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

Study Overview
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Brief Summary
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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.

Official Title
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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)

Conditions
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Hematologic Malignancy, Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: Entospletinib
* Drug: Daunorubicin
* Drug: Cytarabine


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ENTO monotherapy (Group A)<br>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<br>* 400 mg (2 × 200 mg tablets) orally twice daily<br>* Other names: ENTO;|
| Experimental: ENTO + cytarabine + daunorubicin (Group B)<br>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<br>* 400 mg (2 × 200 mg tablets) orally twice daily<br>* Other names: ENTO;Drug: Daunorubicin<br>* 60 mg/m^2 administered intravenously daily on Days 1 to 3 of each 28-day induction cycle<br>Drug: Cytarabine<br>* 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<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Relapsed or Refractory Hematologic Malignancy, Previously untreated AML