of contraception for 4 weeks before the start of treatment with study drugs, for the duration of treatment with study drugs, and for a total of 3 months post-treatment completion.
排除标准
- •Patient has received any of the following therapies:
- •Radiotherapy or systemic therapy within 2 weeks of baseline.
- •Prior Allogeneic hematopoietic stem cell transplantation within 12 weeks of baseline.
- •Prior Treatment with any CD38-antibody (i.e. isatuximab).
- •Clinically significant cardiac disease, including:
- •Myocardial infarction within 6 months, or unstable or uncontrolled condition (e.g., unstable angina, congestive heart failure, New York Heart Association Class III-IV).
- •Cardiac arrhythmia (CTCAE Grade 3 or higher) or clinically significant ECG abnormalities.
- •ECG showing a baseline QT interval as corrected >470 msec.
- •Chronic obstructive pulmonary disease (COPD) with a Forced Expiratory Volume in 1 second (FEV1) <50% of predicted normal. Note that FEV1 testing is required for subjects suspected of having COPD and subjects must be excluded if FEV1 <50% of predicted normal.
- •Known active hepatitis A, B, or C.
- •Known HIV infection.
- •Significant neuropathy (Grades 3-4, or Grade 2 with pain) within 14 days prior to enrolment.
- •Hypersensitivity to the active substance or to any of the excipients.
- •Any concurrent medical or psychiatric condition or disease (e.g., active systemic infection, uncontrolled diabetes, acute diffuse infiltrative pulmonary disease) that is likely to interfere with subject's ability to give informed consent, the study procedures or results, or that in the opinion of the investigator, would constitute a hazard for participating in this study.
- •Pregnant or breastfeeding women.
研究组 & 干预措施
Daratumumab
Daratumumab at a dose of 16 mg/kg administered as an IV infusion at weekly intervals (QW) for 8 weeks, then every 2 weeks (Q2W) for an additional 16 weeks, then every 4 weeks (Q4W) thereafter.
干预措施: Daratumumab (Drug)
结局指标
主要结局
changes in bone resorption marker, C-telopeptide of collagen type 1 (CTX), after 4 months of daratumumab monotherapy
时间窗: assessed on baseline and after 4 months from initiation of daratumumab monotherapy
The evaluation of the changes in bone resorption marker after 4 months of daratumumab monotherapy. CTX (measured in pg/ml) will be evaluated at baseline and then every 2 months of therapy.
changes in bone resorption marker, namely, tartrate-resistant acid phosphatase-5b (TRACP-5b) after 4 months of daratumumab monotherapy
时间窗: assessed on baseline and after 4 months from initiation of daratumumab monotherapy
The evaluation of the changes in bone resorption marker after 4 months of daratumumab monotherapy. TRACP-5b (measured in mU/dL) will be evaluated at baseline and then every 2 months of therapy
次要结局
- Changes in bone formation marker, OC.(from baseline up to 12 months of daratumumab monotherapy or at end of treatment)
- Changes in bone formation marker, bALP.(from baseline up to 12 months of daratumumab monotherapy or at end of treatment)
- Changes in bone formation marker, PINP.(from baseline up to 12 months of daratumumab monotherapy or at end of treatment)
- Changes in bone resorption marker, TRACP-5b.(from baseline up to12 months of daratumumab monotherapy or at end of treatment)
- Changes in bone marker RANKL(from baseline up to 12 months of daratumumab monotherapy or at end of treatment)
- Changes in bone resorption marker, CTX.(from baseline up to12 months of daratumumab monotherapy or at end of treatment)
- Changes in bone marker ratio,RANKL/OPG ratio.(from baseline up to 12 months of daratumumab monotherapy or at end of treatment)
- Changes in bone marker CCL3(from baseline up to 12 months of daratumumab monotherapy or at end of treatment)
- Changes in bone marker Dkk1(from baseline up to 12 months of daratumumab monotherapy or at end of treatment)
- Overall survival(Time from first dose of study treatment to death (approximately up to 2 years))
- The incidence of pathological fractures (Skeletal surveys-Skeletal related events)(From baseline to 24 months (up to 2 years))
- Change in Bone Mineral Density (BMD) of lumbar spine(measured at baseline and after 6 and 12 months after initiation of daratumumab monotherapy)
- Time to next treatment(From first dose until the date to next anti-neoplastic therapy or death from any cause, whichever comes first (approximately up to 2 years))
- Changes in bone marker SOST(from baseline up to 12 months of daratumumab monotherapy or at end of treatment)
- Changes in bone marker activin-A(from baseline up to 12 months of daratumumab monotherapy or at end of treatment)
- Spinal cord compression (Skeletal surveys-Skeletal related events)(From baseline to 24 months (up to 2 years))
- Safety (adverse events)(Continuously throughout the study, starting from informed consent until 30 days after last study treatment (approximately up to 30 months))
- Immunomodulatory effects of daratumumab on T cells by comprehensive molecular and phenotypic studies and correlations with bone markers(: measured at baseline and after 3 and 6 months after initiation of daratumumab monotherapy)
- Need for radiotherapy or surgery to the bones (Skeletal surveys-Skeletal related events)(From baseline to 24 months (up to 2 years))
- Progression free survival (PFS)(from recruitment to the date of the first documented PD or death due to any cause, whichever comes first (approximately up to 2 years).)