Acute Myeloid Leukemia
Conditions
Brief summary
This study will evaluate the efficacy, safety, and tolerability of entospletinib when administered as monotherapy or in combination with chemotherapy in adults with acute myeloid leukemia (AML).
Interventions
DRUGEntospletinib
Tablet(s) administered orally every 12 hours
DRUGDaunorubicin
60 mg/m\^2 administered intravenously daily on Days 1 to 3 for up to two 14-day induction cycles
DRUGCytarabine
100 mg/m\^2 administered intravenously daily on Days 1 to 7 for up to two 14-day cycles
DRUGDecitabine
20 mg/m\^2 administered intravenously
DRUGAzacitidine
75 mg/m\^2 administered intravenously or subcutaneously
Sponsors
Gilead Sciences
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Adults with AML in need of treatment * Group A : Individuals ≥ 18 years of age with previously untreated AML by World Health Organization (WHO) criteria who are able and should receive up to 2 cycles of induction chemotherapy with 7+3 as determined by the treating physician * Group B: Individuals \> 70 years of age with previously untreated AML by WHO criteria; or individuals ≤ 70 years of age with previously untreated AML who refuse or are unable to receive chemotherapy with 7+3 as determined by the treating physician * Group C: Individuals ≥ 18 years of age with relapsed/refractory AML by WHO criteria; or with relapsed/refractory AML with mixed-lineage leukemia (MLL); or with previously untreated AML by WHO criteria and who would have met disease eligibility criteria for Group A or B but refuse or are unable to receive chemotherapy and hypomethylating agent as determined by the treating physician Key
Exclusion criteria
* Known active central nervous system or leptomeningeal lymphoma * Subjects with acute promyelocytic leukemia (M3) * Treatment with proton pump inhibitors (PPIs) within 7 days prior to enrollment. NOTE: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Experiencing Dose Limiting Toxicities (DLTs) | Group A: Cycle 0 Day 1 to Cycle 2 Day 28; Group B: Cycle 0 Day 1 to Cycle 1 Day 28; Group C: Cycle 1 Day 1 to Cycle 1 Day 28 (Cycle length: for Cycle 0 = 14 days, for all other cycles = 28 days) | DLTs refer to toxicities experienced during the first 28 days of study treatment that have been judged to be clinically significant and related to study treatment. DLT assessment was applicable only for Phase 1b and Phase 2 safety run-in participants. |
| Percentage of Participants With Morphologic Complete Remission (CR) at the End of Induction | At the end of induction (Group A: up to end of Cycle 2; Group B: up to end of Cycle 4) (cycle length = up to 28 days); Group C: From Day 1 until meeting the criteria for study treatment discontinuation (up to approximately 3 years) | Clinical response was assessed according to the International Working Group criteria (Cheson 2003). Morphologic CR included CR and cytogenetic CR (CRc). CR required all of the following: \< 5% blasts in bone marrow aspirate; Neutrophils ≥ 1,000/microliter (mcL); Platelets ≥ 100,000/mcL; No extramedullary disease; No blasts with Auer rods detected; and Independent of transfusions. CRc, in addition to CR criteria, required reversion to a normal karyotype with an abnormal karyotype at the time of diagnosis. |
| Percentage of Participants With Composite Complete Remission at the End of Induction | At the end of induction (Group A: up to end of Cycle 2; Group B: up to end of Cycle 4) (cycle length = up to 28 days); Group C: From Day 1 until meeting the criteria for study treatment discontinuation (up to approximately 3 years) | Clinical response was assessed according to the International Working Group criteria (Cheson 2003). Composite complete remission included CR, CRc, and morphologic complete remission with incomplete blood count recovery (CRi). CR required all of the following: \< 5% blasts in bone marrow aspirate; Neutrophils ≥ 1,000/mcL; Platelets ≥ 100,000/mcL; No extramedullary disease; No blasts with Auer rods detected; and Independent of transfusions. CRc, in addition to CR criteria, required reversion to a normal karyotype with an abnormal karyotype at the time of diagnosis. CRi required all of the CR criteria except the criterion of neutrophils and platelets. |
| Percentage of Participants With Overall Response at the End of Induction | At the end of induction (Group A: up to end of Cycle 2; Group B: up to end of Cycle 4) (cycle length = up to 28 days); Group C: From Day 1 until meeting the criteria for study treatment discontinuation (up to approximately 3 years) | Clinical response was assessed according to the International Working Group criteria (Cheson 2003). Overall response included CR, CRc, CRi, and partial remission (PR). CR required all of the following: \< 5% blasts in bone marrow aspirate; Neutrophils ≥ 1,000/mcL; Platelets ≥ 100,000/mcL; No extramedullary disease; No blasts with Auer rods detected; and Independent of transfusions. CRc, in addition to CR criteria, required reversion to a normal karyotype with an abnormal karyotype at the time of diagnosis. CRi required all of the CR criteria except the criterion of neutrophils and platelets. PR required all of the following: ≥ 50% decrease in blasts in bone marrow aspirate to a range of 5% to 25%; Neutrophils ≥ 1,000/mcL; Platelets ≥ 100,000/mcL; Independent of transfusions; and A value of ≤ 5% blasts was also considered a PR if Auer rods were detected. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Exposure of Entospletinib | First dose date up to approximately 3 years | — |
| Percentage of Participants Who Experienced Laboratory Abnormalities | First dose date up to the last dose date plus 30 days (maximum: 18 months) | Treatment-emergent laboratory abnormalities were defined as values that increase at least one toxicity grade from baseline. The most severe graded abnormality from all tests was counted for each participant. |
| Event Free Survival (EFS) | First dose date up to approximately 38 months | EFS was defined as the time interval from the start of the study therapy until the date of treatment failure, acute myeloid leukemia (AML) relapse, or death from any cause, whichever occurred first. Participants who received other anti-cancer therapy (prior to the event if any) were censored. Median EFS was analyzed using Kaplan-Meier (KM) method. |
| Overall Survival (OS) | First dose date up to approximately 38 months | OS was defined as the time interval from the start of the study therapy to death from any cause. Median OS was analyzed using KM method. |
| Percentage of Participants Experiencing Treatment-Emergent Adverse Events | First dose date up to the last dose date plus 30 days (maximum: 18 months) | — |
Countries
Canada, Germany, United States
Participant flow
Recruitment details
Participants were enrolled at study sites in United States, Canada, and Germany. The first participant was screened on 01 July 2015.
Pre-assignment details
233 participants were screened.
Participants by arm
| Arm | Count |
|---|---|
| Group A Phase 1b ENTO 200 mg + Cytarabine + Daunorubicin Participants received ENTO 200 mg tablet orally every 12 hours on Days 1 to 14 (Cycle 0) (during monotherapy lead-in), followed by ENTO 200 mg tablet orally every 12 hours in combination with chemotherapy (cytarabine 100 mg/m\^2 on Days 1-7 and daunorubicin 60 mg/m\^2 on Days 1-3 intravenously) for up to two 14-day cycles (Cycles 1 and 2) (during induction chemotherapy). | 3 |
| Group A Phase 1b/2 ENTO 400 mg + Cytarabine + Daunorubicin Phase1b/2: Participants received ENTO 400 mg tablet orally every 12 hours on Days 1 to 14 (Cycle 0) (monotherapy lead-in), followed by ENTO 400 mg tablet orally every 12 hours in combination with chemotherapy (cytarabine 100 mg/m\^2 on Days 1-7 and daunorubicin 60 mg/m\^2 on Days 1-3 intravenously) for up to two 14-day cycles (Cycles 1 and 2) (induction chemotherapy).
Phase 2 only: Participants who achieved a CR/CRi and did not require or could not proceed to allogeneic stem cell transplantation (SCT) were offered post-remission chemotherapy (cytarabine 3 g/m\^2 intravenously every 12 hours on Days 1, 3, and 5 or 1 g/m\^2 intravenously once daily on Days 1-5) in combination with ENTO 400 mg tablet orally every 12 hours on Days 1-28 of each 28-day cycle for at least 3 and up to 4 cycles. Participants who maintained a CR/CRi after 3 or 4 cycles were offered maintenance therapy with ENTO 400 mg tablet orally every 12 hours on Days 1-28 of each 28-day cycle for up to 12 cycles. | 50 |
| Group B Phase 1b ENTO 200 mg + Decitabine Participants received ENTO 200 mg tablet orally every 12 hours on Days 1-14 (Cycle 0) (during monotherapy lead-in), followed by ENTO 200 mg tablet orally every 12 hours in combination with decitabine 20 mg/m\^2 intravenously on Days 1-10 of every 28-day cycle for 2 cycles (or up to 4 cycles for participants with persistent disease after Cycle 2 Day 28) (induction chemotherapy). Participants who achieved a CR/CRi received SCT (if eligible) per investigator's discretion; other participants were offered maintenance therapy with ENTO every 12 hours on Days 1-28 in combination with decitabine on Days 1-5 of every 28-day cycle for at least 2 cycles (maximum up to 12 cycles). Participants who were intolerant to decitabine were offered maintenance therapy with ENTO 200 mg as monotherapy after completing 2 maintenance cycles. | 5 |
| Group B Phase 1b ENTO 400 mg + Decitabine Participants received ENTO 400 mg tablet orally every 12 hours on Days 1-14 (Cycle 0) (during monotherapy lead-in), followed by ENTO 400 mg tablet orally every 12 hours in combination with decitabine 20 mg/m\^2 intravenously on Days 1-10 of every 28-day cycle for 2 cycles (or up to 4 cycles for participants with persistent disease after Cycle 2 Day 28) (induction chemotherapy). Participants who achieved a CR/CRi received SCT (if eligible) per investigator's discretion; other participants were offered maintenance therapy with ENTO every 12 hours on Days 1-28 in combination with decitabine on Days 1-5 of every 28-day cycle for at least 2 cycles (maximum up to 12 cycles). Participants who were intolerant to decitabine were offered maintenance therapy with ENTO 400 mg as monotherapy after completing 2 maintenance cycles. | 6 |
| Group B Phase 2 ENTO 400 mg + Azacitidine (Safety Run-In) As part of the safety run-in, participants received ENTO 400 mg tablet orally every 12 hours on Days 1-14 (Cycle 0) (during monotherapy lead-in), followed by ENTO 400 mg tablet orally every 12 hours in combination with azacitidine 75 mg/m\^2 intravenously on Days 1-7 of a 28-day cycle (Cycle 1). Participants who were not eligible for SCT were offered maintenance therapy with ENTO every 12 hours on Days 1-28 in combination with azacitidine on Days 1-7 of every 28-day cycle for at least 2 cycles (maximum up to 12 cycles). Participants who were intolerant to azacitidine were offered maintenance therapy with ENTO 400 mg as monotherapy after completing 2 maintenance cycles. | 8 |
| Group B Phase 2 ENTO 400 mg + Decitabine (Randomized) Participants were randomized to receive ENTO 400 mg tablet orally every 12 hours on Days 1-5 (Cycle 0) (during monotherapy lead-in), followed by ENTO 400 mg tablet orally every 12 hours in combination with decitabine 20 mg/m\^2 intravenously on Days 1-10 of every 28-day cycle for 2 cycles (or up to 4 cycles for participants with persistent disease after Cycle 2 Day 28). Participants who were not eligible for SCT were offered maintenance therapy with ENTO every 12 hours on Days 1-28 in combination with decitabine on Days 1-5 of every 28-day cycle for at least 2 cycles (maximum up to 12 cycles). Participants who were intolerant to decitabine were offered maintenance therapy with ENTO 400 mg as monotherapy after completing 2 maintenance cycles. | 17 |
| Group B Phase 2 ENTO 400 mg + Azacitidine (Randomized) Participants were randomized to receive ENTO 400 mg tablet orally every 12 hours on Days 1-5 (Cycle 0) (during monotherapy lead-in), followed by ENTO 400 mg tablet orally every 12 hours in combination with azacitidine 75 mg/m\^2 intravenously on Days 1-7 of every 28-day cycle for 2 cycles (or up to 4 cycles for participants with persistent disease after Cycle 2 Day 28). Participants who were not eligible for SCT were offered maintenance therapy with ENTO every 12 hours on Days 1-28 in combination with azacitidine on Days 1-7 of every 28-day cycle for at least 2 cycles (maximum up to 12 cycles). Participants who were intolerant to azacitidine were offered maintenance therapy with ENTO 400 mg as monotherapy after completing 2 maintenance cycles. | 14 |
| Group C Phase 1b/2 ENTO 400 mg Participants received ENTO 400 mg tablet orally every 12 hours on Days 1-28 of every 28-day cycle until treatment failure, start of new therapy, unacceptable toxicity, withdrawal of consent, withdrawal from study by investigator, or study termination by sponsor. | 35 |
| Group C Phase 1b ENTO 800 mg Participants received ENTO 800 mg tablet orally every 12 hours on Days 1-28 of every 28-day cycle until treatment failure, start of new therapy, unacceptable toxicity, withdrawal of consent, withdrawal from study by investigator, or study termination by sponsor. | 7 |
| Total | 145 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 |
|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Death | 0 | 15 | 4 | 2 | 5 | 11 | 8 | 22 | 1 |
| Overall Study | Investigator's discretion | 0 | 0 | 0 | 1 | 0 | 0 | 1 | 0 | 0 |
| Overall Study | Never Treated With ENTO | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 2 | 0 |
| Overall Study | Study terminated by sponsor | 0 | 27 | 0 | 1 | 1 | 5 | 3 | 4 | 0 |
| Overall Study | Treatment failure | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 1 | 0 |
| Overall Study | Withdrew consent | 3 | 6 | 1 | 2 | 2 | 0 | 0 | 8 | 6 |
Baseline characteristics
| Characteristic | Total | Group A Phase 1b ENTO 200 mg + Cytarabine + Daunorubicin | Group A Phase 1b/2 ENTO 400 mg + Cytarabine + Daunorubicin | Group B Phase 1b ENTO 200 mg + Decitabine | Group B Phase 1b ENTO 400 mg + Decitabine | Group B Phase 2 ENTO 400 mg + Azacitidine (Safety Run-In) | Group B Phase 2 ENTO 400 mg + Decitabine (Randomized) | Group B Phase 2 ENTO 400 mg + Azacitidine (Randomized) | Group C Phase 1b/2 ENTO 400 mg | Group C Phase 1b ENTO 800 mg |
|---|---|---|---|---|---|---|---|---|---|---|
| Age, Customized ≥ 65 years | 90 Participants | 0 Participants | 18 Participants | 5 Participants | 5 Participants | 7 Participants | 16 Participants | 14 Participants | 18 Participants | 7 Participants |
| Age, Customized < 65 Years | 55 Participants | 3 Participants | 32 Participants | 0 Participants | 1 Participants | 1 Participants | 1 Participants | 0 Participants | 17 Participants | 0 Participants |
| Race/Ethnicity, Customized Ethnicity Hispanic or Latino | 4 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants |
| Race/Ethnicity, Customized Ethnicity Not Hispanic or Latino | 137 Participants | 3 Participants | 48 Participants | 5 Participants | 6 Participants | 7 Participants | 15 Participants | 13 Participants | 33 Participants | 7 Participants |
| Race/Ethnicity, Customized Ethnicity Not Permitted | 4 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 2 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Asian | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Black or African American | 11 Participants | 0 Participants | 5 Participants | 2 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 2 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Not Permitted | 5 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 3 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Other | 3 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Race White/Caucasian | 125 Participants | 3 Participants | 44 Participants | 3 Participants | 6 Participants | 6 Participants | 14 Participants | 11 Participants | 31 Participants | 7 Participants |
| Region of Enrollment Canada | 10 Participants | 0 Participants | 4 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 6 Participants | 0 Participants |
| Region of Enrollment Germany | 5 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 3 Participants | 0 Participants | 0 Participants |
| Region of Enrollment United States | 130 Participants | 3 Participants | 46 Participants | 5 Participants | 6 Participants | 8 Participants | 15 Participants | 11 Participants | 29 Participants | 7 Participants |
| Sex: Female, Male Female | 61 Participants | 1 Participants | 21 Participants | 2 Participants | 2 Participants | 2 Participants | 7 Participants | 3 Participants | 18 Participants | 5 Participants |
| Sex: Female, Male Male | 84 Participants | 2 Participants | 29 Participants | 3 Participants | 4 Participants | 6 Participants | 10 Participants | 11 Participants | 17 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 3 | 21 / 50 | 5 / 5 | 4 / 6 | 5 / 8 | 12 / 17 | 11 / 14 | 30 / 35 | 6 / 7 |
| other Total, other adverse events | 3 / 3 | 50 / 50 | 5 / 5 | 6 / 6 | 7 / 8 | 17 / 17 | 14 / 14 | 33 / 35 | 7 / 7 |
| serious Total, serious adverse events | 0 / 3 | 23 / 50 | 5 / 5 | 5 / 6 | 7 / 8 | 11 / 17 | 7 / 14 | 19 / 35 | 4 / 7 |
Outcome results
Primary
Percentage of Participants Experiencing Dose Limiting Toxicities (DLTs)
DLTs refer to toxicities experienced during the first 28 days of study treatment that have been judged to be clinically significant and related to study treatment. DLT assessment was applicable only for Phase 1b and Phase 2 safety run-in participants.
Time frame: Group A: Cycle 0 Day 1 to Cycle 2 Day 28; Group B: Cycle 0 Day 1 to Cycle 1 Day 28; Group C: Cycle 1 Day 1 to Cycle 1 Day 28 (Cycle length: for Cycle 0 = 14 days, for all other cycles = 28 days)
Population: The DLT Analysis Set included all participants who received 21 days of ENTO (applicable to all groups) and all doses of cytarabine and daunorubicin in Group A Phase 1b, decitabine in Group B Phase 1b, or azacitidine in Group B Phase 2 safety run-in during the DLT assessment window; or experienced a DLT during the DLT assessment window.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group A Phase 1b ENTO 200 mg + Cytarabine + Daunorubicin | Percentage of Participants Experiencing Dose Limiting Toxicities (DLTs) | 0 percentage of participants |
| Group A Phase 1b/2 ENTO 400 mg + Cytarabine + Daunorubicin | Percentage of Participants Experiencing Dose Limiting Toxicities (DLTs) | 0 percentage of participants |
| Group B Phase 1b ENTO 200 mg + Decitabine | Percentage of Participants Experiencing Dose Limiting Toxicities (DLTs) | 0 percentage of participants |
| Group B Phase 1b ENTO 400 mg + Decitabine | Percentage of Participants Experiencing Dose Limiting Toxicities (DLTs) | 16.7 percentage of participants |
| Group B Phase 2 ENTO 400 mg + Azacitidine (Safety Run-In) | Percentage of Participants Experiencing Dose Limiting Toxicities (DLTs) | 0 percentage of participants |
| Group C Phase 1b/2 ENTO 400 mg | Percentage of Participants Experiencing Dose Limiting Toxicities (DLTs) | 0 percentage of participants |
| Group C Phase 1b ENTO 800 mg | Percentage of Participants Experiencing Dose Limiting Toxicities (DLTs) | 16.7 percentage of participants |
Primary
Percentage of Participants With Composite Complete Remission at the End of Induction
Clinical response was assessed according to the International Working Group criteria (Cheson 2003). Composite complete remission included CR, CRc, and morphologic complete remission with incomplete blood count recovery (CRi). CR required all of the following: \< 5% blasts in bone marrow aspirate; Neutrophils ≥ 1,000/mcL; Platelets ≥ 100,000/mcL; No extramedullary disease; No blasts with Auer rods detected; and Independent of transfusions. CRc, in addition to CR criteria, required reversion to a normal karyotype with an abnormal karyotype at the time of diagnosis. CRi required all of the CR criteria except the criterion of neutrophils and platelets.
Time frame: At the end of induction (Group A: up to end of Cycle 2; Group B: up to end of Cycle 4) (cycle length = up to 28 days); Group C: From Day 1 until meeting the criteria for study treatment discontinuation (up to approximately 3 years)
Population: Participants in the Full Analysis Set were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group A Phase 1b ENTO 200 mg + Cytarabine + Daunorubicin | Percentage of Participants With Composite Complete Remission at the End of Induction | 100.0 percentage of participants |
| Group A Phase 1b/2 ENTO 400 mg + Cytarabine + Daunorubicin | Percentage of Participants With Composite Complete Remission at the End of Induction | 77.8 percentage of participants |
| Group B Phase 1b ENTO 200 mg + Decitabine | Percentage of Participants With Composite Complete Remission at the End of Induction | 65.9 percentage of participants |
| Group B Phase 1b ENTO 400 mg + Decitabine | Percentage of Participants With Composite Complete Remission at the End of Induction | 40.0 percentage of participants |
| Group B Phase 2 ENTO 400 mg + Azacitidine (Safety Run-In) | Percentage of Participants With Composite Complete Remission at the End of Induction | 50.0 percentage of participants |
| Group C Phase 1b/2 ENTO 400 mg | Percentage of Participants With Composite Complete Remission at the End of Induction | 25.0 percentage of participants |
| Group C Phase 1b ENTO 800 mg | Percentage of Participants With Composite Complete Remission at the End of Induction | 23.5 percentage of participants |
| Group B Phase 2 ENTO 400 mg + Azacitidine (Randomized) | Percentage of Participants With Composite Complete Remission at the End of Induction | 14.3 percentage of participants |
| Group C Phase 1b ENTO 400 mg | Percentage of Participants With Composite Complete Remission at the End of Induction | 14.3 percentage of participants |
| Group C Phase 1b ENTO 800 mg | Percentage of Participants With Composite Complete Remission at the End of Induction | 0.0 percentage of participants |
| Group C Phase 2 ENTO 400 mg (Cohort C1A - R/R AML) | Percentage of Participants With Composite Complete Remission at the End of Induction | 0.0 percentage of participants |
| Group C Phase 2 ENTO 400 mg (Cohort C2 - MLL) | Percentage of Participants With Composite Complete Remission at the End of Induction | 15.4 percentage of participants |
| Group C Phase 2 ENTO 400 mg (Cohort C3 - Untreated AML) | Percentage of Participants With Composite Complete Remission at the End of Induction | 11.1 percentage of participants |
Primary
Percentage of Participants With Morphologic Complete Remission (CR) at the End of Induction
Clinical response was assessed according to the International Working Group criteria (Cheson 2003). Morphologic CR included CR and cytogenetic CR (CRc). CR required all of the following: \< 5% blasts in bone marrow aspirate; Neutrophils ≥ 1,000/microliter (mcL); Platelets ≥ 100,000/mcL; No extramedullary disease; No blasts with Auer rods detected; and Independent of transfusions. CRc, in addition to CR criteria, required reversion to a normal karyotype with an abnormal karyotype at the time of diagnosis.
Time frame: At the end of induction (Group A: up to end of Cycle 2; Group B: up to end of Cycle 4) (cycle length = up to 28 days); Group C: From Day 1 until meeting the criteria for study treatment discontinuation (up to approximately 3 years)
Population: The Full Analysis Set included all participants who received at least 1 dose of study drug with treatment designated according to the planned treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group A Phase 1b ENTO 200 mg + Cytarabine + Daunorubicin | Percentage of Participants With Morphologic Complete Remission (CR) at the End of Induction | 66.7 percentage of participants |
| Group A Phase 1b/2 ENTO 400 mg + Cytarabine + Daunorubicin | Percentage of Participants With Morphologic Complete Remission (CR) at the End of Induction | 66.7 percentage of participants |
| Group B Phase 1b ENTO 200 mg + Decitabine | Percentage of Participants With Morphologic Complete Remission (CR) at the End of Induction | 46.3 percentage of participants |
| Group B Phase 1b ENTO 400 mg + Decitabine | Percentage of Participants With Morphologic Complete Remission (CR) at the End of Induction | 0.0 percentage of participants |
| Group B Phase 2 ENTO 400 mg + Azacitidine (Safety Run-In) | Percentage of Participants With Morphologic Complete Remission (CR) at the End of Induction | 16.7 percentage of participants |
| Group C Phase 1b/2 ENTO 400 mg | Percentage of Participants With Morphologic Complete Remission (CR) at the End of Induction | 25.0 percentage of participants |
| Group C Phase 1b ENTO 800 mg | Percentage of Participants With Morphologic Complete Remission (CR) at the End of Induction | 0.0 percentage of participants |
| Group B Phase 2 ENTO 400 mg + Azacitidine (Randomized) | Percentage of Participants With Morphologic Complete Remission (CR) at the End of Induction | 7.1 percentage of participants |
| Group C Phase 1b ENTO 400 mg | Percentage of Participants With Morphologic Complete Remission (CR) at the End of Induction | 0.0 percentage of participants |
| Group C Phase 1b ENTO 800 mg | Percentage of Participants With Morphologic Complete Remission (CR) at the End of Induction | 0.0 percentage of participants |
| Group C Phase 2 ENTO 400 mg (Cohort C1A - R/R AML) | Percentage of Participants With Morphologic Complete Remission (CR) at the End of Induction | 0.0 percentage of participants |
| Group C Phase 2 ENTO 400 mg (Cohort C2 - MLL) | Percentage of Participants With Morphologic Complete Remission (CR) at the End of Induction | 15.4 percentage of participants |
| Group C Phase 2 ENTO 400 mg (Cohort C3 - Untreated AML) | Percentage of Participants With Morphologic Complete Remission (CR) at the End of Induction | 11.1 percentage of participants |
Primary
Percentage of Participants With Overall Response at the End of Induction
Clinical response was assessed according to the International Working Group criteria (Cheson 2003). Overall response included CR, CRc, CRi, and partial remission (PR). CR required all of the following: \< 5% blasts in bone marrow aspirate; Neutrophils ≥ 1,000/mcL; Platelets ≥ 100,000/mcL; No extramedullary disease; No blasts with Auer rods detected; and Independent of transfusions. CRc, in addition to CR criteria, required reversion to a normal karyotype with an abnormal karyotype at the time of diagnosis. CRi required all of the CR criteria except the criterion of neutrophils and platelets. PR required all of the following: ≥ 50% decrease in blasts in bone marrow aspirate to a range of 5% to 25%; Neutrophils ≥ 1,000/mcL; Platelets ≥ 100,000/mcL; Independent of transfusions; and A value of ≤ 5% blasts was also considered a PR if Auer rods were detected.
Time frame: At the end of induction (Group A: up to end of Cycle 2; Group B: up to end of Cycle 4) (cycle length = up to 28 days); Group C: From Day 1 until meeting the criteria for study treatment discontinuation (up to approximately 3 years)
Population: Participants in the Full Analysis Set were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group A Phase 1b ENTO 200 mg + Cytarabine + Daunorubicin | Percentage of Participants With Overall Response at the End of Induction | 100.0 percentage of participants |
| Group A Phase 1b/2 ENTO 400 mg + Cytarabine + Daunorubicin | Percentage of Participants With Overall Response at the End of Induction | 77.8 percentage of participants |
| Group B Phase 1b ENTO 200 mg + Decitabine | Percentage of Participants With Overall Response at the End of Induction | 70.7 percentage of participants |
| Group B Phase 1b ENTO 400 mg + Decitabine | Percentage of Participants With Overall Response at the End of Induction | 40.0 percentage of participants |
| Group B Phase 2 ENTO 400 mg + Azacitidine (Safety Run-In) | Percentage of Participants With Overall Response at the End of Induction | 50.0 percentage of participants |
| Group C Phase 1b/2 ENTO 400 mg | Percentage of Participants With Overall Response at the End of Induction | 25.0 percentage of participants |
| Group C Phase 1b ENTO 800 mg | Percentage of Participants With Overall Response at the End of Induction | 23.5 percentage of participants |
| Group B Phase 2 ENTO 400 mg + Azacitidine (Randomized) | Percentage of Participants With Overall Response at the End of Induction | 14.3 percentage of participants |
| Group C Phase 1b ENTO 400 mg | Percentage of Participants With Overall Response at the End of Induction | 14.3 percentage of participants |
| Group C Phase 1b ENTO 800 mg | Percentage of Participants With Overall Response at the End of Induction | 0.0 percentage of participants |
| Group C Phase 2 ENTO 400 mg (Cohort C1A - R/R AML) | Percentage of Participants With Overall Response at the End of Induction | 0.0 percentage of participants |
| Group C Phase 2 ENTO 400 mg (Cohort C2 - MLL) | Percentage of Participants With Overall Response at the End of Induction | 15.4 percentage of participants |
| Group C Phase 2 ENTO 400 mg (Cohort C3 - Untreated AML) | Percentage of Participants With Overall Response at the End of Induction | 11.1 percentage of participants |
Secondary
Duration of Exposure of Entospletinib
Time frame: First dose date up to approximately 3 years
Population: The Safety Analysis Set included all participants who received at least 1 dose of study drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group A Phase 1b ENTO 200 mg + Cytarabine + Daunorubicin | Duration of Exposure of Entospletinib | 8.6 weeks |
| Group A Phase 1b/2 ENTO 400 mg + Cytarabine + Daunorubicin | Duration of Exposure of Entospletinib | 7.1 weeks |
| Group B Phase 1b ENTO 200 mg + Decitabine | Duration of Exposure of Entospletinib | 13.7 weeks |
| Group B Phase 1b ENTO 400 mg + Decitabine | Duration of Exposure of Entospletinib | 15.4 weeks |
| Group B Phase 2 ENTO 400 mg + Azacitidine (Safety Run-In) | Duration of Exposure of Entospletinib | 10.1 weeks |
| Group C Phase 1b/2 ENTO 400 mg | Duration of Exposure of Entospletinib | 13.9 weeks |
| Group C Phase 1b ENTO 800 mg | Duration of Exposure of Entospletinib | 10.1 weeks |
| Group B Phase 2 ENTO 400 mg + Azacitidine (Randomized) | Duration of Exposure of Entospletinib | 4.4 weeks |
| Group C Phase 1b ENTO 400 mg | Duration of Exposure of Entospletinib | 7.6 weeks |
Secondary
Event Free Survival (EFS)
EFS was defined as the time interval from the start of the study therapy until the date of treatment failure, acute myeloid leukemia (AML) relapse, or death from any cause, whichever occurred first. Participants who received other anti-cancer therapy (prior to the event if any) were censored. Median EFS was analyzed using Kaplan-Meier (KM) method.
Time frame: First dose date up to approximately 38 months
Population: Participants in the Full Analysis Set were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group A Phase 1b ENTO 200 mg + Cytarabine + Daunorubicin | Event Free Survival (EFS) | NA months |
| Group A Phase 1b/2 ENTO 400 mg + Cytarabine + Daunorubicin | Event Free Survival (EFS) | 1.9 months |
| Group B Phase 1b ENTO 200 mg + Decitabine | Event Free Survival (EFS) | 9.0 months |
| Group B Phase 1b ENTO 400 mg + Decitabine | Event Free Survival (EFS) | 2.2 months |
| Group B Phase 2 ENTO 400 mg + Azacitidine (Safety Run-In) | Event Free Survival (EFS) | 2.9 months |
| Group C Phase 1b/2 ENTO 400 mg | Event Free Survival (EFS) | 2.3 months |
| Group C Phase 1b ENTO 800 mg | Event Free Survival (EFS) | 3.2 months |
| Group B Phase 2 ENTO 400 mg + Azacitidine (Randomized) | Event Free Survival (EFS) | 2.4 months |
| Group C Phase 1b ENTO 400 mg | Event Free Survival (EFS) | 1.8 months |
| Group C Phase 1b ENTO 800 mg | Event Free Survival (EFS) | 1.8 months |
| Group C Phase 2 ENTO 400 mg (Cohort C1A - R/R AML) | Event Free Survival (EFS) | 1.0 months |
| Group C Phase 2 ENTO 400 mg (Cohort C2 - MLL) | Event Free Survival (EFS) | 1.0 months |
| Group C Phase 2 ENTO 400 mg (Cohort C3 - Untreated AML) | Event Free Survival (EFS) | 1.7 months |
Secondary
Overall Survival (OS)
OS was defined as the time interval from the start of the study therapy to death from any cause. Median OS was analyzed using KM method.
Time frame: First dose date up to approximately 38 months
Population: Participants in the Full Analysis Set were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group A Phase 1b ENTO 200 mg + Cytarabine + Daunorubicin | Overall Survival (OS) | 37.1 months |
| Group A Phase 1b/2 ENTO 400 mg + Cytarabine + Daunorubicin | Overall Survival (OS) | 34.1 months |
| Group B Phase 1b ENTO 200 mg + Decitabine | Overall Survival (OS) | NA months |
| Group B Phase 1b ENTO 400 mg + Decitabine | Overall Survival (OS) | 3.2 months |
| Group B Phase 2 ENTO 400 mg + Azacitidine (Safety Run-In) | Overall Survival (OS) | 5.3 months |
| Group C Phase 1b/2 ENTO 400 mg | Overall Survival (OS) | 6.9 months |
| Group C Phase 1b ENTO 800 mg | Overall Survival (OS) | 7.3 months |
| Group B Phase 2 ENTO 400 mg + Azacitidine (Randomized) | Overall Survival (OS) | 6.2 months |
| Group C Phase 1b ENTO 400 mg | Overall Survival (OS) | 5.9 months |
| Group C Phase 1b ENTO 800 mg | Overall Survival (OS) | 5.6 months |
| Group C Phase 2 ENTO 400 mg (Cohort C1A - R/R AML) | Overall Survival (OS) | 8.2 months |
| Group C Phase 2 ENTO 400 mg (Cohort C2 - MLL) | Overall Survival (OS) | 7.9 months |
| Group C Phase 2 ENTO 400 mg (Cohort C3 - Untreated AML) | Overall Survival (OS) | 2.2 months |
Secondary
Percentage of Participants Experiencing Treatment-Emergent Adverse Events
Time frame: First dose date up to the last dose date plus 30 days (maximum: 18 months)
Population: Participants in the Safety Analysis Set were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group A Phase 1b ENTO 200 mg + Cytarabine + Daunorubicin | Percentage of Participants Experiencing Treatment-Emergent Adverse Events | 100.0 percentage of participants |
| Group A Phase 1b/2 ENTO 400 mg + Cytarabine + Daunorubicin | Percentage of Participants Experiencing Treatment-Emergent Adverse Events | 100.0 percentage of participants |
| Group B Phase 1b ENTO 200 mg + Decitabine | Percentage of Participants Experiencing Treatment-Emergent Adverse Events | 100.0 percentage of participants |
| Group B Phase 1b ENTO 400 mg + Decitabine | Percentage of Participants Experiencing Treatment-Emergent Adverse Events | 100.0 percentage of participants |
| Group B Phase 2 ENTO 400 mg + Azacitidine (Safety Run-In) | Percentage of Participants Experiencing Treatment-Emergent Adverse Events | 100.0 percentage of participants |
| Group C Phase 1b/2 ENTO 400 mg | Percentage of Participants Experiencing Treatment-Emergent Adverse Events | 100.0 percentage of participants |
| Group C Phase 1b ENTO 800 mg | Percentage of Participants Experiencing Treatment-Emergent Adverse Events | 100.0 percentage of participants |
| Group B Phase 2 ENTO 400 mg + Azacitidine (Randomized) | Percentage of Participants Experiencing Treatment-Emergent Adverse Events | 100.0 percentage of participants |
| Group C Phase 1b ENTO 400 mg | Percentage of Participants Experiencing Treatment-Emergent Adverse Events | 100.0 percentage of participants |
Secondary
Percentage of Participants Who Experienced Laboratory Abnormalities
Treatment-emergent laboratory abnormalities were defined as values that increase at least one toxicity grade from baseline. The most severe graded abnormality from all tests was counted for each participant.
Time frame: First dose date up to the last dose date plus 30 days (maximum: 18 months)
Population: Participants in the Safety Analysis Set who had non-missing postbaseline value prior to or on the last dosing date plus 30 days were analyzed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Group A Phase 1b ENTO 200 mg + Cytarabine + Daunorubicin | Percentage of Participants Who Experienced Laboratory Abnormalities | Grade 3 or 4 Laboratory Abnormalities | 100 percentage of participants |
| Group A Phase 1b ENTO 200 mg + Cytarabine + Daunorubicin | Percentage of Participants Who Experienced Laboratory Abnormalities | Any Laboratory Abnormality | 100 percentage of participants |
| Group A Phase 1b/2 ENTO 400 mg + Cytarabine + Daunorubicin | Percentage of Participants Who Experienced Laboratory Abnormalities | Grade 3 or 4 Laboratory Abnormalities | 98.0 percentage of participants |
| Group A Phase 1b/2 ENTO 400 mg + Cytarabine + Daunorubicin | Percentage of Participants Who Experienced Laboratory Abnormalities | Any Laboratory Abnormality | 100 percentage of participants |
| Group B Phase 1b ENTO 200 mg + Decitabine | Percentage of Participants Who Experienced Laboratory Abnormalities | Any Laboratory Abnormality | 100 percentage of participants |
| Group B Phase 1b ENTO 200 mg + Decitabine | Percentage of Participants Who Experienced Laboratory Abnormalities | Grade 3 or 4 Laboratory Abnormalities | 100 percentage of participants |
| Group B Phase 1b ENTO 400 mg + Decitabine | Percentage of Participants Who Experienced Laboratory Abnormalities | Grade 3 or 4 Laboratory Abnormalities | 100 percentage of participants |
| Group B Phase 1b ENTO 400 mg + Decitabine | Percentage of Participants Who Experienced Laboratory Abnormalities | Any Laboratory Abnormality | 100 percentage of participants |
| Group B Phase 2 ENTO 400 mg + Azacitidine (Safety Run-In) | Percentage of Participants Who Experienced Laboratory Abnormalities | Any Laboratory Abnormality | 100 percentage of participants |
| Group B Phase 2 ENTO 400 mg + Azacitidine (Safety Run-In) | Percentage of Participants Who Experienced Laboratory Abnormalities | Grade 3 or 4 Laboratory Abnormalities | 85.7 percentage of participants |
| Group C Phase 1b/2 ENTO 400 mg | Percentage of Participants Who Experienced Laboratory Abnormalities | Grade 3 or 4 Laboratory Abnormalities | 94.1 percentage of participants |
| Group C Phase 1b/2 ENTO 400 mg | Percentage of Participants Who Experienced Laboratory Abnormalities | Any Laboratory Abnormality | 94.1 percentage of participants |
| Group C Phase 1b ENTO 800 mg | Percentage of Participants Who Experienced Laboratory Abnormalities | Any Laboratory Abnormality | 100 percentage of participants |
| Group C Phase 1b ENTO 800 mg | Percentage of Participants Who Experienced Laboratory Abnormalities | Grade 3 or 4 Laboratory Abnormalities | 92.9 percentage of participants |
| Group B Phase 2 ENTO 400 mg + Azacitidine (Randomized) | Percentage of Participants Who Experienced Laboratory Abnormalities | Any Laboratory Abnormality | 100 percentage of participants |
| Group B Phase 2 ENTO 400 mg + Azacitidine (Randomized) | Percentage of Participants Who Experienced Laboratory Abnormalities | Grade 3 or 4 Laboratory Abnormalities | 82.9 percentage of participants |
| Group C Phase 1b ENTO 400 mg | Percentage of Participants Who Experienced Laboratory Abnormalities | Any Laboratory Abnormality | 100 percentage of participants |
| Group C Phase 1b ENTO 400 mg | Percentage of Participants Who Experienced Laboratory Abnormalities | Grade 3 or 4 Laboratory Abnormalities | 85.7 percentage of participants |