2023-505659-27-00招募中2 期
A Phase 2, Open-Label, Multi-Center Study of Venetoclax in Combination with Carfilzomib and Dexamethasone in Subjects with Relapsed or Refractory Multiple Myeloma
适应症
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 24
- 试验地点
- 8
- 主要终点
- To assess the safety and tolerability of venetoclax in combination with carfilzomib and dexamethasone when administered in subjects with relapsed or refractory multiple myeloma (RRMM).
研究概览
简要总结
• To assess the safety and tolerability of venetoclax in combination with carfilzomib and dexamethasone when administered in subjects with relapsed or refractory multiple myeloma (RRMM). • To assess the objective response rate (ORR) and very good partial response (VGPR) or better rate of venetoclax carfilzomib dexamethasone (VenKd) at the target dose combination in subjects with RRMM, and in t(11;14)-positive RRMM subjects. • To explore and compare safety and preliminary efficacy of VenKd combination at 400 mg or 800 mg venetoclax dose levels with carfilzomib dexamethasone (Kd) (control) regimen. International Myeloma Working Group (IMWG) response rates (per investigator) including ORR, VGPR, or better rate, and complete response (CR) or better rate will be investigated.
研究设计
- 分配方式
- Not Applicable
- 主要目的
- Follow-up
- 盲法
- None
入排标准
- 年龄范围
- 18 years 至 65+ years（65+ Years, 18-64 Years）
- 接受健康志愿者
- 是
入选标准
- •Eastern Cooperative Oncology Group (ECOG) performance score of ≤
- •Subject has documented relapsed or progressive MM on or after any regimen or is refractory to the most recent line of therapy. ● Relapsed myeloma is defined as previously treated myeloma that progresses and requires initiation of salvage therapy, but does not meet criteria for refractory myeloma. ● Refractory myeloma is defined as disease that is nonresponsive (failure to achieve minimal response or development of progressive disease [PD]) while on primary or salvage therapy, or progresses within 60 days of last therapy. ● For Part 4, subjects must meet the above criteria and also be t(11;14) positive as determined by an analytically validated FISH assay per study central laboratory testing.
- •Subject has received prior treatment for MM. ● Parts 1, 2, and 3: At least 1 but no more than 3 prior lines of therapy ● Part 4: At least 1 prior line of therapy A line of therapy consists of ≥ 1 complete cycle of a single agent, a regimen consisting of a combination of several drugs, or a planned sequential therapy of various regimens.
- •Subject has measurable disease at Screening, defined as at least one of the following: ● Serum M-protein ≥ 0.5 g/dL (≥ 5 g/L), OR ● Urine M-protein ≥ 200 mg/24 hours, OR ● Serum free light chain (FLC) ≥ 10 mg/dL, provided serum FLC ratio is abnormal.
- •Subject must meet the following laboratory parameters within 14 days prior to first dose, per laboratory reference range: ● Absolute neutrophil count (ANC) ≥ 1000/µL; subject may use growth factor support to achieve ANC eligibility criteria. ● Platelet count: ○ ≥ 50,000/mm3 for subject with ≤ 50% myeloma involvement in the bone marrow; ○ ≥ 30,000/mm3 for subject with > 50% myeloma involvement in the bone marrow; ○ Subject may not have received a platelet transfusion within 72 hours prior to the platelet count used for eligibility. ● Hemoglobin ≥ 8.0 g/dL; subject may receive red blood cell (RBC) transfusions in accordance with institutional guidelines to meet this criteria. ● AST and ALT ≤ 3 × upper limit of normal (ULN). ● Total bilirubin ≤ 1.5 × ULN; subject with documented Gilbert's syndrome may have bilirubin > 1.5 × ULN with the approval of the AbbVie TAMD or designee ● Creatinine clearance ≥ 30 mL/min measured by 24-hour urine collection or calculated using Cockcroft-Gault formula.
- •Subject must be ≥ 18 years of age.
- •Subject, or their legally authorized representative, must voluntarily sign and date an informed consent, approved by an Independent Ethics Committee (IEC)/Institutional Review Board (IRB), prior to the initiation of any screening or study-specific procedures.
- •If female, subject is either not of childbearing potential, defined as postmenopausal for at least 1 year or surgically sterile (bilateral tubal ligation at least 3 months before study participation, bilateral oopho-rectomy and/or hysterectomy) or is of childbearing potential and is practicing an approved method of birth control throughout the study and 90 days after last dose of study drug. Examples of approved methods of birth control in this study include the following: ● Intrauterine device (IUD). ● Hormonal contraceptives (examples include birth control pills, vaginal rings, or patches), associated with inhibition of ovulation for at least 3 months prior to taking study drug. ● A vasectomized partner. ● Total abstinence from sexual intercourse with a male partner as the preferred lifestyle of the subject; periodic abstinence is not acceptable. Note: If male, subject agrees to follow one of the protocol-specified pregnancy avoidance measures below, including refraining from donating sperm, for up to 90 days post last dose of study drug. ● Surgically sterile (have had a vasectomy more than 6 months prior to screening). ● Subject using condom and female partner(s) using an approved method of contraception listed above. ● Total abstinence from sexual intercourse with a female partner as the preferred lifestyle of the subject; periodic abstinence is not acceptable.
- •Females of childbearing potential must have negative results for pregnancy test performed: ● At Screening on a serum sample obtained within 28 days prior to randomization. ● Prior to dosing on a urine sample obtained on the first day of study drug administration, if it has been > 24 hours since obtaining the serum pregnancy test results. ● Females with documented non-childbearing potential (either postmenopausal or permanently surgically sterile as defined above) at Screening do not require pregnancy testing.
排除标准
- •Subject has any of the following conditions: ● Non-secretory or oligo-secretory MM ● Active plasma cell leukemia, i.e., either 20% of peripheral white blood cells or > 2.0 × 109/L circulating plasma cells by standard differential ● Waldenström's macroglobulinemia ● Primary amyloidosis ● POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes) ● Known Human Immunodeficiency Virus (HIV) infection ● Known active SARS-CoV-2 infection. If a subject has signs/symptoms suggestive of SARS-CoV-2 infection, they should undergo molecular (e.g., PCR) testing to rule out SARS-CoV-2 infection. If applicable, a negative test result is required prior to first dose. Subjects who do not meet SARS-CoV-2 eligibility criteria must be screen failed and may only rescreen after they meet the following SARS-CoV-2 viral clearance criteria below and do not have any other COVID-19 related medical condition that, in the opinion of the Investigator, would impact risk/benefit ratio of the subject's participation in the study: ○ At least 14 days since first PCR test result have passed in asymptomatic patients or 14 days since recovery, defined as resolution of fever without use of antipyretics and improvement in symptoms, or per institutional guidelines. ● Active hepatitis B or C infection based on screening blood testing ● Significant cardiovascular disease, including uncontrolled angina, hypertension (including uncontrolled hypertension defined as an average systolic blood pressure ≥ 160mm Hg or diastolic ≥ 100mm Hg despite optimal treatment),45 arrhythmia, recent myocardial infarction within 6 months of first dose, congestive heart failure (CHF) New York Heart Association (NYHA) Class ≥ 3, and/or left ventricular ejection fraction ≤ 40% as assessed by multiple gated acquisition scan (MUGA) or two dimensional (2D) echocardiogram (ECHO) ● Major surgery within 4 weeks prior to first dose ● Acute infections requiring antibiotic, antifungal or antiviral therapy within 14 days prior to first dose ● Peripheral neuropathy ≥ Grade 3 or ≥ Grade 2 with pain within 14 days prior to first dose ● Uncontrolled diabetes or uncontrolled hypertension within 14 days prior to first dose ● Any other medical condition that, in the opinion of the Investigator, would adversely affect the subject's participation in the study
- •Subject has a history of other active malignancies, including myelodysplastic syndrome (MDS), within the past 3 years prior to study entry, with the following exceptions: ● Adequately treated in situ carcinoma of the cervix uteri or the breast, ● Adequately treated basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin, ● Adequately treated prostate cancer Gleason grade 6 or lower AND with stable Prostate Specific Antigen (PSA) levels off treatment, ● Previous malignancy with no evidence of disease confined and surgically resected (or treated with other modalities) with curative intent and unlikely to impact survival during the duration of the study.
- •If subject had a prior allogeneic stem cell transplant (SCT), subject has evidence of ongoing graft-versus-host disease (GvHD).
- •Subject has had prior treatment with carfilzomib, or has a hypersensitivity or allergy to any of the components of study therapy including captisol (a cyclodextrin derivative used to solubilize carfilzomib) or dexamethasone.
- •Previous treatment with venetoclax or other BCL-2 inhibitor.
- •Subject has been treated or received any of the following: ● Allogeneic or syngeneic SCT within 6 months prior to first dose. ● Autologous SCT within 12 weeks prior to first dose. ● Immunization with live vaccine within 8 weeks prior to first dose. ● Monoclonal antibodies within 6 weeks prior to first dose. ● Any anti-myeloma therapy (other than monoclonal antibodies), including chemotherapy, radiotherapy, biological, immunotherapy or an investigational therapy, including targeted small molecule agents within 5 half-lives (or 14 days if half-life is unknown) prior to first dose. ● Corticosteroid therapy at a dose equivalent to ≥ 4 mg/day of dexamethasone within 3 weeks prior to first dose. ● A strong or moderate CYP3A inhibitor or inducer within 1 week prior to first dose.
- •Subject who has consumed grapefruit products, Seville oranges (including marmalade containing Seville oranges), or starfruit within 3 days prior to study drug administration.
- •Female subject who is pregnant, breastfeeding or is considering becoming pregnant during the study or for approximately 90 days after the last dose of study drug.
- •Male subject who is considering fathering a child or donating sperm during the study or for approximately 90 days after the last dose of study drug.
结局指标
主要结局
To assess the safety and tolerability of venetoclax in combination with carfilzomib and dexamethasone when administered in subjects with relapsed or refractory multiple myeloma (RRMM).
To assess the safety and tolerability of venetoclax in combination with carfilzomib and dexamethasone when administered in subjects with relapsed or refractory multiple myeloma (RRMM).
To explore and compare safety and preliminary efficacy of VenKd combination at 400 mg or 800 mg venetoclax dose levels with carfilzomib dexamethasone (Kd) (control) regimen. International Myeloma Working Group (IMWG) response rates (per investigator) including ORR, VGPR, or better rate, and complete response (CR) or better rate will be investigated.
To explore and compare safety and preliminary efficacy of VenKd combination at 400 mg or 800 mg venetoclax dose levels with carfilzomib dexamethasone (Kd) (control) regimen. International Myeloma Working Group (IMWG) response rates (per investigator) including ORR, VGPR, or better rate, and complete response (CR) or better rate will be investigated.
To assess the objective response rate (ORR) and very good partial response (VGPR) or better rate of venetoclax carfilzomib dexamethasone (VenKd) at the target dose combination in subjects with RRMM, and in t(11;14)-positive RRMM subjects.
To assess the objective response rate (ORR) and very good partial response (VGPR) or better rate of venetoclax carfilzomib dexamethasone (VenKd) at the target dose combination in subjects with RRMM, and in t(11;14)-positive RRMM subjects.
次要结局
- To investigate the IMWG response rates for subjects with high BCL-2 expression, and for subjects with prior exposure to lenalidomide.
- To assess the time-to-event endpoints: progression-free survival (PFS), time to response (TTR), time to progression (TTP), duration of response (DOR), and overall survival (OS) of the VenKd combination in RRMM subjects.
- To characterize the pharmacokinetics (PK) in plasma of venetoclax and carfilzomib.
- To assess minimal residual disease (MRD) in the bone marrow by next generation sequencing (NGS).
研究者
Global Clinical Trials Helpdesk
Scientific
AbbVie Deutschland GmbH & Co. KG
研究点 (8)
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