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

A Phase 1b Study to Investigate the Safety, Tolerability, and Pharmacokinetics of Entospletinib (ENTO) as Monotherapy in Japanese Subjects With Relapsed or Refractory Hematologic Malignancies and in Combination With Chemotherapy in Japanese Subjects With Previously Untreated Acute Myeloid Leukemia (AML)

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.

Study Overview

• Status: Terminated
• Conditions: Acute Myeloid Leukemia; Hematologic Malignancy
• Intervention / Treatment: Drug: Entospletinib; Drug: Daunorubicin; Drug: Cytarabine

• Study Type: Interventional
• Enrollment (Actual): 9
• Phase: Phase 1

Contacts and Locations

Study Locations

• Japan
  • Fukui, Japan, 910-1193
    • University of Fukui Hospital
  • Fukuoka, Japan, 812-8582
    • Kyushu University Hospital
  • Kanagawa, Japan, 259-1193
    • Tokai University Hospital
  • Miyagi, Japan, 980-8574
    • Tohoku University Hospital
  • Tokyo, Japan, 141-8625
    • NTT Medical Center Tokyo
  • Ōsaka, Japan, 589-8511
    • Kindai University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / 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: GS-9973; ENTO
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: GS-9973; ENTO; 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Cycle 1 (28-day cycle)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	Plasma concentration of drug (ENTO) over different time points is reported.	Cycle 1 (28-days cycle) Day 8 at 0 (predose), 1, 2, 3, 4, 6, 8, and 12 hours postdose

Collaborators and Investigators

• Sponsor: Gilead Sciences

Study record dates

Study Major Dates

• Study Start (Actual): May 19, 2017
• Primary Completion (Actual): February 26, 2019
• Study Completion (Actual): February 26, 2019

Study Registration Dates

• First Submitted: April 26, 2017
• First Submitted That Met QC Criteria: April 26, 2017
• First Posted (Actual): May 1, 2017

Study Record Updates

• Last Update Posted (Actual): March 6, 2020
• Last Update Submitted That Met QC Criteria: February 21, 2020
• Last Verified: February 1, 2020

More Information

Terms related to this study

• Keywords: Relapsed or Refractory Hematologic Malignancy; Previously untreated AML
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms by Site; Hematologic Diseases; Neoplasms; Hematologic Neoplasms; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antibiotics, Antineoplastic; Cytarabine; Daunorubicin
• Other Study ID Numbers: GS-US-429-4104

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes