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Leukemia, Myeloid

Leukemia, Myeloid, Acute

Neoplasms by Histologic Type

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Myeloid Leukemia

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Acute Non Lymphoblastic Leukemia

Acute Graft Versus Host Disease

Anti-Infective Agents

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All Drugs and Chemicals

Cytarabine

Venetoclax

Antimetabolites

Antiviral Agents

Immunosuppressive Agents

Immunologic Factors

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.

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.

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.

Venetoclax will be taken orally once daily.

Low-dose cytarabine will be administered subcutaneously on Days 1 to 10 of each 28-day cycle.

ABBVIE INC.

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.

A Study Evaluating Venetoclax in Combination With Low-Dose Cytarabine in Treatment-Naïve Participants With Acute Myelogenous Leukemia

A Phase 1/2 Study of Venetoclax in Combination With Low-Dose Cytarabine in Treatment-Naïve Subjects With Acute Myelogenous Leukemia Who Are ≥ 60 Years of Age and Who Are Not Eligible for Standard Anthracycline-Based Induction Therapy

AbbVie is committed to responsible data sharing regarding the clinical trials we sponsor. This includes access to anonymized, individual and trial-level data (analysis data sets), as well as other information (e.g., protocols, analyses plans, clinical study reports), as long as the trials are not part of an ongoing or planned regulatory submission. This includes requests for clinical trial data for unlicensed products and indications.

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.

The highest concentration that a drug achieves in the blood after administration in a dosing interval.

The time at which the maximum plasma concentration (Cmax) is observed.

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.

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.

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.

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.

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.

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.

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 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 + 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 + 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.

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.

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 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 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 + 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 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.

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.

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 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.

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.

Genentech, Inc.

AbbVie

All-cause mortality is reported for all enrolled participants. Adverse events are reported for all participants who received at least 1 dose of venetoclax.

Phase 1: 600 mg Venetoclax + LDAC

Phase 1: 800 mg Venetoclax + LDAC

Phase 2: 600 mg Venetoclax + LDAC

Total

Age, Continuous

Sex: Female, Male

Race/Ethnicity, Customized

Global Medical Services

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.

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.

The DLT-evaluable population included participants who received at least 80% of planned Cycle 1 doses during the dose-escalation phase (Phase 1)

Phase 1: Number of Participants With Dose-limiting Toxicities

Cycle 1, Day 10 (Venetoclax with LDAC)

Cycle 1, Day 18 (Venetoclax alone)

Participants enrolled in Phase 1 who had at least one dose of venetoclax and had at least one reported pharmacokinetic (PK) sample concentration.

Phase 1: Maximum Observed Plasma Concentration (Cmax) of Venetoclax

Cycle 1, Day 18 (Venetoclax Alone)

Participants enrolled in Phase 1 who had at least one dose of venetoclax and had at least one reported PK sample concentration

Phase 1: Time to Maximum Observed Plasma Concentration (Tmax) of Venetoclax

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

Phase 1: Area Under the Plasma Concentration-Time Curve Over Time From 0 to 24 Hours (AUC0-24) of Venetoclax

Cycle 1, Day 1 (LDAC Alone)

Cycle 1, Day 10 (LDAC with Venetoclax)

Participants enrolled in Phase 1 who had at least one dose of cytarabine and had at least one reported PK sample concentration.

Phase 1: Maximum Observed Plasma Concentration (Cmax) of Cytarabine

Phase 1: Time to Maximum Observed Plasma Concentration (Tmax) of Cytarabine

Phase 1: Area Under the Plasma Concentration-Time Curve Over Time From 0 to Last Measurable Concentration (AUCt) of Cytarabine

Phase 1+2: 600 mg Venetoclax + LDAC

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.

Overall Response Rate

Any treatment-emergent adverse event (TEAE)

TEAE with CTCAE Grade 3 or 4

TEAE with CTCAE Grade 3 or above

Venetoclax-related TEAE

LDAC-related TEAE

TEAE leading to hospitalization

TEAE leading to venetoclax discontinuation

TEAE leading to LDAC discontinuation

TEAE leading to venetoclax interruption

TEAE leading to LDAC interruption

TEAE leading to venetoclax reduction

TEAE leading to LDAC reduction

TEAE leading to death

All enrolled participants who received at least one dose of study drug

Number of Participants With Treatment-emergent Adverse Events (TEAEs)

All enrolled participants who received venetoclax with LDAC at the recommended Phase 2 dose (600 mg)

Complete Remission Rate

Complete Remission Plus CR With Incomplete Blood Count Recovery (CRi) Rate

CR Plus CRi Rate by Initiation of Cycle 2

Enrolled participants who received venetoclax with LDAC at the recommended Phase 2 dose (600 mg) with a response of CR or CRi

Time to First Response of CR + CRi

Time to Best Response of CR + CRi

Complete Remission With Partial Hematologic Recovery (CRh) Rate

CR Plus CRh Rate

CR Plus CRh Rate by Initiation of Cycle 2

Enrolled participants who received venetoclax with LDAC at the recommended Phase 2 dose (600 mg) with a response of CR or CRh

Time to First Response of CR Plus CRh

Time to Best Response of CR Plus CRh

Best Response Based on IWG Criteria

Enrolled participants who received venetoclax with LDAC at the recommended Phase 2 dose (600 mg) with a response of CR

Duration of Complete Response

Duration of CR Plus CRi

Enrolled participants who received venetoclax with LDAC at the recommended Phase 2 dose (600 mg) with a response of CRi

Duration of CRi

Duration of CR Plus CRh

Enrolled participants who received venetoclax with LDAC at the recommended Phase 2 dose (600 mg)

Overall Survival (OS)

RBC and platelet transfusion independence

RBC transfusion independence

Platelet transfusion independence

Post Baseline Transfusion Independence Rate

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).

Post Baseline Transfusion Independence Rate Among Participants Transfusion-dependent at Baseline

Duration of RBC and platelet transfusion independence

Duration of RBC transfusion independence

Duration of platelet transfusion independence

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).

Spots Global Cancer Trial Database for A Study Evaluating Venetoclax in Combination With Low-Dose Cytarabine in Treatment-Naïve Participants With Acute Myelogenous Leukemia

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