A Phase II Study of CyBorD (Cyclophosphamide, Bortezomib, Dexamethasone) Plus Daratumumab for Patients With Monoclonal Gammopathy of Renal Significance (MGRS)
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 20
- 试验地点
- 22
- 主要终点
- Run-in Phase- Dose-limiting toxicity (DLT) rates
研究概览
简要总结
The purpose of this study is to find out whether cyclophosphamide, bortezomib, dexamethasone (CyBorD) with daratumumab SC is a safe treatment combination for MGRS-associated kidney disease including cast nephropathy associated with multiple myeloma. In addition, the researchers will find out whether the study drug combination is an effective treatment for these conditions.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 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
- •Inclusion criteria for cast nephropathy associated with MM:
- •Subjects must have a confirmed diagnosis of NDMM as per standard IMWG criteria
- •Subjects must have measurable disease, defined as meeting at least 1 of the following criteria ≤ 14 days prior to registration:
- •A monoclonal Immunoglobulin (M-protein) concentration on serum protein electrophoresis (SPEP) of ≥ 0.5 g/dL.
- •Measurable urinary light chain secretion by quantitative analysis using urine protein electrophoresis (UPEP) of ≥ 200 mg/24 hours.
- •Involved serum free light chain (FLC) level ≥ 10 mg/dL, provided the serum FLC ratio is abnormal.
- •eGFR must be <40 ml/min/1.73m2
- •Subjects must have histologically confirmed diagnosis of monoclonal gammopathy associated CN by kidney biopsy OR If a kidney biopsy is not available, a percentage of urine albumin excretion (%UAE) < 25 % AND FLC > 50 mg/dL
- •Inclusion criteria for other MGRS associated renal diseases
- •Histologically confirmed diagnosis of MGRS-associated renal disease by kidney biopsy
- •Presence of monoclonal gammopathy by serum protein electrophoresis, Immunofixation, or Free Light Chain Assay
- •Evidence of plasma cell dyscrasia by bone marrow biopsy confirming clonal plasma cell population
- •eGFR <40 ml/min/1.73m2 or 24h urine total protein > 1gm
- •Inclusion criteria for both cast nephropathy associated with MM and other MGRS associated renal diseases
- •Subjects must be ≥ 18 years of age at time of registration.
- •Subjects must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 ≤ 14 days prior to registration.
- •No evidence of unequivocal recent nephrotoxic exposure (NSAIDs, radiocontrast…)
- •No evidence of obstructive nephropathy by ultrasound
- •Subjects must have adequate hematology laboratory values within 14 days prior to registration defined by the following:
- •Neutrophils ≥ 1.0 × 10^9 /L (Patients cannot have received G-CSF or GM-CSF within 1 week of screening or pegfilgrastim within 2 weeks of screening to meet eligibility).
- •Platelets ≥ 100 × 10^9 /L for run-in and 75 × 10^9 /L for phase II (Note: Platelet support is not permitted to help participants meet eligibility criteria).
- •hemoglobin ≥ 7.5 g/dL without prior red blood cells [RBC] transfusion within 7 days before the laboratory test; recombinant human erythropoietin use is permitted.
- •Subjects must have adequate hepatic function laboratory values ≤ 14 days prior to registration:
- •Aspartate aminotransferase (AST), alkaline phosphatase (AP) or alanine aminotransferase (ALT) ≤ 3 × the upper limit of normal (ULN)
- •Total bilirubin ≤ 1.5 x ULN except for patients with a history of elevated total bilirubin, such as in Gilbert's.
- •Hepatic Child-Pugh score at worse A (patients are eligible for the phase 2 part but not for the Run-in-Period of the trial).
- •Female patients will have to satisfy the following criteria:
- •Be postmenopausal for at least 1 year Prior to registration visit, OR
- •Be surgically sterile, OR
- •If of childbearing potential, agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent form through 90 days after the last dose of study drug, OR
- •Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception). If patient is female and of childbearing potential, she must have a negative serum beta human chorionic gonadotropin (β-HCG) test < 14 days prior to registration and consent to ongoing pregnancy testing during the course of the study.
- •Male patients, even if surgically sterilized (i.e., status post-vasectomy), must agree to one of the following
- •Practice effective barrier contraception during the entire study treatment period and through 90 days after the last dose of study drug, OR
- •Practice true abstinence when this is in line with the preferred and usual lifestyle of he subject. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, postovulation methods] and withdrawal are not acceptable methods of contraception).
- •Subjects must have the willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, study procedures, and research procedures.
排除标准
- •MGRS associated with diseases other than plasma cell dyscrasia (e.g. CLL, B-cell neoplasm, Waldenstrom's macroglobulinemia…)
- •Plasma cell leukemia, AL amyloidosis, or POEMS syndrome.
- •Treatment with prior drugs aimed at the plasma cell dyscrasia.
- •Treatment with prior or concurrent investigational agents aimed at the plasma cell dyscrasia.
- •Female patients who are lactating or have a positive serum pregnancy test during the screening period.
- •Major surgery ≤ 14 days before registration.
- •Focal radiation therapy within 14 days prior to registration with the exception of palliative- radiotherapy for symptomatic management but not on measurable extramedullary plasmacytoma.
- •Disease-related central nervous system involvement.
- •The subject has uncontrolled significant intercurrent illness including, but not limited to, ongoing or active infection.
- •Clinically significant cardiac disease, including:
- •Myocardial infarction within 6 months before randomization, or unstable or uncontrolled disease/condition related to or affection cardiac function (e.g., unstable angina, congestive heart failure, New York Heart Association Class III-IV)
- •Uncontrolled cardiac arrhythmia
- •Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol.
- •Known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent.
- •Concurrent malignancy except for treated non-melanoma skin cancer, cervical carcinoma in situ and low-risk prostate CA being monitored without treatment.
- •Grade 2 or higher peripheral neuropathy on clinical examination during the screening period.
- •Chemotherapy ≤ 14 days of registration.
- •Exposure to an investigational drug (including investigational vaccine) or invasive investigational medical device for any indication within 4 weeks or 5 pharmacokinetic halflives, whichever is longer.
- •Patients with known chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second (FEV1) <50% of predicted normal; moderate or severe persistent asthma within the past 2 years. Note that FEV1 testing is required for participants suspected of having COPD and participants must be excluded if FEV1 is <50% of predicted normal
- •Moderate or severe persistent asthma within the past 2 years, or uncontrolled asthma of any classification. Note that participants who currently have controlled intermittent asthma or controlled mild persistent asthma are allowed to participate.
- •Patients who have a contraindication to the use of any form of anticoagulation or antiplatelet agents.
- •The use of strong CYP3A4 and CYP1A2 inducers or inhibitors will not be allowed while patients are treated on this study.
- •Patients with Hepatic Child-Pugh score B and C. Note that patients with Hepatic Child-Pugh score A are excluded from the Run-in-Period of the trial
- •Patient is:
- •Known history of human immunodeficiency virus (HIV) and those who are seropositive for HIV.
- •Seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]). Subjects with resolved infection (ie, subjects who are HBsAg negative but positive for antibodies to hepatitis B core antigen [anti-HBc] and/or antibodies to hepatitis B surface antigen [anti-HBs]) must be screened using real-time polymerase chain reaction (PCR) measurement of hepatitis B virus (HBV) DNA levels. Those who are PCR positive will be excluded. EXCEPTION: Subjects with serologic findings suggestive of HBV vaccination (anti-HBs positivity as the only serologic marker) AND a known history of prior HBV vaccination, do not need to be tested for HBV DNA by PCR.
- •Seropositive for hepatitis C (except in the setting of a sustained virologic response [SVR], defined as aviremia at least 12 weeks after completion of antiviral therapy).
- •Vaccination with live attenuated vaccines within 4 weeks of first study agent administration.
- •Plasmapheresis within 28 days before randomization.
研究组 & 干预措施
Arm B will include all other MGRS associated diseases with the exclusion of AL amyloidosis
Planned 8 cycles of CyBorD-Dara SC, treatment will be left to the discretion of the treating physician. It is recommended that patients eligible for ASCT undergo ASCT after 8 cycles of induction and that patient ineligible for ASCT, continue maintenance Bortezomib/Dexamethasone administered every other week with daratumumab SC administered every 4 weeks, for a period of 2 years from start of treatment.
干预措施: Dexamethasone (Drug)
Arm B will include all other MGRS associated diseases with the exclusion of AL amyloidosis
Planned 8 cycles of CyBorD-Dara SC, treatment will be left to the discretion of the treating physician. It is recommended that patients eligible for ASCT undergo ASCT after 8 cycles of induction and that patient ineligible for ASCT, continue maintenance Bortezomib/Dexamethasone administered every other week with daratumumab SC administered every 4 weeks, for a period of 2 years from start of treatment.
干预措施: Daratumumab (Drug)
Arm A will include patients with cast nephropathy
Planned 8 cycles of CyBorD-Dara SC, treatment will be left to the discretion of the treating physician. It is recommended that patients eligible for ASCT undergo ASCT after 8 cycles of induction and that patient ineligible for ASCT, continue maintenance Bortezomib/Dexamethasone administered every other week with daratumumab SC administered every 4 weeks, for a period of 2 years from start of treatment.
干预措施: Daratumumab (Drug)
Arm B will include all other MGRS associated diseases with the exclusion of AL amyloidosis
Planned 8 cycles of CyBorD-Dara SC, treatment will be left to the discretion of the treating physician. It is recommended that patients eligible for ASCT undergo ASCT after 8 cycles of induction and that patient ineligible for ASCT, continue maintenance Bortezomib/Dexamethasone administered every other week with daratumumab SC administered every 4 weeks, for a period of 2 years from start of treatment.
干预措施: Bortezomib (Drug)
Arm A will include patients with cast nephropathy
Planned 8 cycles of CyBorD-Dara SC, treatment will be left to the discretion of the treating physician. It is recommended that patients eligible for ASCT undergo ASCT after 8 cycles of induction and that patient ineligible for ASCT, continue maintenance Bortezomib/Dexamethasone administered every other week with daratumumab SC administered every 4 weeks, for a period of 2 years from start of treatment.
干预措施: Dexamethasone (Drug)
Arm B will include all other MGRS associated diseases with the exclusion of AL amyloidosis
Planned 8 cycles of CyBorD-Dara SC, treatment will be left to the discretion of the treating physician. It is recommended that patients eligible for ASCT undergo ASCT after 8 cycles of induction and that patient ineligible for ASCT, continue maintenance Bortezomib/Dexamethasone administered every other week with daratumumab SC administered every 4 weeks, for a period of 2 years from start of treatment.
干预措施: Cyclophosphamide (Drug)
Arm A will include patients with cast nephropathy
Planned 8 cycles of CyBorD-Dara SC, treatment will be left to the discretion of the treating physician. It is recommended that patients eligible for ASCT undergo ASCT after 8 cycles of induction and that patient ineligible for ASCT, continue maintenance Bortezomib/Dexamethasone administered every other week with daratumumab SC administered every 4 weeks, for a period of 2 years from start of treatment.
干预措施: Bortezomib (Drug)
Arm A will include patients with cast nephropathy
Planned 8 cycles of CyBorD-Dara SC, treatment will be left to the discretion of the treating physician. It is recommended that patients eligible for ASCT undergo ASCT after 8 cycles of induction and that patient ineligible for ASCT, continue maintenance Bortezomib/Dexamethasone administered every other week with daratumumab SC administered every 4 weeks, for a period of 2 years from start of treatment.
干预措施: Cyclophosphamide (Drug)
结局指标
主要结局
Run-in Phase- Dose-limiting toxicity (DLT) rates
时间窗: 2 years
Any participant in the run-in-phase who received at least ≥ 75% of the planned doses of the combination regimen in cycle one will be evaluated for DLTs using NCI-CTCAE.
Pilot study (Cohort B) best renal response
时间窗: 2 years
For patients with a decreased eGFR \<50mL/min/1.73 m2 with or without significant proteinuria (UTP\>0.5 gm/24h) at presentation, renal response will be assessed using IMWG renal response criteria
Phase II (Cohort A) best renal response
时间窗: 2 years
For patients with a decreased eGFR \<50mL/min/1.73 m2 with or without significant proteinuria (UTP\>0.5 gm/24h) at presentation, Assessment of renal response will be based on both the IMWG criteria for patient with decreased eGFR and the amyloid criteria for patients with proteinuria.
次要结局
未报告次要终点