Acute Myelogenous Leukemia, AML
Conditions
Keywords
Myelogenous Leukemia, Treatment Naive AML, Untreated AML
Brief summary
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.
Interventions
DRUGVenetoclax
Venetoclax will be taken orally once daily.
DRUGCytarabine
Low-dose cytarabine will be administered subcutaneously on Days 1 to 10 of each 28-day cycle.
Sponsors
Genentech, Inc.
AbbVie
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
60 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participant must be greater than or equal to 65 years of age in Phase 1 and 2. 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)
Exclusion criteria
* 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 2. * 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1: Number of Participants With Dose-limiting Toxicities | 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: Maximum Observed Plasma Concentration (Cmax) of Venetoclax | 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: Time to Maximum Observed Plasma Concentration (Tmax) of Venetoclax | 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: Area Under the Plasma Concentration-Time Curve Over Time From 0 to 24 Hours (AUC0-24) of Venetoclax | 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 | 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. |
| Phase 1: Time to Maximum Observed Plasma Concentration (Tmax) of Cytarabine | 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 | 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 | 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. |
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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. | 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. |
| 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. | 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%. |
| Duration of Complete Response | Median duration of follow-up was 44.5 months (range: 0.3 to 63.7) | 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. |
| Duration of CR Plus CRi | Median duration of follow-up was 44.5 months (range: 0.3 to 63.7) | 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. |
| Duration of CRi | Median duration of follow-up was 44.5 months (range: 0.3 to 63.7) | 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. |
| 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 (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. |
| Overall Survival (OS) | Median duration of follow-up was 44.5 months (range: 0.3 to 63.7) | 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. |
| 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 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. |
| 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. | 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. |
| 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. | 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. |
| Duration of CR Plus CRh | Median duration of follow-up was 44.5 months (range: 0.3 to 63.7) | 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. |
| 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. | 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. |
| CR Plus CRi Rate by Initiation of Cycle 2 | Cycle 2, Day 1 | 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 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. | 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 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. | 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. |
| 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. | 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. |
| 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 + 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. |
| CR Plus CRh Rate by Initiation of Cycle 2 | Cycle 2, Day 1 | 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 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. | 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. |
Countries
Australia, Germany, Italy, United States
Participant flow
Recruitment details
Previously untreated adults with acute myeloid leukemia (AML) who were ineligible for intensive chemotherapy were enrolled at nine study sites in the United States, Australia, Germany, and Italy between December 2014 and May 2017. The study consisted of a dose escalation phase (Phase 1) to determine the recommended Phase 2 dose (RPTD), and a dose expansion phase (Phase 2).
Participants by arm
| Arm | Count |
|---|---|
| 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. | 8 |
| 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. | 10 |
| 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. | 76 |
| Total | 94 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event Not Related to Progression | 1 | 2 | 10 |
| Overall Study | Adverse Event Related to Progression | 0 | 2 | 8 |
| Overall Study | Did Not Receive Treatment | 0 | 0 | 2 |
| Overall Study | Other | 3 | 0 | 15 |
| Overall Study | Physician Decision | 1 | 2 | 4 |
| Overall Study | Progressive Disease with Death | 0 | 0 | 10 |
| Overall Study | Progressive Disease Without Death | 2 | 3 | 20 |
| Overall Study | Withdrawal by Subject | 1 | 1 | 7 |
Baseline characteristics
| Characteristic | Phase 1: 600 mg Venetoclax + LDAC | Phase 1: 800 mg Venetoclax + LDAC | Phase 2: 600 mg Venetoclax + LDAC | Total |
|---|---|---|---|---|
| Age, Continuous | 75.3 years STANDARD_DEVIATION 6.45 | 74.4 years STANDARD_DEVIATION 3.72 | 75.0 years STANDARD_DEVIATION 5.56 | 74.9 years STANDARD_DEVIATION 5.43 |
| Race/Ethnicity, Customized Asian | 0 Participants | 0 Participants | 2 Participants | 2 Participants |
| Race/Ethnicity, Customized Black or African American | 0 Participants | 0 Participants | 2 Participants | 2 Participants |
| Race/Ethnicity, Customized Missing | 0 Participants | 0 Participants | 3 Participants | 3 Participants |
| Race/Ethnicity, Customized White | 8 Participants | 10 Participants | 69 Participants | 87 Participants |
| Sex: Female, Male Female | 3 Participants | 3 Participants | 27 Participants | 33 Participants |
| Sex: Female, Male Male | 5 Participants | 7 Participants | 49 Participants | 61 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 6 / 8 | 10 / 10 | 63 / 76 |
| other Total, other adverse events | 8 / 8 | 10 / 10 | 74 / 74 |
| serious Total, serious adverse events | 7 / 8 | 9 / 10 | 68 / 74 |
Outcome results
Primary
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.
Population: All enrolled participants who received at least one dose of study drug
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase 1: 600 mg Venetoclax + LDAC | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | TEAE leading to LDAC reduction | 0 Participants |
| Phase 1: 600 mg Venetoclax + LDAC | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | TEAE leading to venetoclax interruption | 3 Participants |
| Phase 1: 600 mg Venetoclax + LDAC | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | TEAE leading to hospitalization | 7 Participants |
| Phase 1: 600 mg Venetoclax + LDAC | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | TEAE with CTCAE Grade 3 or above | 8 Participants |
| Phase 1: 600 mg Venetoclax + LDAC | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | TEAE leading to LDAC discontinuation | 3 Participants |
| Phase 1: 600 mg Venetoclax + LDAC | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | TEAE leading to venetoclax discontinuation | 3 Participants |
| Phase 1: 600 mg Venetoclax + LDAC | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any treatment-emergent adverse event (TEAE) | 8 Participants |
| Phase 1: 600 mg Venetoclax + LDAC | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | TEAE with CTCAE Grade 3 or 4 | 8 Participants |
| Phase 1: 600 mg Venetoclax + LDAC | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | TEAE leading to venetoclax reduction | 0 Participants |
| Phase 1: 600 mg Venetoclax + LDAC | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Venetoclax-related TEAE | 8 Participants |
| Phase 1: 600 mg Venetoclax + LDAC | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | TEAE leading to death | 1 Participants |
| Phase 1: 600 mg Venetoclax + LDAC | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | TEAE leading to LDAC interruption | 3 Participants |
| Phase 1: 600 mg Venetoclax + LDAC | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | LDAC-related TEAE | 8 Participants |
| Phase 1: 800 mg Venetoclax + LDAC | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | TEAE leading to venetoclax discontinuation | 5 Participants |
| Phase 1: 800 mg Venetoclax + LDAC | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any treatment-emergent adverse event (TEAE) | 10 Participants |
| Phase 1: 800 mg Venetoclax + LDAC | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | TEAE with CTCAE Grade 3 or 4 | 10 Participants |
| Phase 1: 800 mg Venetoclax + LDAC | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | TEAE with CTCAE Grade 3 or above | 10 Participants |
| Phase 1: 800 mg Venetoclax + LDAC | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Venetoclax-related TEAE | 9 Participants |
| Phase 1: 800 mg Venetoclax + LDAC | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | LDAC-related TEAE | 9 Participants |
| Phase 1: 800 mg Venetoclax + LDAC | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | TEAE leading to hospitalization | 8 Participants |
| Phase 1: 800 mg Venetoclax + LDAC | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | TEAE leading to LDAC discontinuation | 5 Participants |
| Phase 1: 800 mg Venetoclax + LDAC | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | TEAE leading to venetoclax interruption | 4 Participants |
| Phase 1: 800 mg Venetoclax + LDAC | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | TEAE leading to LDAC interruption | 3 Participants |
| Phase 1: 800 mg Venetoclax + LDAC | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | TEAE leading to venetoclax reduction | 1 Participants |
| Phase 1: 800 mg Venetoclax + LDAC | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | TEAE leading to LDAC reduction | 0 Participants |
| Phase 1: 800 mg Venetoclax + LDAC | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | TEAE leading to death | 4 Participants |
| Phase 2: 600 mg Venetoclax + LDAC | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | TEAE leading to venetoclax interruption | 45 Participants |
| Phase 2: 600 mg Venetoclax + LDAC | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Venetoclax-related TEAE | 66 Participants |
| Phase 2: 600 mg Venetoclax + LDAC | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | TEAE leading to LDAC reduction | 1 Participants |
| Phase 2: 600 mg Venetoclax + LDAC | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | TEAE leading to LDAC interruption | 38 Participants |
| Phase 2: 600 mg Venetoclax + LDAC | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | TEAE with CTCAE Grade 3 or above | 72 Participants |
| Phase 2: 600 mg Venetoclax + LDAC | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any treatment-emergent adverse event (TEAE) | 74 Participants |
| Phase 2: 600 mg Venetoclax + LDAC | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | TEAE leading to venetoclax reduction | 6 Participants |
| Phase 2: 600 mg Venetoclax + LDAC | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | TEAE leading to venetoclax discontinuation | 24 Participants |
| Phase 2: 600 mg Venetoclax + LDAC | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | TEAE leading to hospitalization | 64 Participants |
| Phase 2: 600 mg Venetoclax + LDAC | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | TEAE with CTCAE Grade 3 or 4 | 72 Participants |
| Phase 2: 600 mg Venetoclax + LDAC | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | TEAE leading to LDAC discontinuation | 26 Participants |
| Phase 2: 600 mg Venetoclax + LDAC | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | LDAC-related TEAE | 71 Participants |
| Phase 2: 600 mg Venetoclax + LDAC | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | TEAE leading to death | 15 Participants |
Primary
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.
Population: All enrolled participants who received venetoclax with LDAC at the recommended Phase 2 dose (600 mg). Efficacy endpoints were pre-specified for Phase 2 only, and are reported for all participants who received the RPTD.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1: 600 mg Venetoclax + LDAC | Overall Response Rate | 54.9 percentage of participants |
Primary
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)
Population: Participants enrolled in Phase 1 who had at least one dose of venetoclax and had at least one reported PK sample concentration with available data at each time point
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1: 600 mg Venetoclax + LDAC | Phase 1: Area Under the Plasma Concentration-Time Curve Over Time From 0 to 24 Hours (AUC0-24) of Venetoclax | Cycle 1, Day 10 (Venetoclax with LDAC) | 33.3 µg*h/mL | Standard Deviation 27.5 |
| Phase 1: 600 mg Venetoclax + LDAC | Phase 1: Area Under the Plasma Concentration-Time Curve Over Time From 0 to 24 Hours (AUC0-24) of Venetoclax | Cycle 1, Day 18 (Venetoclax Alone) | 51.8 µg*h/mL | Standard Deviation 36.9 |
| Phase 1: 800 mg Venetoclax + LDAC | Phase 1: Area Under the Plasma Concentration-Time Curve Over Time From 0 to 24 Hours (AUC0-24) of Venetoclax | Cycle 1, Day 10 (Venetoclax with LDAC) | 33.4 µg*h/mL | Standard Deviation 14.1 |
| Phase 1: 800 mg Venetoclax + LDAC | Phase 1: Area Under the Plasma Concentration-Time Curve Over Time From 0 to 24 Hours (AUC0-24) of Venetoclax | Cycle 1, Day 18 (Venetoclax Alone) | 35.4 µg*h/mL | Standard Deviation 19.8 |
Primary
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.
Population: Participants enrolled in Phase 1 who had at least one dose of cytarabine and had at least one reported PK sample concentration.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1: 600 mg Venetoclax + LDAC | Phase 1: Area Under the Plasma Concentration-Time Curve Over Time From 0 to Last Measurable Concentration (AUCt) of Cytarabine | Cycle 1, Day 1 (LDAC Alone) | 194 ng*h/mL | Standard Deviation 66.3 |
| Phase 1: 600 mg Venetoclax + LDAC | Phase 1: Area Under the Plasma Concentration-Time Curve Over Time From 0 to Last Measurable Concentration (AUCt) of Cytarabine | Cycle 1, Day 10 (LDAC with Venetoclax) | 231 ng*h/mL | Standard Deviation 89 |
| Phase 1: 800 mg Venetoclax + LDAC | Phase 1: Area Under the Plasma Concentration-Time Curve Over Time From 0 to Last Measurable Concentration (AUCt) of Cytarabine | Cycle 1, Day 1 (LDAC Alone) | 204 ng*h/mL | Standard Deviation 62.9 |
| Phase 1: 800 mg Venetoclax + LDAC | Phase 1: Area Under the Plasma Concentration-Time Curve Over Time From 0 to Last Measurable Concentration (AUCt) of Cytarabine | Cycle 1, Day 10 (LDAC with Venetoclax) | 202 ng*h/mL | Standard Deviation 54.9 |
Primary
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.
Population: Participants enrolled in Phase 1 who had at least one dose of cytarabine and had at least one reported PK sample concentration.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1: 600 mg Venetoclax + LDAC | Phase 1: Maximum Observed Plasma Concentration (Cmax) of Cytarabine | Cycle 1, Day 10 (LDAC with Venetoclax) | 166 ng/mL | Standard Deviation 32.1 |
| Phase 1: 600 mg Venetoclax + LDAC | Phase 1: Maximum Observed Plasma Concentration (Cmax) of Cytarabine | Cycle 1, Day 1 (LDAC Alone) | 175 ng/mL | Standard Deviation 47 |
| Phase 1: 800 mg Venetoclax + LDAC | Phase 1: Maximum Observed Plasma Concentration (Cmax) of Cytarabine | Cycle 1, Day 10 (LDAC with Venetoclax) | 175 ng/mL | Standard Deviation 62.3 |
| Phase 1: 800 mg Venetoclax + LDAC | Phase 1: Maximum Observed Plasma Concentration (Cmax) of Cytarabine | Cycle 1, Day 1 (LDAC Alone) | 174 ng/mL | Standard Deviation 55.4 |
Primary
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)
Population: Participants enrolled in Phase 1 who had at least one dose of venetoclax and had at least one reported pharmacokinetic (PK) sample concentration.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1: 600 mg Venetoclax + LDAC | Phase 1: Maximum Observed Plasma Concentration (Cmax) of Venetoclax | Cycle 1, Day 10 (Venetoclax with LDAC) | 2.04 µg/mL | Standard Deviation 1.45 |
| Phase 1: 600 mg Venetoclax + LDAC | Phase 1: Maximum Observed Plasma Concentration (Cmax) of Venetoclax | Cycle 1, Day 18 (Venetoclax alone) | 2.92 µg/mL | Standard Deviation 2.15 |
| Phase 1: 800 mg Venetoclax + LDAC | Phase 1: Maximum Observed Plasma Concentration (Cmax) of Venetoclax | Cycle 1, Day 10 (Venetoclax with LDAC) | 2.26 µg/mL | Standard Deviation 0.93 |
| Phase 1: 800 mg Venetoclax + LDAC | Phase 1: Maximum Observed Plasma Concentration (Cmax) of Venetoclax | Cycle 1, Day 18 (Venetoclax alone) | 2.36 µg/mL | Standard Deviation 1.22 |
Primary
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)
Population: The DLT-evaluable population included participants who received at least 80% of planned Cycle 1 doses during the dose-escalation phase (Phase 1)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1: 600 mg Venetoclax + LDAC | Phase 1: Number of Participants With Dose-limiting Toxicities | 0 Participants |
| Phase 1: 800 mg Venetoclax + LDAC | Phase 1: Number of Participants With Dose-limiting Toxicities | 1 Participants |
Primary
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.
Population: Participants enrolled in Phase 1 who had at least one dose of cytarabine and had at least one reported PK sample concentration.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Phase 1: 600 mg Venetoclax + LDAC | Phase 1: Time to Maximum Observed Plasma Concentration (Tmax) of Cytarabine | Cycle 1, Day 1 (LDAC Alone) | 0.3 hours |
| Phase 1: 600 mg Venetoclax + LDAC | Phase 1: Time to Maximum Observed Plasma Concentration (Tmax) of Cytarabine | Cycle 1, Day 10 (LDAC with Venetoclax) | 0.3 hours |
| Phase 1: 800 mg Venetoclax + LDAC | Phase 1: Time to Maximum Observed Plasma Concentration (Tmax) of Cytarabine | Cycle 1, Day 1 (LDAC Alone) | 0.3 hours |
| Phase 1: 800 mg Venetoclax + LDAC | Phase 1: Time to Maximum Observed Plasma Concentration (Tmax) of Cytarabine | Cycle 1, Day 10 (LDAC with Venetoclax) | 0.3 hours |
Primary
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)
Population: Participants enrolled in Phase 1 who had at least one dose of venetoclax and had at least one reported PK sample concentration
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Phase 1: 600 mg Venetoclax + LDAC | Phase 1: Time to Maximum Observed Plasma Concentration (Tmax) of Venetoclax | Cycle 1, Day 10 (Venetoclax with LDAC) | 4.0 hours |
| Phase 1: 600 mg Venetoclax + LDAC | Phase 1: Time to Maximum Observed Plasma Concentration (Tmax) of Venetoclax | Cycle 1, Day 18 (Venetoclax Alone) | 7.0 hours |
| Phase 1: 800 mg Venetoclax + LDAC | Phase 1: Time to Maximum Observed Plasma Concentration (Tmax) of Venetoclax | Cycle 1, Day 10 (Venetoclax with LDAC) | 8.0 hours |
| Phase 1: 800 mg Venetoclax + LDAC | Phase 1: Time to Maximum Observed Plasma Concentration (Tmax) of Venetoclax | Cycle 1, Day 18 (Venetoclax Alone) | 6.6 hours |
Secondary
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.
Population: All enrolled participants who received venetoclax with LDAC at the recommended Phase 2 dose (600 mg)
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase 1: 600 mg Venetoclax + LDAC | Best Response Based on IWG Criteria | Complete Remission (CR) | 21 Participants |
| Phase 1: 600 mg Venetoclax + LDAC | Best Response Based on IWG Criteria | Complete Remission with Incomplete Marrow Recovery (CRi) | 23 Participants |
| Phase 1: 600 mg Venetoclax + LDAC | Best Response Based on IWG Criteria | Partial Remission (PR) | 1 Participants |
| Phase 1: 600 mg Venetoclax + LDAC | Best Response Based on IWG Criteria | Morphologically Leukemia Free State (MLFS) | 6 Participants |
| Phase 1: 600 mg Venetoclax + LDAC | Best Response Based on IWG Criteria | Resistant Disease (RD) | 19 Participants |
| Phase 1: 600 mg Venetoclax + LDAC | Best Response Based on IWG Criteria | Disease Progression (PD) | 4 Participants |
| Phase 1: 600 mg Venetoclax + LDAC | Best Response Based on IWG Criteria | Discontinued With No Response Data (DS) | 8 Participants |
Secondary
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.
Population: All enrolled participants who received venetoclax with LDAC at the recommended Phase 2 dose (600 mg)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1: 600 mg Venetoclax + LDAC | Complete Remission Plus CR With Incomplete Blood Count Recovery (CRi) Rate | 53.7 percentage of participants |
Secondary
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.
Population: All enrolled participants who received venetoclax with LDAC at the recommended Phase 2 dose (600 mg)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1: 600 mg Venetoclax + LDAC | Complete Remission Rate | 25.6 percentage of participants |
Secondary
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.
Population: All enrolled participants who received venetoclax with LDAC at the recommended Phase 2 dose (600 mg)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1: 600 mg Venetoclax + LDAC | Complete Remission With Partial Hematologic Recovery (CRh) Rate | 20.7 percentage of participants |
Secondary
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.
Population: All enrolled participants who received venetoclax with LDAC at the recommended Phase 2 dose (600 mg)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1: 600 mg Venetoclax + LDAC | CR Plus CRh Rate | 46.3 percentage of participants |
Secondary
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
Population: All enrolled participants who received venetoclax with LDAC at the recommended Phase 2 dose (600 mg)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1: 600 mg Venetoclax + LDAC | CR Plus CRh Rate by Initiation of Cycle 2 | 30.5 percentage of participants |
Secondary
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
Population: All enrolled participants who received venetoclax with LDAC at the recommended Phase 2 dose (600 mg)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1: 600 mg Venetoclax + LDAC | CR Plus CRi Rate by Initiation of Cycle 2 | 28.0 percentage of participants |
Secondary
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)
Population: Enrolled participants who received venetoclax with LDAC at the recommended Phase 2 dose (600 mg) with a response of CR
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1: 600 mg Venetoclax + LDAC | Duration of Complete Response | 14.8 months |
Secondary
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)
Population: Enrolled participants who received venetoclax with LDAC at the recommended Phase 2 dose (600 mg) with a response of CRi
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1: 600 mg Venetoclax + LDAC | Duration of CRi | 4.7 months |
Secondary
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)
Population: Enrolled participants who received venetoclax with LDAC at the recommended Phase 2 dose (600 mg) with a response of CR or CRh
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1: 600 mg Venetoclax + LDAC | Duration of CR Plus CRh | 11.0 months |
Secondary
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)
Population: Enrolled participants who received venetoclax with LDAC at the recommended Phase 2 dose (600 mg) with a response of CR or CRi
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1: 600 mg Venetoclax + LDAC | Duration of CR Plus CRi | 9.8 months |
Secondary
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.
Population: Enrolled participants who received venetoclax with LDAC at the recommended Phase 2 dose (600 mg) who achieved post-baseline RBC or platelet transfusion independence overall (50), RBC and platelet transfusion independence (37), RBC transfusion independence (39), or platelet transfusion independence (48).
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Phase 1: 600 mg Venetoclax + LDAC | Duration of Post Baseline Transfusion Independence | Duration of RBC and platelet transfusion independence | 150 days |
| Phase 1: 600 mg Venetoclax + LDAC | Duration of Post Baseline Transfusion Independence | Duration of RBC transfusion independence | 123 days |
| Phase 1: 600 mg Venetoclax + LDAC | Duration of Post Baseline Transfusion Independence | Duration of platelet transfusion independence | 155.5 days |
Secondary
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)
Population: Enrolled participants who received venetoclax with LDAC at the recommended Phase 2 dose (600 mg)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1: 600 mg Venetoclax + LDAC | Overall Survival (OS) | 9.7 months |
Secondary
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.
Population: Enrolled participants who received venetoclax with LDAC at the recommended Phase 2 dose (600 mg)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase 1: 600 mg Venetoclax + LDAC | Post Baseline Transfusion Independence Rate | RBC and platelet transfusion independence | 45.1 percentage of participants |
| Phase 1: 600 mg Venetoclax + LDAC | Post Baseline Transfusion Independence Rate | RBC transfusion independence | 47.6 percentage of participants |
| Phase 1: 600 mg Venetoclax + LDAC | Post Baseline Transfusion Independence Rate | Platelet transfusion independence | 58.5 percentage of participants |
Secondary
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.
Population: Enrolled participants who received venetoclax with LDAC at the recommended Phase 2 dose (600 mg) who received a RBC or platelet transfusion within 8 weeks prior to first dose (60), an RBC transfusion within 8 weeks prior to first dose (53) or a platelet transfusion within 8 weeks prior to first dose (23).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase 1: 600 mg Venetoclax + LDAC | Post Baseline Transfusion Independence Rate Among Participants Transfusion-dependent at Baseline | RBC and platelet transfusion independence | 45.0 percentage of participants |
| Phase 1: 600 mg Venetoclax + LDAC | Post Baseline Transfusion Independence Rate Among Participants Transfusion-dependent at Baseline | RBC transfusion independence | 45.3 percentage of participants |
| Phase 1: 600 mg Venetoclax + LDAC | Post Baseline Transfusion Independence Rate Among Participants Transfusion-dependent at Baseline | Platelet transfusion independence | 60.9 percentage of participants |
Secondary
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.
Population: Enrolled participants who received venetoclax with LDAC at the recommended Phase 2 dose (600 mg) with a response of CR or CRi
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1: 600 mg Venetoclax + LDAC | Time to Best Response of CR + CRi | 2.8 months |
Secondary
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.
Population: Enrolled participants who received venetoclax with LDAC at the recommended Phase 2 dose (600 mg) with a response of CR or CRh
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1: 600 mg Venetoclax + LDAC | Time to Best Response of CR Plus CRh | 2.6 months |
Secondary
Time to First Response of CR + CRi
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.
Population: Enrolled participants who received venetoclax with LDAC at the recommended Phase 2 dose (600 mg) with a response of CR or CRi
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1: 600 mg Venetoclax + LDAC | Time to First Response of CR + CRi | 1.4 months |
Secondary
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.
Population: Enrolled participants who received venetoclax with LDAC at the recommended Phase 2 dose (600 mg) with a response of CR or CRh
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1: 600 mg Venetoclax + LDAC | Time to First Response of CR Plus CRh | 1.0 months |