Safety and Efficacy of Entospletinib With Vincristine and Dexamethasone in Adults With Relapsed or Refractory Acute Lymphoblastic Leukemia (ALL)

Study Overview
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Brief Summary
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The primary objective of this study is to evaluate the safety of entospletinib in combination with vincristine (VCR), and dexamethasone (DEX) in adults with previously treated relapsed or refractory B-cell lineage acute lymphoblastic leukemia (ALL). This is a dose escalation study in which after 2 induction cycles participants may be put on maintenance for up to 36 cycles if they have obtained clinical benefit from the treatment.

Official Title
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A Phase 1b/2, Open-Label, Dose Escalation and Expansion Study Evaluating the Safety and Efficacy of Entospletinib (GS-9973) With Vincristine and Dexamethasone in Adult Subjects With Relapsed or Refractory Acute Lymphoblastic Leukemia (ALL)

Conditions
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Acute Lymphoblastic Leukemia

Intervention / Treatment
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* Drug: Entospletinib
* Drug: Vincristine
* Drug: Dexamethasone
* Drug: CNS Prophylaxis


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Adults with ALL in need of treatment Key Exclusion Criteria: Diagnosis of Burkitt's Leukemia, or lymphoid blast crisis of chronic myelogenous leukemia (CML) History of myelodysplastic syndrome or solid organ transplantation Prior allogeneic bone marrow progenitor cell transplant within 100 days or on active immunosuppression for graft versus host disease (GVHD) treatment or prophylaxis within 28 days prior to enrollment 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 200 mg + VCR 0.5 mg<br>Monotherapy Lead-In (Day -7 to Day -1): Entospletinib (ENTO) 200 mg tablet orally twice daily as a single agent. Induction (two 28-day cycles): ENTO 200 mg twice daily continuously in combination with vincristine (VCR) 0.5 mg intravenously (IV) on Days 1, 8, 15, and 22 of each cycle; dexamethasone (DEX) 20 mg twice daily orally on Days 8-11 and Days 22-25 (Cycle 1) and on Days 1-4 and Days 15-18 (Cycle 2); and central nervous system (CNS) prophylaxis per institutional standards on Day 28 of each cycle. Maintenance (up to 36, 28-day cycles): Participants who achieved a complete remission (CR) received stem cell transplant (SCT) (if eligible) per investigator's discretion; others who obtained clinical benefit (ie, at least a partial response [PR]) after induction were offered maintenance therapy with ENTO 200 mg twice daily continuously in combination with VCR 0.5 mg on Day 1 of each cycle and DEX (20 mg daily or 10 mg twice daily) on Days 1-4 and Days 15-18 of each cycle. | Drug: Entospletinib<br> <br> * Other names: ENTO;Drug: Vincristine<br> <br> * Other names: VCR;Drug: Dexamethasone<br> <br> * Other names: DEX;Drug: CNS Prophylaxis<br> <br> |
| Experimental: ENTO 400 mg + VCR 0.5 mg<br>Monotherapy Lead-In (Day -7 to Day -1): ENTO 400 mg tablet orally twice daily as a single agent. Induction (two 28-day cycles): ENTO 400 mg twice daily continuously in combination with VCR 0.5 mg IV on Days 1, 8, 15, and 22 of each cycle; DEX 20 mg twice daily orally on Days 8-11 and Days 22-25 (Cycle 1) and on Days 1-4 and Days 15-18 (Cycle 2); and CNS prophylaxis per institutional standards on Day 28 of each cycle. Maintenance (up to 36, 28-day cycles): Participants who achieved a CR received SCT (if eligible) per investigator's discretion; others who obtained clinical benefit (ie, at least a PR) after induction were offered maintenance therapy with ENTO 400 mg twice daily continuously in combination with VCR 0.5 mg on Day 1 of each cycle and DEX (20 mg daily or 10 mg twice daily) on Days 1-4 and Days 15-18 of each cycle. | Drug: Entospletinib<br> <br> * Other names: ENTO;Drug: Vincristine<br> <br> * Other names: VCR;Drug: Dexamethasone<br> <br> * Other names: DEX;Drug: CNS Prophylaxis<br> <br> |
| Experimental: ENTO 400 mg + VCR 1.0 mg<br>Monotherapy Lead-In (Day -7 to Day -1): ENTO 400 mg tablet orally twice daily as a single agent. Induction (two 28-day cycles): ENTO 400 mg twice daily continuously in combination with VCR 1.0 mg IV on Days 1, 8, 15, and 22 of each cycle; DEX 20 mg twice daily orally on Days 8-11 and Days 22-25 (Cycle 1) and on Days 1-4 and Days 15-18 (Cycle 2); and CNS prophylaxis per institutional standards on Day 28 of each cycle. Maintenance (up to 36, 28-day cycles): Participants who achieved a CR received SCT (if eligible) per investigator's discretion; others who obtained clinical benefit (ie, at least a PR) after induction were offered maintenance therapy with ENTO 400 mg twice daily continuously in combination with VCR 1.0 mg on Day 1 of each cycle and DEX (20 mg daily or 10 mg twice daily) on Days 1-4 and Days 15-18 of each cycle. | Drug: Entospletinib<br> <br> * Other names: ENTO;Drug: Vincristine<br> <br> * Other names: VCR;Drug: Dexamethasone<br> <br> * Other names: DEX;Drug: CNS Prophylaxis<br> <br> |
| Experimental: ENTO 400 mg + VCR 2.0 mg<br>Monotherapy Lead-In (Day -7 to Day -1): ENTO 400 mg tablet orally twice daily as a single agent. Induction (two 28-day cycles): ENTO 400 mg twice daily continuously in combination with VCR 2.0 mg IV on Days 1, 8, 15, and 22 of each cycle; DEX 20 mg twice daily orally on Days 8-11 and Days 22-25 (Cycle 1) and on Days 1-4 and Days 15-18 (Cycle 2); and CNS prophylaxis per institutional standards on Day 28 of each cycle. Maintenance (up to 36, 28-day cycles): Participants who achieved a CR received SCT (if eligible) per investigator's discretion; others who obtained clinical benefit (ie, at least a PR) after induction were offered maintenance therapy with ENTO 400 mg twice daily continuously in combination with VCR 2.0 mg on Day 1 of each cycle and DEX (20 mg daily or 10 mg twice daily) on Days 1-4 and Days 15-18 of each cycle. | Drug: Entospletinib<br> <br> * Other names: ENTO;Drug: Vincristine<br> <br> * Other names: VCR;Drug: Dexamethasone<br> <br> * Other names: DEX;Drug: CNS Prophylaxis<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Experiencing Dose Limiting Toxicities (DLTs) | The occurrence of any of the following toxicities during Lead-in/Cycle 1 (Day -7 through Day 28) was considered a DLT if judged by the investigator to be possibly, probably, or definitely related to the administration of any drug in the treatment regimen (ENTO, VCR, DEX, institutional standard CNS prophylaxis): Grade 4 (or higher) non-hematologic toxicity Grade 3 non-hematologic toxicity lasting ≥ 7 days despite optimal supportive care Any Grade 3 non-hematologic laboratory value if: Medical intervention was required to treat, or The abnormality led to hospitalization, or The abnormality persisted for > 1 week Grade 4 Neutropenia (absolute neutrophil count [ANC] < 500 /μL) persistent for greater than 14 days or associated with febrile neutropenia Grade 4 thrombocytopenia (platelets < 25,000/μL) persisting for greater than 14 days (or greater than 25,000 /μL, but requiring prophylactic platelet transfusion to maintain this level) | ENTO Lead-in and Cycle 1 (Day -7 through Day 28) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Complete Remission (CR) at the End of Induction | Assessment of clinical response was made according to National Comprehensive Cancer Network (NCCN) guidelines on acute lymphoblastic leukemia (ALL) Version 2, 2016. CR required all of the following: No circulating blasts or extramedullary disease (no lymphadenopathy, splenomegaly, skin/gum infiltration/testicular mass/CNS involvement). Trilineage hematopoiesis (TLH) and < 5% blasts in bone marrow aspirate. ANC > 1000/μL. Platelets > 100,000/μL. | End of Induction (Cycle 2, Day 28) | 
| Percentage of Participants With Overall Remission at the End of Induction | Assessment of clinical response was made according to NCCN guidelines on ALL Version 2, 2016. Overall remission included CR and complete remission with incomplete hematologic recovery (CRi). CR required all of the following: No circulating blasts or extramedullary disease (no lymphadenopathy, splenomegaly, skin/gum infiltration/testicular mass/CNS involvement). TLH and < 5% blasts in bone marrow aspirate. ANC > 1000/μL. Platelets > 100,000/μL. CRi required all criteria for CR except platelet count and/or ANC: Platelets ≤ 100,000/μL and/or ANC is ≤ 1000/μL | End of Induction (Cycle 2, Day 28) | 
| Percentage of Participants With Partial Response (PR) at the End of Induction | PR required all of the following: No circulating blasts or extramedullary disease (no lymphadenopathy, splenomegaly, skin/gum infiltration/testicular mass/CNS involvement). TLH and bone marrow may contain ≥ 5% but less than 25% blast morphology. ANC > 1000/μL. Platelets > 100,000/μL. | End of Induction (Cycle 2, Day 28) | 
| Percentage of Participants With Overall Response at the End of Induction | Overall response included CR, CRi, and PR. CR required all of the following: No circulating blasts or extramedullary disease (no lymphadenopathy, splenomegaly, skin/gum infiltration/testicular mass/CNS involvement). TLH and < 5% blasts in bone marrow aspirate. ANC > 1000/μL. Platelets > 100,000/μL. CRi required all criteria for CR except platelet count and/or ANC: Platelets ≤ 100,000/μL and/or ANC is ≤ 1000/μL PR required all criteria for CR except for bone marrow blasts: bone marrow may contain ≥ 5% but less than 25% blast morphology | End of Induction (Cycle 2, Day 28) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Syk inhibitor, Blood malignancy, Leukemia