Acute Lymphoblastic Leukemia
Conditions
Keywords
Syk inhibitor, Blood malignancy, Leukemia
Brief summary
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.
Interventions
Sponsors
Gilead Sciences
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
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/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Experiencing Dose Limiting Toxicities (DLTs) | ENTO Lead-in and Cycle 1 (Day -7 through Day 28) | 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) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Complete Remission (CR) at the End of Induction | End of Induction (Cycle 2, Day 28) | 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. |
| Percentage of Participants With Overall Remission at the End of Induction | End of Induction (Cycle 2, Day 28) | 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 |
| Percentage of Participants With Partial Response (PR) at the End of Induction | End of Induction (Cycle 2, Day 28) | 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. |
| Percentage of Participants With Overall Response at the End of Induction | End of Induction (Cycle 2, Day 28) | 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 |
Countries
Canada, Germany, United States
Participant flow
Recruitment details
Participants were enrolled at study sites in Germany, Canada, and United States. The first participant was screened on 06 May 2015. The last study visit occurred on 17 December 2018.
Pre-assignment details
42 participants were screened.
Participants by arm
| Arm | Count |
|---|---|
| ENTO 200 mg + VCR 0.5 mg Monotherapy Lead-In (Day -7 to Day -1): 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 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 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. | 5 |
| ENTO 400 mg + VCR 0.5 mg 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. | 8 |
| ENTO 400 mg + VCR 1.0 mg 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. | 7 |
| ENTO 400 mg + VCR 2.0 mg 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. | 10 |
| Total | 30 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 1 | 0 |
| Overall Study | Death | 5 | 5 | 3 | 8 |
| Overall Study | Enrolled but Never Treated | 0 | 2 | 0 | 0 |
| Overall Study | Progressive Disease | 0 | 0 | 1 | 1 |
| Overall Study | Study Terminated by Sponsor | 0 | 0 | 2 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | ENTO 200 mg + VCR 0.5 mg | Total | ENTO 400 mg + VCR 2.0 mg | ENTO 400 mg + VCR 1.0 mg | ENTO 400 mg + VCR 0.5 mg |
|---|---|---|---|---|---|
| Age, Continuous | 46.8 years STANDARD_DEVIATION 16.93 | 50.1 years STANDARD_DEVIATION 16.04 | 52.7 years STANDARD_DEVIATION 19.66 | 47.4 years STANDARD_DEVIATION 9.68 | 51.7 years STANDARD_DEVIATION 17.72 |
| Race/Ethnicity, Customized Ethnicity Hispanic or Latino | 1 Participants | 10 Participants | 5 Participants | 2 Participants | 2 Participants |
| Race/Ethnicity, Customized Ethnicity Not Hispanic or Latino | 4 Participants | 17 Participants | 5 Participants | 5 Participants | 3 Participants |
| Race/Ethnicity, Customized Ethnicity Not Permitted | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Race Asian | 1 Participants | 2 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Black | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Not Permitted | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Race White | 4 Participants | 24 Participants | 10 Participants | 5 Participants | 5 Participants |
| Region of Enrollment Canada | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Region of Enrollment Germany | 0 Participants | 2 Participants | 1 Participants | 1 Participants | 0 Participants |
| Region of Enrollment United States | 5 Participants | 27 Participants | 9 Participants | 6 Participants | 7 Participants |
| Sex: Female, Male Female | 5 Participants | 14 Participants | 3 Participants | 2 Participants | 4 Participants |
| Sex: Female, Male Male | 0 Participants | 14 Participants | 7 Participants | 5 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 5 / 5 | 5 / 6 | 5 / 7 | 9 / 10 |
| other Total, other adverse events | 5 / 5 | 5 / 6 | 6 / 7 | 7 / 10 |
| serious Total, serious adverse events | 5 / 5 | 4 / 6 | 5 / 7 | 6 / 10 |
Outcome results
Primary
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)
Time frame: ENTO Lead-in and Cycle 1 (Day -7 through Day 28)
Population: DLT Analysis Set included all participant in the Safety Analysis Set (all participants who received at least 1 dose of study treatment) who met at least one of the following criteria: received at least 21 days of ENTO, \> 50% of planned total dose of VCR and DEX, or experienced a DLT during the DLT assessment window.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ENTO 200 mg + VCR 0.5 mg | Percentage of Participants Experiencing Dose Limiting Toxicities (DLTs) | 33.3 percentage of participants |
| ENTO 400 mg + VCR 0.5 mg | Percentage of Participants Experiencing Dose Limiting Toxicities (DLTs) | 0 percentage of participants |
| ENTO 400 mg + VCR 1.0 mg | Percentage of Participants Experiencing Dose Limiting Toxicities (DLTs) | 16.7 percentage of participants |
| ENTO 400 mg + VCR 2.0 mg | Percentage of Participants Experiencing Dose Limiting Toxicities (DLTs) | 0 percentage of participants |
Secondary
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.
Time frame: End of Induction (Cycle 2, Day 28)
Population: The Full Analysis Set included all participants who received at least 1 dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ENTO 200 mg + VCR 0.5 mg | Percentage of Participants With Complete Remission (CR) at the End of Induction | 20.0 percentage of participants |
| ENTO 400 mg + VCR 0.5 mg | Percentage of Participants With Complete Remission (CR) at the End of Induction | 33.3 percentage of participants |
| ENTO 400 mg + VCR 1.0 mg | Percentage of Participants With Complete Remission (CR) at the End of Induction | 14.3 percentage of participants |
| ENTO 400 mg + VCR 2.0 mg | Percentage of Participants With Complete Remission (CR) at the End of Induction | 0 percentage of participants |
Secondary
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
Time frame: End of Induction (Cycle 2, Day 28)
Population: Participants in the Full Analysis Set were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ENTO 200 mg + VCR 0.5 mg | Percentage of Participants With Overall Remission at the End of Induction | 20.0 percentage of participants |
| ENTO 400 mg + VCR 0.5 mg | Percentage of Participants With Overall Remission at the End of Induction | 33.3 percentage of participants |
| ENTO 400 mg + VCR 1.0 mg | Percentage of Participants With Overall Remission at the End of Induction | 14.3 percentage of participants |
| ENTO 400 mg + VCR 2.0 mg | Percentage of Participants With Overall Remission at the End of Induction | 0.0 percentage of participants |
Secondary
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
Time frame: End of Induction (Cycle 2, Day 28)
Population: Participants in the Full Analysis Set were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ENTO 200 mg + VCR 0.5 mg | Percentage of Participants With Overall Response at the End of Induction | 20.0 percentage of participants |
| ENTO 400 mg + VCR 0.5 mg | Percentage of Participants With Overall Response at the End of Induction | 33.3 percentage of participants |
| ENTO 400 mg + VCR 1.0 mg | Percentage of Participants With Overall Response at the End of Induction | 28.6 percentage of participants |
| ENTO 400 mg + VCR 2.0 mg | Percentage of Participants With Overall Response at the End of Induction | 10.0 percentage of participants |
Secondary
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.
Time frame: End of Induction (Cycle 2, Day 28)
Population: Participants in the Full Analysis Set were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ENTO 200 mg + VCR 0.5 mg | Percentage of Participants With Partial Response (PR) at the End of Induction | 0.0 percentage of participants |
| ENTO 400 mg + VCR 0.5 mg | Percentage of Participants With Partial Response (PR) at the End of Induction | 0.0 percentage of participants |
| ENTO 400 mg + VCR 1.0 mg | Percentage of Participants With Partial Response (PR) at the End of Induction | 14.3 percentage of participants |
| ENTO 400 mg + VCR 2.0 mg | Percentage of Participants With Partial Response (PR) at the End of Induction | 10.0 percentage of participants |