An Open-label Phase I/II Trial of Venetoclax-Dexamethasone in Relapsed and/or Refractory t(11;14) Systemic Light-Chain Amyloidosis
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 53
- 试验地点
- 9
- 主要终点
- Hematologic ≥ Very Good Partial Response (VGPR) Rate (Phase 2)
研究概览
简要总结
The purpose of this study is assess safety, safest dose, and effectiveness of venetoclax in combination with dexamethasone in participants with t(11;14) positive relapsed (comes back) or refractory (did not get better) light chain amyloidosis.
详细描述
This study is a phase 1/2 study of venetoclax-dexamethasone combination therapy in relapsed/refractory t(11;14) systemic immunoglobulin light chain amyloidosis (AL) amyloidosis. The phase 1 is a dose escalation designed to determine the maximum tolerated dose (MTD) and the recommended phase 2 dose (RP2D) of venetoclax in combination with low-dose weekly dexamethasone. There will be four candidate-dosing cohorts of venetoclax with or without dexamethasone in the Phase I dose-escalation. Dose escalation will be guided by the Bayesian optimal interval (BOIN) design with accelerated titration up to a total sample size of 15 participants.
The phase 2 portion is a randomized open-label study comparing the MTD or RP2D of venetoclax in combination with dexamethasone versus investigator's choice (daratumumab, pomalidomide, bendamustine, or ixazomib (with or without dexamethasone).
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 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age ≥ 18 years at time of signing Informed Consent Form
- •Ability to comply with the study protocol, in the investigator's judgment
- •Confirmed diagnosis of systemic AL amyloidosis by mass spectrometry or immunohistochemistry (IHC) on a tissue biopsy
- •Has received ≥1 prior lines of therapy, including an anti-cluster of differentiation 38 (CD 38) monoclonal antibody
- •Participants with a history of autologous hematopoietic cell transplantation must have recovered from any transplant-related toxicities
- •Presence of t(11;14) on FISH at any time since diagnosis (Eligibility must confirmed by FISH testing at Columbia University Irving Medical Center (CUIMC)
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
排除标准
- •Known hypersensitivity to any of the study drugs
- •History of other malignancy that could affect compliance with the protocol or interpretation of results (Patients with a history of curatively treated basal or squamous cell carcinoma of the skin, in situ carcinoma of the cervix, breast cancer, or Hodgkin's Lymphoma are generally eligible. Patients with a malignancy that has been treated, but not with curative intent, will be excluded, unless the malignancy has been in remission without treatment for ≥ 2 years prior to enrollment.)
- •Evidence of other clinically significant uncontrolled condition(s) including, but not limited to, uncontrolled systemic infection (viral, bacterial, or fungal)
- •Patients on renal replacement therapy
- •Known GI disease or GI procedure that could interfere with oral absorption (including difficulty swallowing)
- •New York Heart Association (NYHA) Class III or IV heart failure
- •Mayo stage three-B (IIIB) with N-terminal pro-hormone B-type natriuretic peptide (NT-Pro BNP) > 8500 pg/mL
- •Prior exposure to anti-apoptotic protein B-cell lymphoma 2 (BCL-2) inhibitors
- •Patients with human immunodeficiency virus (HIV) who are not on highly active antiretroviral therapy (HAART) or those with active hepatitis A, B, or C infection
- •Patients meeting criteria for symptomatic multiple myeloma by one of the following:(a) Lytic lesions on imaging (b) Plasmacytoma, (c) Hypercalcemia without any alternate etiology, or (c) Bone marrow plasma cell infiltrate of greater than 60%
研究组 & 干预措施
Phase 1: Venetoclax 200 mg
Cohort 1: Venetoclax 200 mg tablet, once daily for up to 2 cycles after achieving best response, for a maximum of 6 cycles (1 cycle = 28 days)
干预措施: Venetoclax Oral Tablet, 200 mg (Drug)
Phase 1: Venetoclax 400mg
Cohort 2: Venetoclax 400 mg tablet, once daily for up to 2 cycles after achieving best response, for a maximum of 6 cycles (1 cycle = 28 days)
干预措施: Venetoclax Oral Tablet, 400 mg (Drug)
Phase 1: Venetoclax 400mg + Dexamethasone 10 mg
Cohort 3: Venetoclax 400 mg tablet, once daily and Dexamethasone 10 mg tablet once weekly, for up to 2 cycles after achieving best response, for a maximum of 6 cycles (1 cycle = 28 days)
干预措施: Venetoclax Oral Tablet, 400 mg (Drug)
Phase 2: Control Arm (Investigator's Choice)
Participants will receive one of the following as determined by the investigator:
Daratumumab, Pomalidomide, Bendamustine, or Ixazomib (+/- dexamethasone)
干预措施: Pomalidomide (Drug)
Phase 2: Control Arm (Investigator's Choice)
Participants will receive one of the following as determined by the investigator:
Daratumumab, Pomalidomide, Bendamustine, or Ixazomib (+/- dexamethasone)
干预措施: Bendamustine (Drug)
Phase 1: Venetoclax 200 mg
Cohort 1: Venetoclax 200 mg tablet, once daily for up to 2 cycles after achieving best response, for a maximum of 6 cycles (1 cycle = 28 days)
干预措施: FISH assay (Device)
Phase 1: Venetoclax 400mg + Dexamethasone 10 mg
Cohort 3: Venetoclax 400 mg tablet, once daily and Dexamethasone 10 mg tablet once weekly, for up to 2 cycles after achieving best response, for a maximum of 6 cycles (1 cycle = 28 days)
干预措施: FISH assay (Device)
Phase 1: Venetoclax 400mg + Dexamethasone 10 mg
Cohort 3: Venetoclax 400 mg tablet, once daily and Dexamethasone 10 mg tablet once weekly, for up to 2 cycles after achieving best response, for a maximum of 6 cycles (1 cycle = 28 days)
干预措施: Dexamethasone Oral, 10 mg (Drug)
Phase 1: Venetoclax 400mg + Dexamethasone 20 mg
Cohort 4: Venetoclax 400 mg tablet, once daily and Dexamethasone 20 mg tablet once weekly, for up to 2 cycles after achieving best response, for a maximum of 6 cycles (1 cycle = 28 days)
干预措施: FISH assay (Device)
Phase 1: Venetoclax 400mg + Dexamethasone 20 mg
Cohort 4: Venetoclax 400 mg tablet, once daily and Dexamethasone 20 mg tablet once weekly, for up to 2 cycles after achieving best response, for a maximum of 6 cycles (1 cycle = 28 days)
干预措施: Venetoclax Oral Tablet, 400 mg (Drug)
Phase 2: Control Arm (Investigator's Choice)
Participants will receive one of the following as determined by the investigator:
Daratumumab, Pomalidomide, Bendamustine, or Ixazomib (+/- dexamethasone)
干预措施: Dexamethasone Oral, 20 mg (Drug)
Phase 2: Control Arm (Investigator's Choice)
Participants will receive one of the following as determined by the investigator:
Daratumumab, Pomalidomide, Bendamustine, or Ixazomib (+/- dexamethasone)
干预措施: Daratumumab Injection (Drug)
Phase 1: Venetoclax 400mg + Dexamethasone 20 mg
Cohort 4: Venetoclax 400 mg tablet, once daily and Dexamethasone 20 mg tablet once weekly, for up to 2 cycles after achieving best response, for a maximum of 6 cycles (1 cycle = 28 days)
干预措施: Dexamethasone Oral, 20 mg (Drug)
Phase 1: Venetoclax 400mg
Cohort 2: Venetoclax 400 mg tablet, once daily for up to 2 cycles after achieving best response, for a maximum of 6 cycles (1 cycle = 28 days)
干预措施: FISH assay (Device)
Phase 2: Venetoclax MTD with Dexamethasone
Venetoclax MTD (200 mg or 400 mg) with Dexamethasone (10 mg or 20 mg) as determined by the phase I results
干预措施: Venetoclax MTD with Dexamethasone (Drug)
Phase 2: Control Arm (Investigator's Choice)
Participants will receive one of the following as determined by the investigator:
Daratumumab, Pomalidomide, Bendamustine, or Ixazomib (+/- dexamethasone)
干预措施: Ixazomib (Drug)
结局指标
主要结局
Hematologic ≥ Very Good Partial Response (VGPR) Rate (Phase 2)
时间窗: Up to 6 cycles (approximately 6 months)
Hematologic ≥VGPR rate defined as proportion of participants achieving VGPR, low serum differential free light chain concentration (dFLC) partial response (PR), or a complete (CR). VGPR is defined as the difference between involved and uninvolved free light chain (FLC) \[dFLC\] \< 40 mg/L. Low dFLC PR is defined as achieving a dFLC\<10 mg/L, low dFLC PR will be considered as a deep hematologic response and included in the ≥VGPR category). CR is defined as negative serum and urine immunofixation electrophoresis along with a serum free light chain ratio that lies within the normal range or skewed towards the non-amyloid forming light chain, as per institutional laboratory values
Number of Participants with Dose Limiting Toxicities (DLT) (Phase 1)
时间窗: Up to 6 cycles (approximately 6 months)
The number of participants with dose limiting toxicities for each treatment dose will be used to determine the MTD. Dose limiting toxicity defined as grade 4 neutropenia lasting more than 5 days, any grade febrile neutropenia, grade 4 thrombocytopenia, grade 3 thrombocytopenia with bleeding, other therapy related non-hematologic toxicity of grade 2 or higher that requires discontinuation of therapy, clinical tumor lysis syndrome (TLS), laboratory TLS if the metabolic abnormalities are considered clinically significant by the investigator. All other grade 3 or higher adverse events (AEs) will be considered as DLTs with a few exceptions.
次要结局
- Overall Hematologic Response Rate (HRR) (Phase 2)(Up to 1 year)
- Duration of Hematologic Response (DOHR) (Phase 2)(Up to 1 year)
- Overall Organ Response Rate (ORR) (Phase 2)(Up to 1 year)
- Progression Free Survival (PFS) (Phase 2)(Up to 1 year)
- Time to hematologic ≥VGPR (Phase 2)(Up to 1 year)
- Time to next treatment (TTNT) (Phase 2)(Up to 1 year)
- Major Organ Deterioration-Progression Free Survival (MOD-PFS) (Phase 2)(Up to 1 year)
- Patient-reported outcomes (PROs) (Phase 2)(Start of each cycle (Day 1 of each 28 day cycle) and Follow-up (every 8 weeks for up to 1 year))
- Overall Survival (OS) (Phase 2)(Up to 1 year)
研究者
Rajshekhar Chakraborty, MD
Assistant Professor of Medicine
Columbia University