A Multicenter, Open Label, Randomized Phase II Study Comparing Daratumumab Combined With Bortezomib-Cyclophosphamide-dexamethasone (Dara-VCd) Versus the Association of Bortezomib-Thalidomide-dexamethasone (VTd) as Pre Transplant Induction and Post Transplant Consolidation, Both Followed by a Maintenance Phase With Ixazomib Alone or in Combination With Daratumumab, in Newly Diagnosed Multiple Myeloma (MM) Young Patients Eligible for Autologous Stem Cell Transplantation
试验速览
- 阶段
- 2 期
- 状态
- 进行中（未招募）
- 入组人数
- 401
- 试验地点
- 26
- 主要终点
- MRD negativity
研究概览
简要总结
This protocol is a phase II multicenter, randomized, open label study designed to assess the efficacy and safety of daratumumab combined with bortezomib, cyclophosphamide and dexamethasone (Dara-VCd) versus the association of bortezomib, thalidomide and dexamethasone (VTd) as pre transplant induction and post transplant consolidation, followed by maintenance with ixazomib alone or in combination with daratumumab, in newly diagnosed multiple myeloma (MM) patients eligible for autologous stem cell transplantation.
Patients enrolled in the Dara-VCd arm will receive: 4 cycles of daratumumab-bortezomib-cyclophosphamide-dexamethasone induction, followed by transplantation and 2 cycles of daratumumab-bortezomib-cyclophosphamide-dexamethasone consolidation. The choice of cyclophosphamide in combination with bortezomib and dexamethasone is suggested by the better safety profile of cyclophosphamide, in comparison with thalidomide and the efficacy of the alkylator agent, when combined with bortezomib.
Once-weekly bortezomib seems to be equally effective and better tolerated than the standard twice weekly schedule. The outcomes and response rate did not appear to be affected by the bortezomib dosing schedule.
Patients enrolled in the VTd arm will receive: 4 cycles of bortezomib-thalidomide-dexamethasone induction, followed by autologous transplantation and 2 cycles of bortezomib-thalidomide dexamethasone as consolidation. The VTd drug association is the current standard first line induction therapy for multiple myeloma patients who are eligible to stem cell transplantation.
At the end of consolidation phase patients with at least a partial response (≥ PR) will be rerandomized (assigned by chance) to one of 2 treatment groups to receive maintenance treatment with ixazomib alone or in combination with daratumumab. Patients will receive treatment until any sign of progression or intolerance, up to 24 months.
详细描述
INDUCTION AND CONSOLIDATION REGIMEN:
Arm Dara-VCd:
Daratumumab: 16 mg/Kg given by IV infusion on days 1, 8, 15, 22, on cycles 1-2 and on days 1, 15 on cycles 3-4.
Bortezomib: 1.3 mg/m2 given subcutaneous (SC) injection on days 1, 8,15, 22; Cyclophosphamide: 300 mg/ m2 given orally or by IV infusion on days 1, 8, 15, 22; Dexamethasone: 40 mg given orally or by IV infusion on days 1, 8, 15, 22 Repeat for four 4-week induction cycles. After induction all patients will be given Cyclophosphamide at the dose of 3 g/m2, followed by Granulocyte Colony-Stimulating Factor (G-CSF) for stem cell collection. Cyclophosphamide will start 4-6 weeks after start of the fourth cycle of therapy.
Stem cell collection will be performed as soon as CD34+ cells are present in peripheral blood, which is usually between 9-14 days after first day of Cyclophosphamide. Stem cells will be harvested at a minimum of 4 x 106 CD34+ cells/kg and cryopreserved. In case insufficient stem cells are collected the procedure may be repeated or alternatively bone marrow stem cell collection may be performed or Plerixafor may be used.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patient at least 18 years of age and ≤ 65 years.
- •Patient eligible for autologous stem cell transplantation (ASCT).
- •Left Ventricular Ejection Fraction (LVEF) ≥ 40%. 2-D transthoracic echocardiogram (ECHO) is the preferred method of evaluation. Multigated Acquisition Scan (MUGA) is acceptable if ECHO is not available.
- •Newly diagnosed multiple myeloma patient.
- •Patient has given voluntary written informed consent before performance of any study related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.
- •Patient with documented multiple myeloma and measurable disease as defined by:
- •Monoclonal plasma cells in the bone marrow ≥10% or presence of a biopsy proven plasmacytoma
- •Measurable disease as defined by at least one of the following:
- •serum M-protein level ≥1 g/dL or urine M-protein level ≥200 mg/24 hours; or
- •Light chain multiple myeloma: Serum immunoglobulin free light chain ≥10 mg/dL and abnormal serum immunoglobulin kappa lambda free light chain ratio.
- •Evidence of end organ damage/presence of biomarkers of malignancies, 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 (CLcr)<40 mL per minute (measured or estimated by validated equations) or serum creatinine >177 μmol/L (>2 mg/dL)
- •Anaemia: haemoglobin value of >20 g/L below the lower limit of normal, or haemoglobin value <100 g/L
- •Bone lesions: one or more osteolytic lesions on skeletal radiography, CT, or PET-CT. If bone marrow has <10% clonal plasma cells, more than one bone lesion is required to distinguish from solitary plasmacytoma with minimal marrow involvement
- •Any one or more of the following biomarkers of malignancy:
- •Clonal bone marrow plasma cell percentage ≥ 60% (clonality should be established by showing κ/λ-light-chain restriction on flow cytometry, immunohistochemistry, or immunofluorescence. Bone marrow plasma cell percentage should preferably be estimated from a core biopsy specimen; in case of a disparity between the aspirate and core biopsy, the highest value should be used)
- •Involved:uninvolved serum free light chain ration ≥ 100 (values based on the serum Free light assay. The involved free light chain must be ≥100 mg/L)
- •> 1 focal lesion on MRI (magnetic resonance imaging) studies (each focal lesion must be 5 mm or more in size) Patient is, in the investigator(s) opinion willing and able to comply with the protocol requirements.
- •Women of childbearing potential must commit to either abstain continuously from heterosexual intercourse or to use 2 methods of reliable birth control simultaneously. This includes one highly effective form of contraception (tubal ligation, intrauterine device, hormonal [birth control pills, hormonal patches, vaginal rings or implants] or partner's vasectomy) and one additional effective contraceptive method (male latex or synthetic condom, diaphragm, or cervical cap). Contraception must begin prior to dosing through 90 days after the last dose of study drug. Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy or bilateral oophorectomy.
- •Male patient agrees to use an acceptable method for contraception (i.e., condom or abstinence) during study drug therapy (including dose interruption) and for 90 days after the last dose of study drug.
- •Patient with an Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2 or Karnofsky performance status ≥ 60%.
- •Pretreatment clinical laboratory values within 30 days of enrolment:
- •Platelet count ≥75 x 109/L;
- •Absolute neutrophil count (ANC) ≥ 1 x 109/L (G-CSF use is permitted);
- •Corrected serum calcium <14 mg/dL (<3.5 mmol/L);
- •Aspartate transaminase (AST) ≤ 2.5 x the upper limit of normal (ULN);
- •Alanine transaminase (ALT) ≤ 2.5 x the ULN;
- •Total bilirubin ≤ 1.5 x the ULN;
- •Calculated or measured creatinine clearance ≥ 30 mL/minute.
- •Patient has a life-expectancy >3 months.
排除标准
- •Patient with a diagnosis of primary amyloidosis, monoclonal gammopathy of undetermined significance, smoldering MM or Plasma Cell Leukemia (PCL). Monoclonal gammopathy of undetermined significance is defined by presence of serum M-protein <3 g/dL, clonal bone marrow plasma cells <10%, and absence of end-organ damage or amyloidosis that can be attributed to the plasma cell proliferative disorder. Smoldering multiple myeloma is defined as serum monoclonal protein ≥ 30 g/L or urinary monoclonal protein ≥ 500 mg per 24 h and/or clonal bone marrow plasma cell 10-60% with absence of related organ or tissue impairment or end-organ damage or amyloidosis. Plasma cell leukemia is defined as presence of circulating plasmacells (PCs) >2×109/L in peripheral blood or a peripheral blood plasmacytosis >20%
- •Patient with a diagnosis of Waldenström's disease, or other conditions in which immunoglobulin M (IgM) M-protein is present in the absence of a clonal plasma cell infiltration with lytic bone lesions.
- •Patient has prior or current systemic therapy or SCT for multiple myeloma, with the exception of an emergency use of a short course (equivalent of dexamethasone 40 mg/day for a maximum 4 days) of corticosteroids before treatment.
- •Patient has peripheral neuropathy of grade 2 or higher as defined by National Cancer Institute Common Toxicity Criteria (NCI CTC) 4.
- •Patient is exhibiting clinical signs of meningeal involvement of multiple myeloma.
- •Clinical active infectious hepatitis type A, B, C or HIV.
- •Subject has known chronic obstructive pulmonary disease (COPD) (defined as a Forced Expiratory Volume In 1 second (FEV1) <60% of predicted normal), persistent asthma, or a history of asthma within the last 2 years. Subjects with known or suspected COPD or asthma must have a FEV1 test during screening.
- •Evidence of current uncontrolled cardiovascular conditions, including uncontrolled hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart failure, unstable angina, or myocardial infarction within the past 6 months.
- •Known allergy to any of the study medications, their analogues, or excipients in the various formulations.
- •Contraindication to any of the required concomitant drugs or supportive treatments.
- •Pregnant or lactating females.
研究组 & 干预措施
Dara-VCd
treatment period includes administration of four 28-day cycles of induction with Dara- VCd; then patients will undergo transplant and finally they will receive two 28-day cycles of Dara-VCd consolidation treatment.
The response will be assessed after each cycle. Patients in the first randomization will be stratified according to FISH (standard/missing vs high risk,defined as del17, t 4;14, t 14;16) and ISS (I vs II and III).
TREATMENT SCHEMA - INDUCTION Daratumumab: 16 mg/Kg given by IV infusion on days 1, 8, 15, 22, on cycles 1-2 and on days 1, 15 on cycles 3-4.
Bortezomib: 1.3 mg/m2 given SC injection on days 1, 8,15, 22; Cyclophosphamide: 300 mg/ m2 given orally or IV infusion on days 1, 8, 15, 22; Dexamethasone: 40 mg given orally or by IV infusion on days 1, 8, 15,22 Repeat for four 4-week induction cycles.
干预措施: Daratumumab plus Velcade Cyclophosphamide Dexamethasone (Drug)
VTd
treatment period includes administration of four 28-day cycles of induction with VTd; then patients will undergo transplant and finally they will receive two 28-day cycles of VTd consolidation treatment.
TREATMENT SCHEMA INDUCTION
ARM VTd:
Bortezomib: 1.3 mg/m2 given by SC injection on days 1, 4, 8, 11 of 28-day cycle; Thalidomide: 100 mg given orally on days 1-28. Dexamethasone: 20 mg given orally or by IV injection on days 1, 2, 3, 4, 8, 9, 10 and 11 of every 28-day cycle.
Repeat for four 4-week induction cycles.
干预措施: Velcade Thalidomide Dexamethasone (Drug)
结局指标
主要结局
MRD negativity
时间窗: 5 years
MRD evaluation by clonotypic analysis of Immunoglobulin heavy chain (IgH) Variable-Diversity-Junctional (VDJ) gene rearrangement will be performed on bone marrow (BM) samples obtained by the end of induction and consolidation and thereafter every 6 mm after the first maintenance treatment dose. The Clonal Sequencing (ClonoSEQTM) assay (Adaptive Biotechnologies, Seattle) will be used at sensitivity thresholds of 10-3 (1 cancer cell per 1,000 nucleated cells), 10-4 and \>/= 10-5. The rate of MRD negativity in each of the treatment arms of study protocol is determined as the proportion of patients with MRD negativity (\>/=10-5 sensitivity level) at any established treatment point. Patients who withdraw from the study or are lost to Follow-up (FU) will be considered censored a t the time of the last MRD assessment. Patients will be classified as MRD positive if they have only MRD positive test results or do not undergo MRD assessment.
Progression free survival (PFS)
时间窗: 5 years
PFS in part 1 and part 2 of the study will be measured from the date of first or second randomization to the date of first observation of disease progression or death to any cause as an event. Subjects who withdraw from the study will be considered censored at the time of the last complete disease assessment. Subjects who complete the study, have no progressed, and are still alive at the cut-off date of final analysis will be censored at the cut-off date. All subjects who were lost to followup prior to the end of the study have no progressed, and are still alive will also be censored at the time of last contact.
次要结局
- Progression free survival 2 (PFS2)(5 years)
- Time to the next anti-myeloma therapy (TNT)(5 years)
- MRD by NGF and Positron Emission Tomography (PET)/CT(5 years)
- Overall response rate (ORR)(5 years)
- Definition of prognostic factors, as assessed by Next Generation Sequencing (NGS) (MM-panel)(5 years)
- Duration of response (DoR)(5 years)
- Overall survival (OS):(5 years)