Randomized Phase 3 Trial of Belantamab Mafodotin or Daratumumab in Combination With Bortezomib, Lenalidomide and Dexamethasone for Newly Diagnosed Multiple Myeloma
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 发起方
- PrECOG, LLC.
- 入组人数
- 500
- 试验地点
- 1
- 主要终点
- MRD Negative Status in All-Comers
研究概览
简要总结
Eligible participants with newly diagnosed myeloma who are not considered eligible or refuse bone marrow transplant will be enrolled. Participants will be randomized to either belantamab mafodotin or daratumumab given in combination with bortezomib, lenalidomide and dexamethasone. Treatment will continue until disease progression, unacceptable side effects or withdrawal of consent.
Belantamab mafodotin is a targeted cancer treatment that works against multiple myeloma cells. It combines a homing device (an antibody) with a powerful cell-killing drug (a toxin), delivering the toxin directly to cancer cells while largely sparing healthy cells.
Minimal residual disease (MRD) testing will be done on bone marrow samples obtained standardly during your treatment. MRD shows whether a very small number of cancer cells can still be detected after treatment, even if standard lab tests shows no signs of cancer.
The purpose of this study is to evaluate if belantamab mafodotin, bortezomib, lenalidomide and dexamethasone (BVRd) improves minimal residual disease (MRD) negative status and/or prolongs progression-free survival (PFS) compared with daratumumab, bortezomib, lenalidomide and dexamethasone (DVRd) in participants with newly diagnosed multiple myeloma.
详细描述
This proposed Phase III multicenter, study is a randomized (1:1), open-label trial designed to show belantamab mafodotin in combination with bortezomib, lenalidomide and dexamethasone (VRd) will lead to higher minimal residual disease (MRD) negativity rate compared with daratumumab in combination with VRd newly diagnosed multiple myeloma (TI-NDMM). Patients must be ineligible for autologous stem cell transplantation because of their age (≥ 70 years) or aged 18 - 70 years with the presence of underlying medical conditions likely to have a negative impact on tolerability of high-dose chemotherapy with stem-cell transplantation, making them transplant ineligible OR transplant-eligible and refusing stem-cell transplantation until first relapse or later. In addition, progression-free survival (PFS) will also be longer.
After enrolling approximately 320 standard-risk patients (anticipated at approximately 400 total patients), the study will limit accrual to patients with high risk NDMM to allow for enrichment of this subgroup of patients.
Belantamab mafodotin is a monoclonal antibody that targets B-cell maturation antigen (BCMA), a protein expressed on the surface of plasma cells, and releases a cytotoxic agent called Monomethyl auristatin F, which destroys the plasma cells.
International Myeloma Working Group (IMWG) criteria will be used for disease response.
MRD samples will be obtained on standard of care bone marrow procedures. MRD testing will be performed on samples at time of screening, suspected complete response (sCR), after confirmed CR at applicable time points from Cycle1, Day 1 at 6, 12, 18 (optional), 24, 30 (optional) and 36 months then annually until progression. MRD testing will not be performed in real-time for this study. Bone marrow samples will also be obtained for future research at screening and time of progression.
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 79 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Eligibility Criteria:
- •Patient must have suspected or confirmed newly diagnosed multiple myeloma (MM) by International Myeloma Working Group (IMWG) criteria and must not have received more than one cycle of any myeloma treatment.
- •Patient must be considered ineligible for autologous stem cell transplantation by the treating physician because of their age (≥ 70 years) or aged 18 - 70 years with the presence of underlying medical conditions likely to have a negative impact on tolerability of high-dose chemotherapy with stem-cell transplantation, making them transplant ineligible, OR transplant-eligible and refusing stem-cell transplantation until first relapse or later.
- •Patient must have measurable or evaluable disease as defined by having one or more of the following, obtained within 28 days prior to randomization.
- •≥ 1g/dL monoclonal protein (M-protein) on serum protein electrophoresis
- •Involved free light chain ≥ 10 mg/dL or ≥ 100 mg/L AND abnormal serum immunoglobulin kappa to lambda free light chain ratio (<0.26 or >1.65)
- •≥ 200 mg/24 hours of monoclonal protein on a 24-hour urine protein electrophoresis
- •Monoclonal bone marrow plasmacytosis ≥ 30% (evaluable disease)
- •Patient must be ≥ 18 years and <80 years of age.
- •Patient must have an Eastern Cooperative Group (ECOG) Performance Status (PS) of 0-2 (PS 3 allowed if secondary to pain).
- •Patient must have IMWG Frailty Score <
- •Patient must have the ability to understand and willingness to sign a written informed consent document.
- •Patient must be willing to provide bone marrow (aspirate and/or biopsy) and blood samples for determination of International Myeloma Society (IMS) risk status and for research. Indeterminate patients with missing or unevaluable samples will be excluded.
- •Patient must have received no more than one cycle (28 days or less) of prior chemotherapy and no more than 160 mg of prior dexamethasone (or equivalent dose of prednisone) for treatment of symptomatic myeloma. Prior radiation therapy to symptomatic lesions is allowed provided there is no residual toxicity related to radiation and blood counts meet the study requirements. NOTE: Patients who have received prior treatment for smoldering multiple myeloma (SMM) are eligible.
- •Patient must have a Serum Protein Electrophoresis (SPEP), Urine Protein Electrophoresis (UPEP), and serum Free Light Chain (FLC) assay performed within 28 days prior to registration. In addition, a bone marrow biopsy and/or aspirate is required within 28 days prior to registration if measurable disease is only present in bone marrow. Otherwise, a bone marrow examination must have been performed within 90 days prior to registration.
- •Patient must have adequate organ function and marrow function as defined below, obtained ≤ 2 weeks prior to registration.
- •Absolute Neutrophil Count (ANC) ≥ 1000/microliter (mcL)
- •Platelets ˃75,000/mcL
- •Creatinine clearance (CrCl) ≥ 30 mL/min
- •Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) ≤ 3x upper limit of normal (ULN)
- •Total Bilirubin ≤ 1.5x ULN or ≤ 3x ULN for patients with documented Gilbert's disease
- •Patient must agree to register to the mandatory lenalidomide (Revlimid) Risk Evaluation and Mitigation Strategy (REMS) program and be willing and able to comply with the requirements of the REMS program.
- •Patient must not be pregnant or breast-feeding due to the potential harm and teratogenic effects to an unborn fetus and possible risk for adverse events in nursing infants with the treatment regimens being used.
- •Patient must not expect to conceive or father children by using an accepted and effective method(s) of contraception or by abstaining from sexual intercourse for the duration of their participation in the study, and for 3 months after the last dose of protocol treatment.
- •Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months of registration are eligible for this trial.
- •For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.
- •Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.
- •Patient with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, must have a clinical risk assessment of cardiac function using the New York Heart Association (NYHA) Functional Classification. To be eligible for this trial, patient must be class 2 or better.
- •Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.
- •Patients must not have peripheral neuropathy ≥ Grade 2 on clinical examination or Grade 1 with pain at time of registration.
- •Patients must not have any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol.
- •Patient may have a history of current or previous deep vein thrombosis (DVT) or pulmonary embolism (PE) but must be willing to take some form of anti-coagulation as prophylaxis if they are not currently on full-dose anticoagulation.
- •Patients must not have any known allergies, hypersensitivity, or intolerance to corticosteroids, monoclonal antibodies or human proteins, or their excipients, or known sensitivity to mammalian-derived products.
- •Patients must not have current corneal epithelial disease except mild punctuate keratopathy.
- •Contact lenses must be avoided for participants while they are receiving belantamab mafodotin treatment unless cleared by an eye-care specialist. If cleared for use, bandaged contact lenses are specifically recommended. Contact lens use may be restarted after discontinuation of belantamab mafodotin treatment, provided the eye-care specialist confirms there are no other contraindications.
- •Patients must not have symptomatic amyloidosis or active POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma-proliferative disorder, skin changes) at the time of screening.
- •Patients must not receive any other concurrent chemotherapy, or any ancillary therapy considered investigational while on this protocol.
排除标准
- 未提供
研究组 & 干预措施
Arm A: Belantamab Mafodotin
Belantamab mafodotin in combination with bortezomib, lenalidomide and dexamethasone (VRd) until progression, unacceptable toxicity or participant withdrawal. 1 cycle = 28 days.
干预措施: Arm A: Belantamab Mafodotin (Drug)
Arm B:
Daratumumab in combination with bortezomib, lenalidomide and dexamethasone (VRd) until progression, unacceptable toxicity or participant withdrawal. 1 cycle = 28 days.
干预措施: Arm B: Daratumumab Hyaluronidase (Drug)
Arm B:
Daratumumab in combination with bortezomib, lenalidomide and dexamethasone (VRd) until progression, unacceptable toxicity or participant withdrawal. 1 cycle = 28 days.
干预措施: Bortezomib (Drug)
Arm A: Belantamab Mafodotin
Belantamab mafodotin in combination with bortezomib, lenalidomide and dexamethasone (VRd) until progression, unacceptable toxicity or participant withdrawal. 1 cycle = 28 days.
干预措施: Bortezomib (Drug)
Arm A: Belantamab Mafodotin
Belantamab mafodotin in combination with bortezomib, lenalidomide and dexamethasone (VRd) until progression, unacceptable toxicity or participant withdrawal. 1 cycle = 28 days.
干预措施: Dexamethasone (Drug)
Arm A: Belantamab Mafodotin
Belantamab mafodotin in combination with bortezomib, lenalidomide and dexamethasone (VRd) until progression, unacceptable toxicity or participant withdrawal. 1 cycle = 28 days.
干预措施: Lenalidomide (Drug)
Arm B:
Daratumumab in combination with bortezomib, lenalidomide and dexamethasone (VRd) until progression, unacceptable toxicity or participant withdrawal. 1 cycle = 28 days.
干预措施: Dexamethasone (Drug)
Arm B:
Daratumumab in combination with bortezomib, lenalidomide and dexamethasone (VRd) until progression, unacceptable toxicity or participant withdrawal. 1 cycle = 28 days.
干预措施: Lenalidomide (Drug)
结局指标
主要结局
MRD Negative Status in All-Comers
时间窗: 9 to 15 months
MRD negative status, defined as achieving MRD negativity at 10\^-5 sensitivity threshold assessed by next-generation sequencing (NGS) in patients achieving CR or better response per IMWG criteria by Independent Review Committee (IRC) after 12 (+/- 3) months of treatment; MRD negativity is determined by the Adaptive Biotechnologies clonoSEQ® assay result; All-comers: the initial cohort of 400 consecutively enrolled patients, irrespective of IMS-IMWG risk status.
Progression-Free Survival (PFS) in High-Risk Cytogenetics Enriched Cohort
时间窗: Up to 7 years
PFS, defined as the time from the date of randomization to the date of first documented disease progression per IMWG criteria by IRC or death from any cause in the absence of progression, whichever occurs first; High-risk cytogenetics enriched cohort: includes the 400 all-comers and 100 additional patients with high-risk cytogenetics.
Progression-Free Survival (PFS)
时间窗: Up to 86 months
PFS, defined as the time from the date of randomization to the date of first documented disease progression per IMWG criteria by IRC or death from any cause in the absence of progression, whichever occurs first
MRD Negative Status
时间窗: Up to 86 months
MRD negative status, defined as achieving MRD negativity at 10-5 sensitivity threshold assessed by NGS at least once during the time of confirmed CR or better response per IMWG criteria by Independent Review Committee (IRC); MRD negativity is determined by the Adaptive Biotechnologies clonoSEQ® assay result
次要结局
- PFS in High-Risk Cytogenetics Cohort(Up to 7 years)
- Best Response of Complete Response (CR)(Up to 7 years)
- Best Response of Very Good Partial Response (VGPR)(Up to 7 years)
- Duration of Response (DoR)(Up to 7 years)
- Sustained MRD (sMRD) Negative Status(Up to 7 years)
- Overall Survival (OS)(Up to 86 months)
- Best Response of Complete Response (CR)(Up to 86 months)
- Best Response of Very Good Partial Response (VGPR)(Up to 86 months)
- Overall Response Rate (ORR)(Up to 86 months)
- Duration of Response (DoR)(Up to 86 months)
- MRD Negative Status at 12-Month(Up to 86 months)
- Sustained MRD (sMRD) Negative Status(Up to 86 months)
- Patient-Reported Outcomes-Common Terminology Criteria for Adverse Events (PRO-CTCAE)(Up to 86 months)
- Health-Related Quality of Life (HRQoL)(Up to 86 months)
- Overall Survival (OS)(Up to 7 years)
- Adverse Events (AEs)(While on study treatment and up to 70 days after the last dose of study medication)
- AEs Leading to Dose Modifications(While on study treatment and up to 70 days after the last dose of study medication)
- Corneal Events(While on study treatment and up to 70 days after the last dose of study medication)
- Patient-Reported Outcomes-Common Terminology Criteria for Adverse Events (PRO-CTCAE)(Up to 7 years)
- Health-Related Quality of Life (HRQoL)(Up to 7 years)