Entospletinib (ENTO) as Monotherapy and in Combination With Chemotherapy in Japanese Adults

Phase 1

Terminated

Conditions: Acute Myeloid Leukemia
Hematologic Malignancy

Interventions: Drug: Entospletinib
Drug: Daunorubicin
Drug: Cytarabine

Registration Number: NCT03135028

Lead Sponsor: Gilead Sciences

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.

Detailed Description: Not available

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 9

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
ENTO + cytarabine + daunorubicin (Group B)	Daunorubicin	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.
ENTO + cytarabine + daunorubicin (Group B)	Cytarabine	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.
ENTO monotherapy (Group A)	Entospletinib	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.
ENTO + cytarabine + daunorubicin (Group B)	Entospletinib	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.

Primary Outcome Measures

Name	Time	Method
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

Name	Time	Method
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.

Trial Locations

Locations (6): University of Fukui Hospital
🇯🇵
Fukui, Japan
Tokai University Hospital
🇯🇵
Kanagawa, Japan
Tohoku University Hospital
🇯🇵
Miyagi, Japan
Kindai University Hospital
🇯🇵
Ōsaka, Japan
NTT Medical Center Tokyo
🇯🇵
Tokyo, Japan
Kyushu University Hospital
🇯🇵
Fukuoka, Japan