A Phase 1/2 Study of Venetoclax in Combination With Low-Dose Cytarabine in Treatment-Naïve Subjects With Acute Myelogenous Leukemia Who Are ≥ 60 Years of Age and Who Are Not Eligible for Standard Anthracycline-Based Induction Therapy
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 94
- 试验地点
- 9
- 主要终点
- Phase 1: Maximum Observed Plasma Concentration (Cmax) of Venetoclax
研究概览
简要总结
This study consists of two parts: A Phase 1 dose-escalation part that will evaluate the safety and pharmacokinetic profile of venetoclax in combination with low-dose cytarabine (LDAC), define the maximum tolerated dose (MTD), and generate data to support a recommended Phase 2 dose (RPTD) in treatment-naïve participants with acute myelogenous leukemia (AML); and a Phase 2 part that will evaluate if the RPTD has sufficient efficacy and acceptable toxicity to warrant further development of the combination therapy.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 60 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Participant must be greater than or equal to 65 years of age in Phase 1 and
- •Participants enrolled in Cohort C must be either:
- •greater than or equal to 75 years of age; OR
- •greater than or equal to 60 to 74 years will be eligible if the participants has at least one of the following co-morbidities, which make the participant unfit for intensive chemotherapy:
- •Eastern Cooperative Oncology Group (ECOG) Performance Status of 2 - 3;
- •Cardiac history of congestive heart failure (CHF) requiring treatment or ejection fraction less than or equal to 50% or chronic stable angina;
- •Diffusion capacity of carbon monoxide (DLCO) less than or equal to 65% or forced expiratory volume in one second (FEV1) less than or equal to 65%;
- •Creatinine clearance greater than or equal to 30 mL/min to less than 45 ml/min (calculated by Cockcroft-Gault formula)
- •Moderate hepatic impairment with total bilirubin greater than 1.5 to less than or equal to 3.0 × upper limit of normal (ULN)
- •Any other comorbidity that the physician judges to be incompatible with intensive chemotherapy must be reviewed and approved by the study medical monitor before study enrollment
- •Participant must have a projected life expectancy of at least 12 weeks.
- •Participant must have histological confirmation of AML and be ineligible for treatment with a standard cytarabine and anthracycline induction regimen due to co-morbidity or other factors.
- •Participant must have received no prior treatment for AML with the exception of hydroxyurea, allowed through the first cycle of study treatment. Note: Participant may have been treated for prior Myelodysplastic Syndrome.
- •Participant must have an ECOG performance status:
- •of 0 to 2 for participants greater than equal to 75 years of age
- •of 0 to 3 for participants greater than equal to 60 to 74 years of age, if 0 - 1 another co-morbidity is required to make participant eligible.
- •Participant must have adequate renal function as demonstrated by a creatinine clearance greater than or equal to 30 mL/min; determined via urine collection for 24-hour creatinine clearance or by the Cockcroft Gault formula.
- •Participant must have adequate liver function as demonstrated by:
- •aspartate aminotransferase (AST) less than or equal to 2.5 × ULN
- •alanine aminotransferase (ALT) less than or equal to 2.5 × ULN
- •bilirubin less than or equal to 1.5 × ULN for all participants age 75 and older
- •Participants who are less than 75 years of age must have a bilirubin of less than 3.0 × ULN.
- •Note: Participants with Gilbert's Syndrome may have a bilirubin greater than 1.5 × ULN per discussion between the investigator and AbbVie medical monitor.
- •Male participants must agree to refrain from unprotected sex and sperm donation from initial study drug administration until 180 days after the last dose of study drug.
- •Participant 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, participant must be either:
- •Postmenopausal defined as no menses for 12 or more months without an alternative medical cause OR
- •Permanently surgical sterile (bilateral oophorectomy, bilateral salpingectomy or hysterectomy)
排除标准
- •Participant has received treatment with cytarabine for a pre-existing myeloid disorder.
- •Participant has acute promyelocytic leukemia (French-American-British Class M3 AML).
- •Participant has known active central nervous system (CNS) involvement with AML.
- •Participant has tested positive for human immunodeficiency virus (HIV).
- •Participant has received the following within 7 days prior to the initiation of study treatment:
- •Strong and moderate CYP3A inducers such as rifampin, carbamazepine, phenytoin, and St. John's wort.
- •Participant has consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or Starfruit within 3 days prior to the initiation of study treatment.
- •Participant has a cardiovascular disability status of New York Heart Association Class greater than
- •Participant has a significant history of renal, neurologic, psychiatric, endocrinologic, metabolic, immunologic, hepatic, cardiovascular disease, or any other medical condition that in the opinion of the investigator would adversely affect his/her participating in this study.
- •Participant has chronic respiratory disease that requires continuous oxygen use.
- •Participant has a malabsorption syndrome or other condition that precludes enteral route of administration.
- •Participant exhibits evidence of other clinically significant uncontrolled condition(s) including, but not limited to:
- •Uncontrolled systemic infection requiring intravenous (IV) therapy (viral, bacterial or fungal).
- •Participant has a history of other malignancies prior to study entry, with the exception of:
- •Adequately treated in situ carcinoma of the breast or cervix uteri;
- •Basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin;
- •Previous malignancy confined and surgically resected (or treated with other modalities) with curative intent.
- •Participant has a white blood cell count greater than 25 × 10^9/L. Note: Hydroxyurea is permitted to meet this criterion.
- •Participant is a candidate for a bone marrow or stem cell transplant within 12 weeks after study enrollment.
- •Participant has a history of myeloproliferative neoplasm (MPN) including polycythemia vera, myelofibrosis, essential thrombocythemia, or chronic myelogenous leukemia.
研究组 & 干预措施
Phase 1: 600 mg Venetoclax + LDAC
Venetoclax was administered orally once daily (QD) on Days 2 through 28 of Cycle 1. Dosing started at 50 mg (Day 2) and increased up to 600 mg by Day 6. Beginning with Cycle 2, 600 mg venetoclax was administered Days 1 through 28 of each 28-day cycle. Participants also received low-dose cytarabine (LDAC; 20 mg/m²) administered by subcutaneous injection once daily on Days 1 to 10 of each cycle.
Participants could continue receiving treatment until disease progression or until discontinuation criteria were met.
干预措施: Venetoclax (Drug)
Phase 1: 600 mg Venetoclax + LDAC
Venetoclax was administered orally once daily (QD) on Days 2 through 28 of Cycle 1. Dosing started at 50 mg (Day 2) and increased up to 600 mg by Day 6. Beginning with Cycle 2, 600 mg venetoclax was administered Days 1 through 28 of each 28-day cycle. Participants also received low-dose cytarabine (LDAC; 20 mg/m²) administered by subcutaneous injection once daily on Days 1 to 10 of each cycle.
Participants could continue receiving treatment until disease progression or until discontinuation criteria were met.
干预措施: Cytarabine (Drug)
Phase 1: 800 mg Venetoclax + LDAC
Venetoclax was administered orally once daily (QD) on Days 2 through 28 of Cycle 1. Dosing started at 100 mg (Day 2) and increased up to 800 mg by Day 6. Beginning with Cycle 2, 800 mg venetoclax was administered Days 1 through 28 of each 28-day cycle. Participants also received LDAC (20 mg/m²) administered by subcutaneous injection once daily on Days 1 to 10 of each cycle.
Participants could continue receiving treatment until disease progression or until discontinuation criteria were met.
干预措施: Venetoclax (Drug)
Phase 1: 800 mg Venetoclax + LDAC
Venetoclax was administered orally once daily (QD) on Days 2 through 28 of Cycle 1. Dosing started at 100 mg (Day 2) and increased up to 800 mg by Day 6. Beginning with Cycle 2, 800 mg venetoclax was administered Days 1 through 28 of each 28-day cycle. Participants also received LDAC (20 mg/m²) administered by subcutaneous injection once daily on Days 1 to 10 of each cycle.
Participants could continue receiving treatment until disease progression or until discontinuation criteria were met.
干预措施: Cytarabine (Drug)
Phase 2: 600 mg Venetoclax + LDAC
Venetoclax was administered orally once daily (QD) on Days 2 through 28 of Cycle 1. Dosing started at 50 mg, and increased up to 600 mg by Day 6. Beginning with Cycle 2, 600 mg venetoclax was administered Days 1 through 28 of each 28-day cycle. Participants also received LDAC (20 mg/m²) administered by subcutaneous injection once daily on Days 1 to 10 of each cycle.
Participants could continue receiving treatment until disease progression or until discontinuation criteria were met.
干预措施: Venetoclax (Drug)
Phase 2: 600 mg Venetoclax + LDAC
Venetoclax was administered orally once daily (QD) on Days 2 through 28 of Cycle 1. Dosing started at 50 mg, and increased up to 600 mg by Day 6. Beginning with Cycle 2, 600 mg venetoclax was administered Days 1 through 28 of each 28-day cycle. Participants also received LDAC (20 mg/m²) administered by subcutaneous injection once daily on Days 1 to 10 of each cycle.
Participants could continue receiving treatment until disease progression or until discontinuation criteria were met.
干预措施: Cytarabine (Drug)
结局指标
主要结局
Phase 1: Maximum Observed Plasma Concentration (Cmax) of Venetoclax
时间窗: Cycle 1, Day 10 at predose and 2, 4, 6, 8, and 24 hours postdose (venetoclax with LDAC); Cycle 1, Day 18 at predose, 2, 4, 6, 8, and 24 hours postdose (venetoclax alone)
The highest concentration that a drug achieves in the blood after administration in a dosing interval.
Phase 1: Area Under the Plasma Concentration-Time Curve Over Time From 0 to 24 Hours (AUC0-24) of Venetoclax
时间窗: Cycle 1, Day 10 at predose and 2, 4, 6, 8, and 24 hours postdose (venetoclax with LDAC); Cycle 1, Day 18 at predose, 2, 4, 6, 8, and 24 hours postdose (venetoclax alone)
Phase 1: Number of Participants With Dose-limiting Toxicities
时间窗: Up to 28 days (Cycle 1)
Dose-limiting toxicities (DLTs) were determined during cycle 1 of the dose-escalation phase and defined as Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 grade 4 (life threatening requiring urgent intervention) or 5 (resulted in death) toxicity, excluding adverse events commonly caused by AML (eg, neutropenia, fever). Hematologic DLT was defined as failure of platelet recovery to 25 × 10\^9/L or greater and absolute neutrophil count (ANC) to 0.5 × 10\^9/L or greater within 14 days of the last dose of venetoclax in the absence of residual AML.
Phase 1: Time to Maximum Observed Plasma Concentration (Tmax) of Venetoclax
时间窗: Cycle 1, Day 10 at predose and 2, 4, 6, 8, and 24 hours postdose (venetoclax with LDAC); Cycle 1, Day 18 at predose, 2, 4, 6, 8, and 24 hours postdose (venetoclax alone)
The time at which the maximum plasma concentration (Cmax) is observed.
Phase 1: Maximum Observed Plasma Concentration (Cmax) of Cytarabine
时间窗: Cycle 1, Day 1 and Day 10 at pre-dose and at 15 and 30 minutes and 1, 3, 6 hours post-dose.
The highest concentration that a drug achieves in the blood after administration in a dosing interval.
Number of Participants With Treatment-emergent Adverse Events (TEAEs)
时间窗: From first dose of study drug until 30 days after last dose of study drug; median (minimum, maximum) duration of treatment was 4.1 (0.2, 62.8) months overall.
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. The investigator rated the severity of each AE according to the CTCAE Version 4.0 and the following: Grade 1: The AE is transient and easily tolerated (mild). Grade 2: The AE causes discomfort and interrupts usual activities (moderate). Grade 3: The AE causes considerable interference with usual activities and may be incapacitating (moderate to severe). Grade 4: The AE is life threatening requiring urgent intervention. Grade 5: The AE resulted in death. The investigator assessed each event as either having a reasonable possibility or no reasonable possibility of being related to the use of study drug. Treatment-emergent events are defined as events that began or worsened in severity after the first dose of study drug.
Phase 1: Time to Maximum Observed Plasma Concentration (Tmax) of Cytarabine
时间窗: Cycle 1, Day 1 and Day 10 at pre-dose and at 15 and 30 minutes and 1, 3, 6 hours post-dose.
The time at which the maximum plasma concentration (Cmax) is observed.
Phase 1: Area Under the Plasma Concentration-Time Curve Over Time From 0 to Last Measurable Concentration (AUCt) of Cytarabine
时间窗: Cycle 1, Day 1 and Day 10 at pre-dose and at 15 and 30 minutes and 1, 3, 6 hours post-dose.
Overall Response Rate
时间窗: Response was assessed at Cycle 2, Day 1, Cycle 4, Day 1, and every 3 cycles thereafter; median duration of treatment was 4.2 months.
Overall response rate (ORR) is defined as the percentage of participants who achieved a complete remission (CR), complete remission with incomplete marrow recovery (CRi), or partial remission (PR) per the International Working Group (IWG) for AML response criteria, per investigator assessment. CR: absolute neutrophil count (ANC) ≥ 10\^3 /µL, platelet counts ≥ 10\^5 /µL, red blood cell (RBC) transfusion independence (a period of at least 56 days with no RBC transfusion), and bone marrow with \< 5% blasts. CRi: lack of morphologic evidence of leukemia (blasts \< 5%), and platelet counts \< 10\^5 /µL or ANC \< 10\^3 /µL. PR: all of the hematologic values for a CR but with a decrease of at least 50% in the percentage of blasts to 5% to 25% in the bone marrow aspirate.
次要结局
- Complete Remission With Partial Hematologic Recovery (CRh) Rate(Response was assessed at Cycle 2, Day 1, Cycle 4, Day 1, and every 3 cycles thereafter; median duration of treatment was 4.2 months.)
- CR Plus CRi Rate by Initiation of Cycle 2(Cycle 2, Day 1)
- Complete Remission Rate(Response was assessed at Cycle 2, Day 1, Cycle 4, Day 1, and every 3 cycles thereafter; median duration of treatment was 4.2 months.)
- Complete Remission Plus CR With Incomplete Blood Count Recovery (CRi) Rate(Response was assessed at Cycle 2, Day 1, Cycle 4, Day 1, and every 3 cycles thereafter; median duration of treatment was 4.2 months.)
- Time to First Response of CR + CRi(Response was assessed at Cycle 2, Day 1, Cycle 4, Day 1, and every 3 cycles thereafter; median duration of treatment was 4.2 months.)
- Time to Best Response of CR + CRi(Response was assessed at Cycle 2, Day 1, Cycle 4, Day 1, and every 3 cycles thereafter; median duration of treatment was 4.2 months.)
- CR Plus CRh Rate(Response was assessed at Cycle 2, Day 1, Cycle 4, Day 1, and every 3 cycles thereafter; median duration of treatment was 4.2 months.)
- CR Plus CRh Rate by Initiation of Cycle 2(Cycle 2, Day 1)
- Time to First Response of CR Plus CRh(Response was assessed at Cycle 2, Day 1, Cycle 4, Day 1, and every 3 cycles thereafter; median duration of treatment was 4.2 months.)
- Time to Best Response of CR Plus CRh(Response was assessed at Cycle 2, Day 1, Cycle 4, Day 1, and every 3 cycles thereafter; median duration of treatment was 4.2 months.)
- Post Baseline Transfusion Independence Rate(From the first dose of study drug to the last dose of study drug plus 30 days, disease progression (including clinical progression), or death, whichever was earlier; median duration of treatment was 4.2 months.)
- Post Baseline Transfusion Independence Rate Among Participants Transfusion-dependent at Baseline(From the first dose of study drug to the last dose of study drug plus 30 days, disease progression (including clinical progression), or death, whichever was earlier; median duration of treatment was 4.2 months.)
- Best Response Based on IWG Criteria(Response was assessed at Cycle 2, Day 1, Cycle 4, Day 1, and every 3 cycles thereafter; median duration of treatment was 4.2 months.)
- Duration of Complete Response(Median duration of follow-up was 44.5 months (range: 0.3 to 63.7))
- Duration of CR Plus CRh(Median duration of follow-up was 44.5 months (range: 0.3 to 63.7))
- Overall Survival (OS)(Median duration of follow-up was 44.5 months (range: 0.3 to 63.7))
- Duration of Post Baseline Transfusion Independence(From the first dose of study drug to the last dose of study drug plus 30 days, disease progression (including clinical progression), or death, whichever was earlier; median duration of treatment was 4.2 months.)
- Duration of CR Plus CRi(Median duration of follow-up was 44.5 months (range: 0.3 to 63.7))
- Duration of CRi(Median duration of follow-up was 44.5 months (range: 0.3 to 63.7))