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.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
94
Venetoclax will be taken orally once daily.
Low-dose cytarabine will be administered subcutaneously on Days 1 to 10 of each 28-day cycle.
Univ Kansas Med Ctr /ID# 131175
Kansas City, Kansas, United States
Weill Cornell Medical College /ID# 131170
New York, New York, United States
University of Pittsburgh MC /ID# 131168
Pittsburgh, Pennsylvania, United States
Vanderbilt University Medical Center /ID# 131177
Nashville, Tennessee, United States
Fred Hutchinson Cancer Research Center /ID# 131178
Seattle, Washington, United States
Calvary Mater Newcastle /ID# 136076
Waratah, New South Wales, Australia
Alfred Health /ID# 131180
Melbourne, Victoria, Australia
Universitaetsklinikum Hamburg-Eppendorf (UKE) /ID# 133979
Hamburg, Germany
Duplicate_A.O.U. Policlinico S.Orsola-Malpighi /ID# 131183
Bologna, Emilia-Romagna, Italy
Phase 1: Number of Participants With Dose-limiting Toxicities
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.
Time frame: Up to 28 days (Cycle 1)
Phase 1: Maximum Observed Plasma Concentration (Cmax) of Venetoclax
The highest concentration that a drug achieves in the blood after administration in a dosing interval.
Time frame: 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: Time to Maximum Observed Plasma Concentration (Tmax) of Venetoclax
The time at which the maximum plasma concentration (Cmax) is observed.
Time frame: 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: Area Under the Plasma Concentration-Time Curve Over Time From 0 to 24 Hours (AUC0-24) of Venetoclax
Time frame: 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: Maximum Observed Plasma Concentration (Cmax) of Cytarabine
The highest concentration that a drug achieves in the blood after administration in a dosing interval.
Time frame: Cycle 1, Day 1 and Day 10 at pre-dose and at 15 and 30 minutes and 1, 3, 6 hours post-dose.
Phase 1: Time to Maximum Observed Plasma Concentration (Tmax) of Cytarabine
The time at which the maximum plasma concentration (Cmax) is observed.
Time frame: Cycle 1, Day 1 and Day 10 at pre-dose and at 15 and 30 minutes and 1, 3, 6 hours post-dose.
Phase 1: Area Under the Plasma Concentration-Time Curve Over Time From 0 to Last Measurable Concentration (AUCt) of Cytarabine
Time frame: 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
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.
Time frame: 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.
Number of Participants With Treatment-emergent Adverse Events (TEAEs)
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.
Time frame: 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.
Complete Remission Rate
Complete remission (CR) rate is defined as the percentage of participants who achieved a complete remission at any time point during the study per the modified IWG criteria for AML and 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. Participants who never achieved CR or had no IWG disease assessment were considered to be non-responders in the calculation of CR rate.
Time frame: 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
The percentage of participants who achieved a CR or CRi at any time point during the study per the modified IWG criteria for AML and 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 Participants who never achieved CR or CRi or had no IWG disease assessment were considered to be non-responders in the calculation of CR + CRi rate.
Time frame: 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
The percentage of participants who achieved a CR or CRi by initiation of Cycle 2 of study treatment per the modified IWG criteria for AML and investigator assessment. CR: ANC ≥ 10\^3 /µL, platelet counts ≥ 10\^5 /µL, 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. Participants who never achieved CR or CRi or had no IWG disease assessment by initiation of Cycle 2 were considered to be non-responders in the calculation of CR + CRi rate by initiation of Cycle 2.
Time frame: Cycle 2, Day 1
Time to First Response of CR + CRi
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.
The time to the first response of CR + CRi is defined as the time from the first date of study drug to the first response of CR or CRi per the IWG AML response criteria assessed by the investigator. CR: absolute neutrophil count (ANC) ≥ 10\^3 /µL, platelet counts ≥ 10\^5 /µL, 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.
Time frame: 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
The time to the best response of CR + CRi is defined as the time from the first date of study drug to the best response of CR or CRi per the IWG AML response criteria assessed by the investigator. CR: absolute neutrophil count (ANC) ≥ 10\^3 /µL, platelet counts ≥ 10\^5 /µL, 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.
Time frame: 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 With Partial Hematologic Recovery (CRh) Rate
Complete remission with partial hematologic recovery is a derived response based on bone marrow blast and hematology laboratory values. CRh rate is defined as the percentage of participants who achieved CRh as the best response at any time point during the study. A participant achieved a CRh when meeting the following criteria: * Bone marrow with \< 5% blasts and * Peripheral blood neutrophil count of \> 0.5 × 10\^3 /µL and * Peripheral blood platelet count of \> 0.5 × 10\^5 /µL and * A 1 week (≥ 7 days) platelet transfusion-free period prior to the hematology lab collection. Participants who never achieved CRh or did not have disease assessment or hematology data were considered to be non-responders in the calculation of CRh rate.
Time frame: 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
CR + CRh rate is defined as the percentage of participants who achieved CR or CRh at any time point during the study. CR: ANC ≥ 10\^3 /µL, platelet counts ≥ 10\^5 /µL, RBC transfusion independence (a period of at least 56 days with no RBC transfusion), and bone marrow with \< 5% blasts. CRh is a derived response based on bone marrow blast and hematology lab values. A participant achieved a CRh when meeting the following criteria: * Bone marrow with \< 5% blasts and * Peripheral blood neutrophil count of \> 0.5 × 10\^3 /µL and * Peripheral blood platelet count of \> 0.5 × 10\^5 /µL and * A 1 week (≥ 7 days) platelet transfusion-free period prior to the hematology lab collection. Participants who never achieved CR/CRh or did not have disease assessment or hematology data were considered to be non-responders in the calculation of CR + CRh rate.
Time frame: 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
CR + CRh rate by initiation of Cycle 2 is defined as the percentage of participants who achieved CR or CRh by initiation of Cycle 2 of study treatment. CR: ANC ≥ 10\^3 /µL, platelet counts ≥ 10\^5 /µL, RBC transfusion independence (a period of at least 56 days with no RBC transfusion), and bone marrow with \< 5% blasts. CRh is a derived response based on bone marrow blast and hematology lab values. A participant achieved a CRh when meeting the following criteria: * Bone marrow with \< 5% blasts and * Peripheral blood neutrophil count of \> 0.5 × 10\^3 /µL and * Peripheral blood platelet count of \> 0.5 × 10\^5 /µL and * A 1 week (≥ 7 days) platelet transfusion-free period prior to the hematology lab collection. Participants who never achieved CR/CRh or did not have disease assessment by initiation of Cycle 2 were considered to be non-responders in the calculation of CR + CRh rate by initiation of Cycle 2.
Time frame: Cycle 2, Day 1
Time to First Response of CR Plus CRh
The time to the first response of CR + CRh is defined as the time from the first date of study drug to the first response of CR or CRh. CR: ANC ≥ 10\^3 /µL, platelet counts ≥ 10\^5 /µL, RBC transfusion independence (a period of at least 56 days with no RBC transfusion), and bone marrow with \< 5% blasts. CRh is a derived response based on bone marrow blast and hematology lab values. A participant achieved a CRh when meeting the following criteria: * Bone marrow with \< 5% blasts and * Peripheral blood neutrophil count of \> 0.5 × 10\^3 /µL and * Peripheral blood platelet count of \> 0.5 × 10\^5 /µL and * A 1 week (≥ 7 days) platelet transfusion-free period prior to the hematology lab collection.
Time frame: 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
The time to the best response of CR + CRh is defined as the time from the first date of study drug to the best response of CR or CRh. CR: ANC ≥ 10\^3 /µL, platelet counts ≥ 10\^5 /µL, RBC transfusion independence (a period of at least 56 days with no RBC transfusion), and bone marrow with \< 5% blasts. CRh is a derived response based on bone marrow blast and hematology lab values. A participant achieved a CRh when meeting the following criteria: * Bone marrow with \< 5% blasts and * Peripheral blood neutrophil count of \> 0.5 × 10\^3 /µL and * Peripheral blood platelet count of \> 0.5 × 10\^5 /µL and * A 1 week (≥ 7 days) platelet transfusion-free period prior to the hematology lab collection.
Time frame: 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.
Best Response Based on IWG Criteria
Best response determined using the IWG-AML response criteria during the course of treatment. * CR: ANC ≥ 10\^3 /µL, platelet counts ≥ 10\^5 /µL, RBC transfusion independence, 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; * MLFS: \< 5% blasts in an aspirate and/or bone marrow core sample; * RD: failure to achieve CR, CRi, PR; only including subjects surviving at least 7 days following completion of initial treatment cycle with evidence of persistent leukemia by blood and/or bone marrow examination; * PD: one or more of the following: ≥ 50% decrement from maximum response levels in neutrophils or platelets; a reduction in hemoglobin by at least 2 g/dL; or transfusion dependence not due to other toxicities and bone marrow blast ≥ 5%.
Time frame: 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
Duration of CR is defined as the time from date that a participant achieved CR to the first date of relapse, clinical disease progression or death due to disease progression, whichever occurred earliest. Duration of CR was estimated using Kaplan-Meier methodology. If a participant was still responding at the data cutoff date, then the participant's data were censored at their last disease assessment date. Disease assessment data after the onset of any post-treatment therapy were not included in the duration of CR analysis.
Time frame: Median duration of follow-up was 44.5 months (range: 0.3 to 63.7)
Duration of CR Plus CRi
Duration of CR + CRi is defined as the time from the date that a participant achieved CR or CRi to the first date of relapse, clinical disease progression or death due to disease progression, whichever occurred earliest. Duration of CR + CRi was estimated using Kaplan-Meier methodology. If a participant was still responding at the data cutoff date, then the participant's data were censored at their last disease assessment date. Disease assessment data after the onset of any post-treatment therapy were not included in the analysis.
Time frame: Median duration of follow-up was 44.5 months (range: 0.3 to 63.7)
Duration of CRi
Duration of CRi is defined as the time from date that a participant achieved CRi to the first date of relapse, clinical disease progression or death due to disease progression, whichever occurred earliest. Duration of CRi was estimated using Kaplan-Meier methodology. If a participant was still responding at the data cutoff date, then the participant's data were censored at their last disease assessment date. Disease assessment data after the onset of any post-treatment therapy were not included in the analysis.
Time frame: Median duration of follow-up was 44.5 months (range: 0.3 to 63.7)
Duration of CR Plus CRh
Duration of CR + CRh is defined as the time from date that a participant achieved CR or CRh to the first date of relapse, clinical disease progression or death due to disease progression, whichever occurred earliest. Duration of CR + CRh was estimated using Kaplan-Meier methodology. If a participant was still responding at the data cutoff date, then the participant's data were censored at their last disease assessment date. Disease assessment data after the onset of any post-treatment therapy were not included in the analysis.
Time frame: Median duration of follow-up was 44.5 months (range: 0.3 to 63.7)
Overall Survival (OS)
Overall survival is defined as the time from the date of first dose to the date of death. All events of death were included, regardless of whether the event occurred while the participant was still taking study drug, or after the participant discontinued study drug. OS was estimated using Kaplan-Meier methodology. Participants who were still alive were censored at the analysis date.
Time frame: Median duration of follow-up was 44.5 months (range: 0.3 to 63.7)
Post Baseline Transfusion Independence Rate
Post baseline transfusion independence rate was estimated as the percentage of participants who achieved transfusion independence during the evaluation period. Post-baseline transfusion independence is defined as a period of at least 56 days (≥ 56 days) with no RBC or platelet transfusion during the evaluation period. The evaluation period is from the first dose of study drug to the last dose of study drug until the 30 day follow-up visit, disease progression (including clinical progression), or death, whichever was earlier. Results are reported for participants who achieved both RBC and platelet transfusion independence and for participants who received RBC transfusion independence and platelet transfusion independence.
Time frame: 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
Post baseline transfusion independence rate was estimated as the percentage of participants who achieved transfusion independence during the evaluation period. Post-baseline transfusion independence is defined as a period of at least 56 days (≥ 56 days) with no RBC or platelet transfusion during the evaluation period. The evaluation period is from the first dose of study drug to the last dose of study drug until the 30 day follow-up visit, disease progression (including clinical progression), or death, whichever was earlier. Results are reported for participants who achieved both RBC and platelet transfusion independence and for participants who received RBC transfusion independence and platelet transfusion independence.
Time frame: 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 Post Baseline Transfusion Independence
The duration of transfusion independence is defined as the first time period that a participant received no RBC/platelet transfusions for at least 56 days during the evaluation period. Post-baseline transfusion independence is defined as a period of at least 56 days with no RBC or platelet transfusion during the evaluation period. The evaluation period is from the first dose of study drug to the last dose of study drug until the 30 day follow-up visit, disease progression (including clinical progression), or death, whichever was earlier.
Time frame: 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.