Japanese AML: Entospletinib (ENTO) as Monotherapy and in Combination With Chemotherapy in Japanese Adults
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 1 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: ENTO monotherapy (Group A) Participants with relapsed or refractory hematologic malignancies will receive ENTO twice daily of every 28-day cycle until participants meet treatment discontinuation criteria or do not experience clinical benefit. |
Drug: Entospletinib
400 mg (2 × 200 mg tablets) orally twice daily
Other Names:
|
| Experimental: ENTO + cytarabine + daunorubicin (Group B) Lead-in (Cycle 0): Participants with previously untreated AML will receive ENTO twice daily for 14 days. Induction (Up to 2 cycles): ENTO in combination with daunorubicin and cytarabine for up to two 28-day cycles. Post-remission chemotherapy (at least 2 cycles, up to 4 cycles): Some participants (who have achieved complete remission [CR] or morphologic complete remission with incomplete blood count recovery [CRi] and do not require or cannot proceed to allogeneic stem cell transplantation [SCT] and participants who are awaiting a donor or transitioning to allogeneic SCT per investigator discretion) will have the option to receive post-remission chemotherapy with ENTO twice daily in combination with high-dose cytarabine (Hi-DAC) for up to four 28-day cycles. |
Drug: Entospletinib
400 mg (2 × 200 mg tablets) orally twice daily
Other Names:
Drug: Daunorubicin
60 mg/m^2 administered intravenously daily on Days 1 to 3 of each 28-day induction cycle
Drug: Cytarabine
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
|
Outcome Measures
Primary Outcome Measures
- 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 Outcome Measures
- 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.
Eligibility Criteria
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/ Exclusion criteria may apply.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | University of Fukui Hospital | Fukui | Japan | 910-1193 | |
| 2 | Kyushu University Hospital | Fukuoka | Japan | 812-8582 | |
| 3 | Tokai University Hospital | Kanagawa | Japan | 259-1193 | |
| 4 | Tohoku University Hospital | Miyagi | Japan | 980-8574 | |
| 5 | NTT Medical Center Tokyo | Tokyo | Japan | 141-8625 | |
| 6 | Kindai University Hospital | Ōsaka | Japan | 589-8511 |
Sponsors and Collaborators
- Gilead Sciences
Investigators
- Study Director: Gilead Study Director, Gilead Sciences
Study Documents (Full-Text)
More Information
Publications
None provided.- GS-US-429-4104
Study Results
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 Detail | 13 participants were screened. |
| Arm/Group Title | ENTO 400 mg |
|---|---|
| Arm/Group Description | Participants received entospletinib (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. |
| Period Title: Overall Study | |
| STARTED | 9 |
| COMPLETED | 0 |
| NOT COMPLETED | 9 |
Baseline Characteristics
| Arm/Group Title | ENTO 400 mg |
|---|---|
| Arm/Group Description | 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. |
| Overall Participants | 9 |
| Age (years) [Mean (Standard Deviation) ] | |
| Mean (Standard Deviation) [years] |
71
(8.3)
|
| Sex: Female, Male (Count of Participants) | |
| Female |
4
44.4%
|
| Male |
5
55.6%
|
| Race/Ethnicity, Customized (Count of Participants) | |
| American Indian or Alaska Native |
0
0%
|
| Asian |
8
88.9%
|
| Black |
0
0%
|
| Native Hawaiian or Other Pacific Islander |
0
0%
|
| White |
0
0%
|
| Not Permitted |
0
0%
|
| Other |
1
11.1%
|
| Race/Ethnicity, Customized (Count of Participants) | |
| Hispanic or Latino |
0
0%
|
| Not Hispanic or Latino |
9
100%
|
| Not Permitted |
0
0%
|
Outcome Measures
| Title | Percentage of Participants With Adverse Events (AEs) and Laboratory Abnormalities Defined as Dose Limiting Toxicities (DLT) |
|---|---|
| Description | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | ENTO 400 mg |
|---|---|
| Arm/Group Description | 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. |
| Measure Participants | 6 |
| Number [percentage of participants] |
0.0
0%
|
| Title | Percentage of Participants With AEs and Laboratory Abnormalities Not Defined as DLT |
|---|---|
| Description | |
| Time Frame | Day 1 Up to 30 days after permanent discontinuation of study treatment (maximum approximately 80 weeks) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Full Analysis Set included all participants who received at least 1 dose of study drug (ENTO). |
| Arm/Group Title | ENTO 400 mg |
|---|---|
| Arm/Group Description | 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. |
| Measure Participants | 9 |
| Number [percentage of participants] |
100.0
1111.1%
|
| Title | Plasma Concentration of ENTO |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | ENTO 400 mg |
|---|---|
| Arm/Group Description | 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. |
| Measure Participants | 7 |
| Cycle 1 Day 8, predose |
921.9
(610.47)
|
| Cycle 1 Day 8, 1 hour postdose |
1395.7
(1081.40)
|
| Cycle 1 Day 8, 2 hours postdose |
1892.7
(1285.08)
|
| Cycle 1 Day 8, 3 hours postdose |
1529.1
(994.69)
|
| Cycle 1 Day 8, 4 hours postdose |
1350.0
(862.21)
|
| Cycle 1 Day 8, 6 hours postdose |
1139.3
(709.22)
|
| Cycle 1 Day 8, 8 hours postdose |
1075.9
(659.08)
|
| Cycle 1 Day 8, 12 hours postdose |
855.1
(568.18)
|
Adverse Events
| Time Frame | Day 1 up to 30 days after permanent discontinuation of study treatment (maximum approximately 80 weeks) | |
|---|---|---|
| Adverse Event Reporting Description | Full Analysis Set included all participants who received at least 1 dose of study drug (ENTO). | |
| Arm/Group Title | ENTO 400 mg | |
| Arm/Group Description | 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. | |
All Cause Mortality |
||
| ENTO 400 mg | ||
| Affected / at Risk (%) | # Events | |
| Total | 6/9 (66.7%) | |
Serious Adverse Events |
||
| ENTO 400 mg | ||
| Affected / at Risk (%) | # Events | |
| Total | 4/9 (44.4%) | |
| Blood and lymphatic system disorders | ||
| Anaemia | 1/9 (11.1%) | |
| Eye disorders | ||
| Cataract | 1/9 (11.1%) | |
| Choroidal haemorrhage | 1/9 (11.1%) | |
| General disorders | ||
| Pyrexia | 1/9 (11.1%) | |
| Hepatobiliary disorders | ||
| Hepatic function abnormal | 1/9 (11.1%) | |
| Infections and infestations | ||
| Clostridium difficile colitis | 1/9 (11.1%) | |
| Enterococcal infection | 1/9 (11.1%) | |
| Pneumonia | 1/9 (11.1%) | |
| Injury, poisoning and procedural complications | ||
| Hyphaema | 1/9 (11.1%) | |
| Metabolism and nutrition disorders | ||
| Diabetes mellitus | 1/9 (11.1%) | |
Other (Not Including Serious) Adverse Events |
||
| ENTO 400 mg | ||
| Affected / at Risk (%) | # Events | |
| Total | 9/9 (100%) | |
| Blood and lymphatic system disorders | ||
| Anaemia | 1/9 (11.1%) | |
| Disseminated intravascular coagulation | 1/9 (11.1%) | |
| Febrile neutropenia | 1/9 (11.1%) | |
| Cardiac disorders | ||
| Tachycardia | 1/9 (11.1%) | |
| Eye disorders | ||
| Cataract | 1/9 (11.1%) | |
| Conjunctival haemorrhage | 1/9 (11.1%) | |
| Glaucoma | 1/9 (11.1%) | |
| Gastrointestinal disorders | ||
| Abdominal pain | 1/9 (11.1%) | |
| Constipation | 1/9 (11.1%) | |
| Diarrhoea | 3/9 (33.3%) | |
| Dry mouth | 1/9 (11.1%) | |
| Gingival bleeding | 1/9 (11.1%) | |
| Melaena | 1/9 (11.1%) | |
| Nausea | 4/9 (44.4%) | |
| Stomatitis | 2/9 (22.2%) | |
| Vomiting | 3/9 (33.3%) | |
| General disorders | ||
| Oedema | 1/9 (11.1%) | |
| Oedema peripheral | 1/9 (11.1%) | |
| Pyrexia | 2/9 (22.2%) | |
| Infections and infestations | ||
| Nasopharyngitis | 1/9 (11.1%) | |
| Oral herpes | 1/9 (11.1%) | |
| Pneumonia | 1/9 (11.1%) | |
| Urinary tract infection | 1/9 (11.1%) | |
| Injury, poisoning and procedural complications | ||
| Allergic transfusion reaction | 1/9 (11.1%) | |
| Skin abrasion | 1/9 (11.1%) | |
| Investigations | ||
| Alanine aminotransferase increased | 4/9 (44.4%) | |
| Amylase increased | 1/9 (11.1%) | |
| Aspartate aminotransferase increased | 3/9 (33.3%) | |
| Blood bilirubin increased | 2/9 (22.2%) | |
| Blood lactate dehydrogenase increased | 1/9 (11.1%) | |
| Lipase increased | 1/9 (11.1%) | |
| Platelet count decreased | 1/9 (11.1%) | |
| White blood cell count decreased | 1/9 (11.1%) | |
| Metabolism and nutrition disorders | ||
| Dehydration | 1/9 (11.1%) | |
| Hyperammonaemia | 1/9 (11.1%) | |
| Hypercalcaemia | 1/9 (11.1%) | |
| Hyperchloraemia | 1/9 (11.1%) | |
| Hyperuricaemia | 1/9 (11.1%) | |
| Hypoalbuminaemia | 2/9 (22.2%) | |
| Hypocalcaemia | 1/9 (11.1%) | |
| Hypokalaemia | 2/9 (22.2%) | |
| Musculoskeletal and connective tissue disorders | ||
| Back pain | 1/9 (11.1%) | |
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||
| Cancer pain | 1/9 (11.1%) | |
| Tumour associated fever | 1/9 (11.1%) | |
| Nervous system disorders | ||
| Headache | 1/9 (11.1%) | |
| Seizure | 1/9 (11.1%) | |
| Psychiatric disorders | ||
| Delirium | 3/9 (33.3%) | |
| Insomnia | 2/9 (22.2%) | |
| Renal and urinary disorders | ||
| Renal impairment | 1/9 (11.1%) | |
| Respiratory, thoracic and mediastinal disorders | ||
| Dyspnoea | 1/9 (11.1%) | |
| Epistaxis | 2/9 (22.2%) | |
| Hiccups | 1/9 (11.1%) | |
| Oropharyngeal pain | 1/9 (11.1%) | |
| Pneumonitis | 1/9 (11.1%) | |
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
After conclusion of the study and without prior written approval from Gilead, investigators in this study may communicate, orally present, or publish in scientific journals or other media only after the following conditions have been met: The results of the study in their entirety have been publicly disclosed by or with the consent of Gilead in an abstract, manuscript, or presentation form; or The study has been completed at all study sites for at least 2 years
Results Point of Contact
| Name/Title | Gilead Clinical Study Information Center |
|---|---|
| Organization | Gilead Sciences |
| Phone | 1-833-445-3230 (GILEAD-0) |
| GileadClinicalTrials@gilead.com |
- GS-US-429-4104