Myeloma-Developing Regimens Using Genomics (MyDRUG) (Genomics Guided Multi-arm Trial of Targeted Agents Alone or in Combination With a Backbone Regimen)
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 103
- 试验地点
- 16
- 主要终点
- Overall Response Rate - Actionable Genetic Alteration
研究概览
简要总结
The MyDRUG study is a type of Precision Medicine trial to treat patients with drugs targeted to affect specific genes that are mutated as part of the disease. Mutations in genes can lead to uncontrolled cell growth and cancer. Patients with a greater than 25% mutation to any of the following genes; CDKN2C, FGFR3, KRAS, NRAS, BRAF V600E, IDH2 or T(11;14) can be enrolled to one of the treatment arms. These arms have treatments specifically directed to the mutated genes. Patients that do not have a greater than 25% mutation to the genes listed can be enrolled to a non-actionable treatment arm.
The genetic sequencing of the patient's tumor is required via enrollment to the MMRF002 study: Clinical-grade Molecular Profiling of Patients with Multiple Myeloma and Related Plasma Cell Malignancies. (NCT02884102).
详细描述
The study will enroll 228 patients enrolled to one of eight treatment arms. The study is open to patients relapsing with relapsed refractory multiple myeloma, who have
- received at least one prior but no more than 3 prior therapies
- exposed to both a PI and an IMiD
- had early relapse after initial treatment. Relapse is defined as the IMWG uniform response criteria (Kumar et al, 2016). Early relapse as defined by at least one of the following:
- Relapse within 3 years post autologous stem cell transplantation (ASCT) on maintenance, or 18 months if unmaintained
- Relapse within 18 months of initial non-ASCT based therapy
研究设计
- 研究类型
- Interventional
- 分配方式
- Non 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 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Willing to be registered into the pomalidomide (POMALYST®) Risk Evaluation and Mitigation Strategy (REMS®) program
- •Enrolled in the MMRF002 Molecular Profiling Protocol (NCT02884102) with report less than 120 days old
- •Disease free of prior malignancies for ≥ 3 years with exception of currently treated basal cell, squamous cell carcinoma of the skin, carcinoma "in situ" of the cervix or breast, or prostate cancer not requiring therapy
- •High risk patients with relapsed refractory multiple myeloma (RRMM), who have:
- •received at least one prior but no more than 3 prior therapies
- •exposed to both a PI and an IMiD
- •had early relapse after initial treatment Early relapse as defined by at least one of the following: (Relapse is defined as the IMWG uniform response)
- •Relapse within 3 years of initiation of induction chemo therapy for post autologous stem cell transplantation (ASCT) followed by maintenance, or 18 months if unmaintained after ASCT
- •Within 18 months of initial non-ASCT based therapy
- •Patients must have progressed after their most recent treatment and require therapy for myeloma
- •Females of reproductive potential must have a negative pregnancy test at baseline, be non-lactating, and willing to adhere to scheduled pregnancy testing
- •Females of reproductive potential and males must practice and acceptable method of birth control
- •Laboratory values obtained ≤ 14 days prior to registration:
- •Absolute neutrophil count (ANC) ≥ 1000/ul
- •Hemoglobin (Hgb) ≥ 8 g/dl
- •Platelet (PLT) ≥ 75,000/ul
- •Total bilirubin <1.5 x upper limit of normal (ULN) or if total bilirubin is >1.5 x ULN, the direct bilirubin must be ≤ 2.0 mg/dL
- •Aspartate aminotransferase (AST) <3 x ULN
- •Creatinine Clearance ≥ 30 mL/min
- •Measurable disease of Multiple Myeloma (MM) as defined by at least one of the following:
- •Serum monoclonal protein ≥ 0.5 g by protein electrophoresis
- •≥200 mg of monoclonal protein in the urine on 24-hour electrophoresis
- •Serum immunoglobulin free light chain (FLC) ≥10 mg/dL AND abnormal serum immunoglobulin kappa to lambda FLC ratio
- •Monoclonal bone marrow plasmacytosis ≥30% (evaluable disease)
- •Eastern Cooperative Oncology Group (ECOG) Performance Status 0, 1, or 2
- •Ability to take aspirin, warfarin, or low molecular weight heparin
- •Sub-Protocol Inclusion Criteria:
- •Refer to each respective Sub Protocol for additional inclusion criteria.
排除标准
- •Patients will be ineligible for this study if they meet any one of the following criteria:
- •Aggressive multiple myeloma requiring immediate treatment as defined by:
- •Lactate dehydrogenase (LDH) > 2 times ULN
- •Presence of symptomatic extramedullary disease or central nervous system involvement
- •Hypercalcemia >11.5 mg/dl
- •Acute worsening of renal function (CrCl < 30 ml/min) directly related to myeloma relapse
- •Any neurological emergency related to myeloma
- •Clinical symptoms of hyperviscosity related to monoclonal protein
- •Involved serum free light chain > 100 mg/dL (1000 mg/L) in the setting of prior diagnosis of cast nephropathy
- •Infection requiring systemic antibiotic therapy or other serious infection within 14 days of enrolment
- •Known hypersensitivity or development of erythema nodosum if characterized by a desquamating rash while taking thalidomide, lenalidomide, pomalidomide or similar drug. Known allergy to any of the study medications, their analogues, or excipients in the various formulations of the agents
- •Prior Ixazomib/Pomalidomide/Dexamethasone combination therapy
- •Pregnant or breast-feeding females
- •Serious medical or psychiatric illness, active alcoholism, or drug addiction that may hinder or confuse compliance, interfere in the completion of treatment per protocol, or follow-up evaluation
- •Active hepatitis A, B or C viral infection or known human immunodeficiency virus (HIV) infection
- •Concurrent symptomatic amyloidosis or plasma cell leukemia
- •POEMS syndrome [plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein (M-protein) and skin changes]
- •Residual side effects to previous therapy > Grade 1 prior to initiation of therapy (Alopecia any grade and/or neuropathy Grade 2 without pain are permitted)
- •Prior allogeneic or ASCT within 12 weeks of initiation of therapy. Prior allogeneic stem cell transplant with active graft-versus-host disease (GVHD)
- •Prior experimental therapy within 14 days of protocol treatment or 5 half-lives of the investigational drug, whichever is longer
- •Prior anticancer therapy within 14 days of initiation of protocol therapy (Dexamethasone/ 40mg/day) for a maximum of 4 days before screening is allowed
- •Prior major surgical procedure or radiation therapy within 4 weeks of the initiation of therapy (this does not include limited course of radiation used for management of bone pain within 7 days of initiation of therapy).
- •Known to have dysphagia, short-gut syndrome, gastroparesis, or other conditions that limit the ingestion or Gastro Intestinal (GI) absorption of drugs administered orally
- •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
- •Other co-morbidity, which would interfere with patient's ability to participate in trial or that confounds the ability to interpret data from the study
- •Sub-Protocol Exclusion Criteria:
- •Refer to each respective Sub Protocol for additional exclusion criteria.
研究组 & 干预措施
Sub-Protocol A1
Patients with CDK activating alteration receive Abemaciclib in combination with ixazomib, pomalidomide and dexamethasone (IPd)
干预措施: Abemaciclib, dexamethasone, ixazomib, pomalidomide (Drug)
Sub-Protocol B1
Patients with IDH2 activating mutation receive Enasidenib in combination with ixazomib, pomalidomide and dexamethasone (IPd)
干预措施: Enasidenib, dexamethasone, ixazomib, pomalidomide (Drug)
Sub-Protocol C1
Patients with the presence of RAF/RAS mutation receive Cobimetinib in combination with ixazomib, pomalidomide and dexamethasone (IPd)
干预措施: Cobimetinib, dexamethasone, ixazomib, pomalidomide (Drug)
Sub-Protocol D1
Patients with presence of FGFR3 activating mutations receive Erdafitinib in combination with ixazomib, pomalidomide and dexamethasone (IPd)
干预措施: Erdafitinib, dexamethasone, ixazomib, pomalidomide (Drug)
Sub-Protocol E1
Patients with t(11;14) translocation will be enrolled in arm E1 and randomized to the venetoclax or the IPd control arm. Patients with relapsed Multiple Myeloma will receive Venetoclax, Ixazomib, Pomalidomide and Dexamethasone every cycle. Each cycle is 28 days long.
干预措施: Venetoclax, dexamethasone, ixazomib, pomalidomide (Drug)
Sub-Protocol Y1
Patients with Non-Actionable Genetic Abnormality receive Daratumumab in combination with ixazomib, pomalidomide and dexamethasone (IPd)
干预措施: Daratumumab, dexamethasone, ixazomib, pomalidomide (Drug)
Sub-Protocol Y2
Patients with Non-Actionable Genetic Abnormality receive Belantamab mafodotin in combination with ixazomib, pomalidomide and dexamethasone (IPd)
干预措施: Belantamab mafodotin, dexamethasone, ixazomib, pomalidomide (Drug)
Sub-Protocol Y3
Patients with Non-Actionable Genetic Abnormality receive Selinexor in combination with ixazomib, pomalidomide and dexamethasone (IPd)
干预措施: Selinexor, dexamethasone, ixazomib, pomalidomide (Drug)
结局指标
主要结局
Overall Response Rate - Actionable Genetic Alteration
时间窗: Patients will be evaluated monthly for response from the start of the study until the date of documented disease progression, assessed up to 2 years
• To evaluate the overall response rate (ORR) with targeted agents used in combination with backbone regimen ixazomib, pomalidomide and dexamethasone (IPd) in patients with an actionable genetic alteration per the International Myeloma Working Group \[IMWG\] consensus criteria (Kumar et al, 2016)
Overall Response Rate - Non-Actionable Genetic Alteration
时间窗: Patients will be evaluated monthly for response from the start of the study until the date of documented disease progression, assessed up to 2 years
• To evaluate the ORR with agents used in combination with backbone (or IPd) regimen in patients with no actionable genetic alteration per IMWG consensus criteria (Kumar et al, 2016).
次要结局
未报告次要终点