Hematologic Malignancy, Acute Myeloid Leukemia
Conditions
Keywords
Relapsed or Refractory Hematologic Malignancy, Previously untreated AML
Brief summary
The primary objective of this study is to evaluate the safety and tolerability of entospletinib (ENTO) monotherapy and in combination with chemotherapy in Japanese participants.
Interventions
DRUGEntospletinib
400 mg (2 × 200 mg tablets) orally twice daily
DRUGDaunorubicin
60 mg/m\^2 administered intravenously daily on Days 1 to 3 of each 28-day induction cycle
DRUGCytarabine
100 mg/m\^2 intravenous administration twice daily on Days 1 to 7 of each 28-day induction cycle Hi-DAC: 3 g/m\^2 IV administration twice daily on days 1, 3, and 5 (≤ 60 years of age) or 1 g/m\^2 IV administration once daily on Days 1 to 5 (\> 60 years of age) of each 28-day post-remission cycle
Sponsors
Gilead Sciences
Study design
Allocation
NON_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: * ENTO monotherapy (Group A): relapsed or refractory hematologic malignancies by World Health Organisation (WHO) criteria and who are not eligible to receive standard of care * ENTO + cytarabine + daunorubicin (Group B): previously untreated AML by WHO criteria, who are deemed fit for cytarabine and daunorubicin (7+3) induction chemotherapy and are able to undergo up to 2 cycles of induction chemotherapy, as determined by the treating physician * Must have been born in Japan and must not have lived outside of Japan for a period \> 1 year in the 5 years prior to Day 1 of study treatment * Must be able to confirm the Japanese origin of their maternal and paternal ancestry Key
Exclusion criteria
* Known active central nervous system or leptomeningeal leukemic involvement * Ongoing liver injury, or known infection with chronic active hepatitis C virus (HCV) or chronic active hepatitis B virus (HBV) NOTE: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Adverse Events (AEs) and Laboratory Abnormalities Defined as Dose Limiting Toxicities (DLT) | Cycle 1 (28-day cycle) | Occurrence of any of the following toxicities, attributable to ENTO, during Cycle 1 was considered DLT: * Grade 4 non-hematologic toxicity except alopecia, nausea, and vomiting controllable with anti-emetic therapy, line associated venous thrombosis, infection-related toxicities such as fever/sepsis, and fatigue. * In participants without bone marrow evidence of hematologic malignancy, hematologic toxicity defined as failure to recover absolute neutrophil count (ANC \> 500/μL) or platelet count (\>25000/μL) within 28 days * Grade 4, clinically significant, electrolyte abnormalities that were not correctable within 24 hours * Liver function test abnormalities that did not resolve to Grade 2 within 10 days * Infection that resulted from unexpectedly complicated prolonged myelosuppression * Toxicities that required temporary interruption of treatment and did not resolve to Grade 2 within 10 days or ENTO was suspended or dose reduced for a period of more than 10 days. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With AEs and Laboratory Abnormalities Not Defined as DLT | Day 1 Up to 30 days after permanent discontinuation of study treatment (maximum approximately 80 weeks) | — |
| Plasma Concentration of ENTO | Cycle 1 (28-days cycle) Day 8 at 0 (predose), 1, 2, 3, 4, 6, 8, and 12 hours postdose | Plasma concentration of drug (ENTO) over different time points is reported. |
Countries
Japan
Participant flow
Recruitment details
Participants were enrolled at study sites in Japan. The first participant was screened on 19 May 2017. The last study visit occurred on 26 February 2019.
Pre-assignment details
13 participants were screened.
Participants by arm
| Arm | Count |
|---|---|
| ENTO 400 mg Participants received ENTO 400 mg (2 × 200 mg tablets) orally twice daily in a fasted state on Days 1 through 28 of every 28-day cycle, and continued on study treatment as long as the participant experienced benefit and did not meet the criteria for study treatment discontinuation. | 9 |
| Total | 9 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 6 |
| Overall Study | Study Terminated by Sponsor | 2 |
| Overall Study | Withdrew Consent | 1 |
Baseline characteristics
| Characteristic | ENTO 400 mg |
|---|---|
| Age, Continuous | 71 years STANDARD_DEVIATION 8.3 |
| Race/Ethnicity, Customized Ethnicity Hispanic or Latino | 0 Participants |
| Race/Ethnicity, Customized Ethnicity Not Hispanic or Latino | 9 Participants |
| Race/Ethnicity, Customized Ethnicity Not Permitted | 0 Participants |
| Race/Ethnicity, Customized Race American Indian or Alaska Native | 0 Participants |
| Race/Ethnicity, Customized Race Asian | 8 Participants |
| Race/Ethnicity, Customized Race Black | 0 Participants |
| Race/Ethnicity, Customized Race Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race/Ethnicity, Customized Race Not Permitted | 0 Participants |
| Race/Ethnicity, Customized Race Other | 1 Participants |
| Race/Ethnicity, Customized Race White | 0 Participants |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 6 / 9 |
| other Total, other adverse events | 9 / 9 |
| serious Total, serious adverse events | 4 / 9 |
Outcome results
Primary
Percentage of Participants With Adverse Events (AEs) and Laboratory Abnormalities Defined as Dose Limiting Toxicities (DLT)
Occurrence of any of the following toxicities, attributable to ENTO, during Cycle 1 was considered DLT: * Grade 4 non-hematologic toxicity except alopecia, nausea, and vomiting controllable with anti-emetic therapy, line associated venous thrombosis, infection-related toxicities such as fever/sepsis, and fatigue. * In participants without bone marrow evidence of hematologic malignancy, hematologic toxicity defined as failure to recover absolute neutrophil count (ANC \> 500/μL) or platelet count (\>25000/μL) within 28 days * Grade 4, clinically significant, electrolyte abnormalities that were not correctable within 24 hours * Liver function test abnormalities that did not resolve to Grade 2 within 10 days * Infection that resulted from unexpectedly complicated prolonged myelosuppression * Toxicities that required temporary interruption of treatment and did not resolve to Grade 2 within 10 days or ENTO was suspended or dose reduced for a period of more than 10 days.
Time frame: Cycle 1 (28-day cycle)
Population: The DLT Analysis Set included all participants in the Full Analysis Set (all participants who received at least 1 dose of study drug \[ENTO\]) who received at least 21 days of ENTO or experienced a DLT during DLT assessment window.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ENTO 400 mg | Percentage of Participants With Adverse Events (AEs) and Laboratory Abnormalities Defined as Dose Limiting Toxicities (DLT) | 0.0 percentage of participants |
Secondary
Percentage of Participants With AEs and Laboratory Abnormalities Not Defined as DLT
Time frame: Day 1 Up to 30 days after permanent discontinuation of study treatment (maximum approximately 80 weeks)
Population: Full Analysis Set included all participants who received at least 1 dose of study drug (ENTO).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ENTO 400 mg | Percentage of Participants With AEs and Laboratory Abnormalities Not Defined as DLT | 100.0 percentage of participants |
Secondary
Plasma Concentration of ENTO
Plasma concentration of drug (ENTO) over different time points is reported.
Time frame: Cycle 1 (28-days cycle) Day 8 at 0 (predose), 1, 2, 3, 4, 6, 8, and 12 hours postdose
Population: Pharmacokinetic (PK) Analysis Set included all participants in the Full Analysis Set who had necessary baseline and at least 1 non-missing post-treatment assessments. Participants with available data were analyzed. PK parameters were not derived from the collected data due to the early study termination.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ENTO 400 mg | Plasma Concentration of ENTO | Cycle 1 Day 8, 4 hours postdose | 1350.0 ng/mL | Standard Deviation 862.21 |
| ENTO 400 mg | Plasma Concentration of ENTO | Cycle 1 Day 8, predose | 921.9 ng/mL | Standard Deviation 610.47 |
| ENTO 400 mg | Plasma Concentration of ENTO | Cycle 1 Day 8, 1 hour postdose | 1395.7 ng/mL | Standard Deviation 1081.4 |
| ENTO 400 mg | Plasma Concentration of ENTO | Cycle 1 Day 8, 2 hours postdose | 1892.7 ng/mL | Standard Deviation 1285.08 |
| ENTO 400 mg | Plasma Concentration of ENTO | Cycle 1 Day 8, 3 hours postdose | 1529.1 ng/mL | Standard Deviation 994.69 |
| ENTO 400 mg | Plasma Concentration of ENTO | Cycle 1 Day 8, 6 hours postdose | 1139.3 ng/mL | Standard Deviation 709.22 |
| ENTO 400 mg | Plasma Concentration of ENTO | Cycle 1 Day 8, 8 hours postdose | 1075.9 ng/mL | Standard Deviation 659.08 |
| ENTO 400 mg | Plasma Concentration of ENTO | Cycle 1 Day 8, 12 hours postdose | 855.1 ng/mL | Standard Deviation 568.18 |