Acute Leukemia
Conditions
Keywords
Acute Myelogenous Leukemia, Acute Lymphoblastic Leukemia, Chronic Myelogenous Leukemia,Blast Crisis
Brief summary
This study is a multicenter, nonrandomized, open-label, dose-escalation with intra-patient dose-escalation, Phase 1 study of intravenous LY2523355 to determine the dose of LY2523355 that can be safely administered to participants with acute leukemia. Part A and Part B are dose escalation of two schedules in participants with acute leukemia. Parts A and B will enroll concurrently. Part C is a dose expansion for each schedule in participants with acute myeloblastic leukemia (AML).
Interventions
DRUGLY2523355
Administered as a 1-hour IV infusion for at least 2 cycles. Cycle length is 21 days. Participants may continue on study drug until disease progression, unacceptable toxicity, or other withdrawal criterion is met.
Sponsors
Eli Lilly and Company
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Dose escalation period for both schedules: * Participants must have a confirmed diagnosis of acute leukemia regardless of sub-type and for whom experimental Phase 1 therapy is appropriate. * Are greater than or equal to 18 years of age. * Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) scale. * Females with childbearing potential must have had a negative urine or serum pregnancy test less than or equal to 7 days prior to the first dose of study drug. Dose confirmation period for both schedules: * Participant must have a confirmed diagnosis of untreated acute myeloblastic leukemia (AML), should not be a candidate for standard therapy, and a clinical trial is a preferred treatment option or have acute AML that is relapsed or refractory to no more than 2 prior induction regimens. Hydroxyurea to control prior blast counts is not considered a prior regimen. * Are greater than or equal to 60 years of age. * Have a performance status of 0 or 1 on the ECOG scale. * Females with childbearing potential must have had a negative urine or serum pregnancy test less than or equal to 7 days prior to the first dose of study drug.
Exclusion criteria
* Have received treatment within 28 days of the initial dose of study drug with a drug that has not received regulatory approval for any indication. * Participants with known central nervous system (CNS) leukemia by spinal fluid cytology or imaging. A lumbar puncture is not required unless CNS involvement is clinically suspected. Participants with signs or symptoms of leukemic meningitis or a history of leukemic meningitis must have a negative lumbar puncture within 2 weeks of study enrollment. * Have other active malignancy (with the exception of basal and squamous cell skin cancer) at time of study entry. * Have had an autologous or allogenic bone marrow transplant within 3 months. All organ toxicity must be resolved. * Have evidence of graft-versus-host disease due to an allogenic bone marrow transplant. * Have uncontrolled systemic infection. * Females who are pregnant or lactating. * Have known positive test results in human immunodeficiency virus (HIV), hepatitis B surface antigen (HBSAg), or hepatitis C antibodies (HCAb) (screening not required).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Recommended Dose and Schedule for Phase 2 Studies in Acute Leukemia | Baseline up to the end of Cycle 2 (Day 42) | The recommended dose and schedule for Phase 2 studies of LY2523355 with acute leukemia was determined by a modification of the continual reassessment method. The sample size to adequately determine the maximum tolerated dose (MTD) for both schedules in this study was a function of a priori estimates for the dose-toxicity relationship as well as the initial dose in each schedule, the rate of dose escalation, and the observed dose-toxicity relationship. Before MTD could be determined for Part B (Days 1, 5, and 9 of a 21-day cycle), this study was paused for futility analysis. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Clinically Significant Effects | Baseline up to study completion (up to 213 days) | Clinically significant effects were defined as serious and other non-serious adverse events (AEs). A summary of serious and other non-serious adverse events regardless of causality is located in the Reported Adverse Events module. |
| Pharmacokinetics, Maximum Plasma Concentration (Cmax), Single Dose | Cycle 1(Day 1),: Predose, 1 hour (hr), 2 hr, 3 hr, 4 hr, 6 hr, 8, hr, 12 hr, 24 hr, 48 hr, 72 hr postdose | The maximum plasma concentration (Cmax) was the maximum plasma concentration obtained from the plasma concentration versus time curves of LY2523355 were calculated to assess intra and intercycle variability, depending on dosage cycle. |
| Pharmacokinetics, Maximum Plasma Concentration (Cmax), Multiple Dose | Days 3 (Parts A or C) or 9 (Part B), Cycle 1: Predose, 1 hour (hr), 2 hr, 3 hr, 4 hr, 6 hr, 8, hr, 12 hr, 24 hr, 48 hr, 72 hr postdose | The maximum plasma concentration (Cmax) was the maximum plasma concentration obtained from the plasma concentration versus time curves of LY2523355. Multiple dose LY2523355 plasma Cmax values are shown at each dose level for both schedules of administration (Day 3 of Cycle 1 for the Day 1, 2, and 3 schedule of administration and Day 9 of Cycle 1 for the Days 1, 5, and 9 schedule of administration). The maximum plasma concentration (Cmax) was the maximum plasma concentration obtained from the plasma concentration versus time curves of LY2523355 were calculated to assess intra and intercycle variability, depending on dosage cycle. |
| Pharmacokinetics, Area Under the Concentration Versus Time Curve (AUC), Single Dose | Day 1, Cycle 1: Predose, 1 hour (hr), 2 hr, 3 hr, 4 hr, 6 hr, 8, hr, 12 hr, 24 hr, 48 hr, 72 hr postdose | The AUC(0-24) was calculated from area under the plasma concentration versus time curves of LY2523355 from time zero to 24 hours. The AUC(0-inf) was calculated from area under the plasma concentration versus time curves of LY2523355 from time zero to infinity. Single dose LY2523355 AUC values are shown for each dose level for Day 1 of Cycle 1 for both schedules of administration. When only individual participant parameters are available or N=2, for a given dose, the AUC CV is not calculated for that dose group and is not presented (4 milligrams per meter squared per day \[mg/m\^2/day\], 14 mg/m\^2/day, 12 mg/m\^2/day and 16 mg/m\^2/day). Individual data will be presented. |
| Percentage of Participants With a Response for Acute Myelogenous Leukemia Using The Revised International Working Group Criteria | Baseline up to disease progression or discontinuation (up to 213 days) | Response rate for participants with acute myelogenous leukemia include the proportion of participants who achieved a morphologic complete remission, morphologic complete remission with incomplete blood count recovery, cytogenetic complete remission, molecular complete remission, or partial remission. The Revised International Working Group Criteria was used to determine response rate for participants with acute myelogenous leukemia. |
| Response Rates for Chronic Myelogenous Leukemia in Blast Crisis (Complete Hematologic Response, no Evidence of Leukemia, Return to Chronic Phase) | Baseline up to disease progression or discontinuation (up to 213 days) | Response rate for participants with chronic myelogenous leukemia in blast crisis include the proportion of participants who achieved a complete hematologic response, had no evidence of leukemia, or had returned to chronic phase. The criteria outlined in Cohen 2005 (Cohen MH, Johnson JR, Pazdur R. 2005. U.S. Food and Drug Administration Drug Approval Summary: conversion of imatinib mesylate (STI571; Gleevec) tablets from accelerated approval to full approval. Clin Cancer Res. 11(1):12-19.) was used to determine response rate for participants with chronic myelogenous leukemia in blast crisis. |
| Response Rate (Percentage) for Acute Lymphoblastic Leukemia Using The Revised International Working Group Criteria | Baseline up to disease progression or discontinuation (up to 213 days) | Response rate for participants with acute lymphoblastic leukemia include the proportion of participants who achieved a morphologic complete remission, morphologic complete remission with incomplete blood count recovery, cytogenetic complete remission, molecular complete remission, or partial remission. The Revised International Working Group Criteria was used to determine response rate for participants with acute lymphoblastic leukemia by early treatment assessment, morphologic leukemia-free state (less than 5% blasts in an aspirate sample with marrow spicules and with a count of at least 200 nucleated cells) and morphologic complete remission (and have an absolute neutrophil count of more than 1000 per microliter and platelets of 100,000 per microliter. |
| Pharmacokinetics, Area Under the Concentration Versus Time (AUC), Multiple Dose | Days 3 (Parts A or C) or 9 (Part B):Predose, 1 hour (hr), 2 hr, 3 hr, 4 hr, 6 hr, 8, hr, 12 hr, 24 hr 48 hr, 72 hr postdose | The AUC(0-24) was calculated from area under the plasma concentration versus time curves of LY2523355 from time zero to 24 hours. The AUC(0-inf) was calculated from area under the plasma concentration versus time curves of LY2523355 from time zero to infinity.. Multiple dose LY2523355 AUC values are shown at each dose level for both schedules of administration (Day 3 of Cycle 1 for the Day 1, 2, and 3 schedule of administration and Day 9 of Cycle 1 for the Days 1, 5, and 9 schedule of administration). When only individual participant parameters are available or N=2, for a given dose, the AUC CV is not calculated for that dose group and is not presented (4 milligrams per meter squared per day \[mg/m\^2/day\], 12 mg/m\^2/day, and 14 mg/m\^2/day). Individual data will be presented. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Death of Participants on Study up to the Follow-up Period | Baseline up to end of treatment follow-up (up to 213 days) | The number of participants who died through the follow-up period of the study. This does not include the outcomes for the two participants who died while on treatment through Cycle 2 as captured in the Participant Flow Table. A summary of serious and other non-serious adverse events regardless of causality is located in the Reported Adverse Events module. |
Countries
United States
Participant flow
Pre-assignment details
A participant was considered to have completed the trial if they received at 2 cycles of treatment. Participant Flow Arms represent schedule of dosing, with dose escalation, dose levels and participants who joined the dose level presented as Milestones. Study was based on best Schedule of dosing, not dose levels.
Participants by arm
| Arm | Count |
|---|---|
| Schedule A LY2523355 Starting dose was 2 milligrams per meter squared per day (mg/m\^2/day) administered by intravenous (IV) infusion over 1 hour on Days 1, 2, and 3 of every 21-day Cycle. | 10 |
| Schedule B LY2523355 Starting dose was 8 mg/m\^2/day administered by IV infusion over 1 hour on Days 1, 5, and 9 of every 21-day Cycle. | 15 |
| Schedule C LY2523355 Starting dose was 5 mg/m\^2/day administered by IV infusion over 1 hour on Days 1, 2, and 3 of every 21-day Cycle.
No participants in Part C escalated from their initial dose. | 8 |
| Total | 33 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Part A | Physician Decision | 1 | 0 | 0 |
| Part A | Progressive Disease | 7 | 0 | 0 |
| Part B | Death | 0 | 1 | 0 |
| Part B | Progressive disease | 0 | 10 | 0 |
| Part B | Withdrawal by Subject | 0 | 2 | 0 |
| Part C | Death | 0 | 0 | 1 |
| Part C | Physician Decision | 0 | 0 | 1 |
| Part C | Progressive Disease | 0 | 0 | 5 |
Baseline characteristics
| Characteristic | Schedule A LY2523355 | Total | Schedule C LY2523355 | Schedule B LY2523355 |
|---|---|---|---|---|
| Age, Continuous | 63.2 years STANDARD_DEVIATION 19.43 | 66.0 years STANDARD_DEVIATION 13.98 | 70.7 years STANDARD_DEVIATION 5.75 | 65.3 years STANDARD_DEVIATION 12.98 |
| Eastern Cooperative Oncology Group (ECOG) Performance Status ECOG Status 0 | 6 Participants | 9 Participants | 1 Participants | 2 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status ECOG Status 1 | 4 Participants | 17 Participants | 6 Participants | 7 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status ECOG Status 2 | 0 Participants | 7 Participants | 1 Participants | 6 Participants |
| Race/Ethnicity, Customized African | 2 Participants | 3 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Caucasian | 7 Participants | 28 Participants | 7 Participants | 14 Participants |
| Race/Ethnicity, Customized East Asian | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Hispanic | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Native American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized West Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment United States | 10 Participants | 33 Participants | 8 Participants | 15 Participants |
| Sex: Female, Male Female | 6 Participants | 14 Participants | 5 Participants | 3 Participants |
| Sex: Female, Male Male | 4 Participants | 19 Participants | 3 Participants | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 3 | 3 / 4 | 2 / 2 | 5 / 5 | 3 / 4 | 5 / 5 | 7 / 7 | 4 / 4 | 8 / 8 |
| serious Total, serious adverse events | 1 / 3 | 3 / 4 | 1 / 2 | 3 / 5 | 2 / 4 | 1 / 5 | 3 / 7 | 3 / 4 | 4 / 8 |
Outcome results
Primary
Recommended Dose and Schedule for Phase 2 Studies in Acute Leukemia
The recommended dose and schedule for Phase 2 studies of LY2523355 with acute leukemia was determined by a modification of the continual reassessment method. The sample size to adequately determine the maximum tolerated dose (MTD) for both schedules in this study was a function of a priori estimates for the dose-toxicity relationship as well as the initial dose in each schedule, the rate of dose escalation, and the observed dose-toxicity relationship. Before MTD could be determined for Part B (Days 1, 5, and 9 of a 21-day cycle), this study was paused for futility analysis.
Time frame: Baseline up to the end of Cycle 2 (Day 42)
Population: Participants who received at least one dose of study medication (LY2523355).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LY2523355 | Recommended Dose and Schedule for Phase 2 Studies in Acute Leukemia | 5 mg/m^2/day; Days 1, 2, and 3 |
Secondary
Number of Participants With Clinically Significant Effects
Clinically significant effects were defined as serious and other non-serious adverse events (AEs). A summary of serious and other non-serious adverse events regardless of causality is located in the Reported Adverse Events module.
Time frame: Baseline up to study completion (up to 213 days)
Population: Participants who received at least one dose of study medication (LY2523355).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| LY2523355 | Number of Participants With Clinically Significant Effects | 7 Participants |
| Schedule B LY2523355 | Number of Participants With Clinically Significant Effects | 9 Participants |
| Schedule C LY2523355 | Number of Participants With Clinically Significant Effects | 4 Participants |
Secondary
Percentage of Participants With a Response for Acute Myelogenous Leukemia Using The Revised International Working Group Criteria
Response rate for participants with acute myelogenous leukemia include the proportion of participants who achieved a morphologic complete remission, morphologic complete remission with incomplete blood count recovery, cytogenetic complete remission, molecular complete remission, or partial remission. The Revised International Working Group Criteria was used to determine response rate for participants with acute myelogenous leukemia.
Time frame: Baseline up to disease progression or discontinuation (up to 213 days)
Population: Participants with acute myelogenous leukemia who received at least one dose of study medication (LY2523355).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LY2523355 | Percentage of Participants With a Response for Acute Myelogenous Leukemia Using The Revised International Working Group Criteria | 0.0 percentage of responders |
| Schedule B LY2523355 | Percentage of Participants With a Response for Acute Myelogenous Leukemia Using The Revised International Working Group Criteria | 11.1 percentage of responders |
| Schedule C LY2523355 | Percentage of Participants With a Response for Acute Myelogenous Leukemia Using The Revised International Working Group Criteria | 12.5 percentage of responders |
Secondary
Pharmacokinetics, Area Under the Concentration Versus Time (AUC), Multiple Dose
The AUC(0-24) was calculated from area under the plasma concentration versus time curves of LY2523355 from time zero to 24 hours. The AUC(0-inf) was calculated from area under the plasma concentration versus time curves of LY2523355 from time zero to infinity.. Multiple dose LY2523355 AUC values are shown at each dose level for both schedules of administration (Day 3 of Cycle 1 for the Day 1, 2, and 3 schedule of administration and Day 9 of Cycle 1 for the Days 1, 5, and 9 schedule of administration). When only individual participant parameters are available or N=2, for a given dose, the AUC CV is not calculated for that dose group and is not presented (4 milligrams per meter squared per day \[mg/m\^2/day\], 12 mg/m\^2/day, and 14 mg/m\^2/day). Individual data will be presented.
Time frame: Days 3 (Parts A or C) or 9 (Part B):Predose, 1 hour (hr), 2 hr, 3 hr, 4 hr, 6 hr, 8, hr, 12 hr, 24 hr 48 hr, 72 hr postdose
Population: Participants who received more than one dose of LY2523355 with evaluable pharmacokinetic data on Cycle 1 Day 3 or Day 9, schedule dependent.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| LY2523355 | Pharmacokinetics, Area Under the Concentration Versus Time (AUC), Multiple Dose | AUC(0-24) | 134 nanograms hours per milliliter (ng*h/mL) | Geometric Coefficient of Variation 38 |
| LY2523355 | Pharmacokinetics, Area Under the Concentration Versus Time (AUC), Multiple Dose | AUC(0-inf), | 187 nanograms hours per milliliter (ng*h/mL) | Geometric Coefficient of Variation 45 |
| Schedule B LY2523355 | Pharmacokinetics, Area Under the Concentration Versus Time (AUC), Multiple Dose | AUC(0-24) | 2540 nanograms hours per milliliter (ng*h/mL) | — |
| Schedule B LY2523355 | Pharmacokinetics, Area Under the Concentration Versus Time (AUC), Multiple Dose | AUC(0-inf), | 3120 nanograms hours per milliliter (ng*h/mL) | — |
| Schedule C LY2523355 | Pharmacokinetics, Area Under the Concentration Versus Time (AUC), Multiple Dose | AUC(0-24) | 696 nanograms hours per milliliter (ng*h/mL) | Geometric Coefficient of Variation 126 |
| Schedule C LY2523355 | Pharmacokinetics, Area Under the Concentration Versus Time (AUC), Multiple Dose | AUC(0-inf), | 992 nanograms hours per milliliter (ng*h/mL) | Geometric Coefficient of Variation 117 |
| Schedule A 6 mg LY2523355 | Pharmacokinetics, Area Under the Concentration Versus Time (AUC), Multiple Dose | AUC(0-24) | 624 nanograms hours per milliliter (ng*h/mL) | Geometric Coefficient of Variation 66 |
| Schedule A 6 mg LY2523355 | Pharmacokinetics, Area Under the Concentration Versus Time (AUC), Multiple Dose | AUC(0-inf), | 990 nanograms hours per milliliter (ng*h/mL) | Geometric Coefficient of Variation 107 |
| Schedule B 8 mg LY2523355 | Pharmacokinetics, Area Under the Concentration Versus Time (AUC), Multiple Dose | AUC(0-24) | 623 nanograms hours per milliliter (ng*h/mL) | Geometric Coefficient of Variation 81 |
| Schedule B 8 mg LY2523355 | Pharmacokinetics, Area Under the Concentration Versus Time (AUC), Multiple Dose | AUC(0-inf), | 834 nanograms hours per milliliter (ng*h/mL) | Geometric Coefficient of Variation 98 |
| Schedule B 10 mg LY2523355 | Pharmacokinetics, Area Under the Concentration Versus Time (AUC), Multiple Dose | AUC(0-24) | 844 nanograms hours per milliliter (ng*h/mL) | Geometric Coefficient of Variation 14 |
| Schedule B 10 mg LY2523355 | Pharmacokinetics, Area Under the Concentration Versus Time (AUC), Multiple Dose | AUC(0-inf), | 1050 nanograms hours per milliliter (ng*h/mL) | Geometric Coefficient of Variation 8 |
| Schedule B 12 mg LY2523355 | Pharmacokinetics, Area Under the Concentration Versus Time (AUC), Multiple Dose | AUC(0-inf), | NA nanograms hours per milliliter (ng*h/mL) | — |
| Schedule B 12 mg LY2523355 | Pharmacokinetics, Area Under the Concentration Versus Time (AUC), Multiple Dose | AUC(0-24) | NA nanograms hours per milliliter (ng*h/mL) | — |
| Schedule B 14 mg 2523355 | Pharmacokinetics, Area Under the Concentration Versus Time (AUC), Multiple Dose | AUC(0-24) | 2910 nanograms hours per milliliter (ng*h/mL) | — |
| Schedule B 14 mg 2523355 | Pharmacokinetics, Area Under the Concentration Versus Time (AUC), Multiple Dose | AUC(0-inf), | 4120 nanograms hours per milliliter (ng*h/mL) | — |
Secondary
Pharmacokinetics, Area Under the Concentration Versus Time Curve (AUC), Single Dose
The AUC(0-24) was calculated from area under the plasma concentration versus time curves of LY2523355 from time zero to 24 hours. The AUC(0-inf) was calculated from area under the plasma concentration versus time curves of LY2523355 from time zero to infinity. Single dose LY2523355 AUC values are shown for each dose level for Day 1 of Cycle 1 for both schedules of administration. When only individual participant parameters are available or N=2, for a given dose, the AUC CV is not calculated for that dose group and is not presented (4 milligrams per meter squared per day \[mg/m\^2/day\], 14 mg/m\^2/day, 12 mg/m\^2/day and 16 mg/m\^2/day). Individual data will be presented.
Time frame: Day 1, Cycle 1: Predose, 1 hour (hr), 2 hr, 3 hr, 4 hr, 6 hr, 8, hr, 12 hr, 24 hr, 48 hr, 72 hr postdose
Population: Participants who received one dose of LY2523355 on Day 1 of Cycle 1 with evaluable pharmacokinetic data to enable calculation of the LY2523355 AUC on Day 1 of Cycle 1.Schedule A,C data was combined for 5 mg, 2 participants received and incorrect dose of 6 mg and 16 mg are included in data.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| LY2523355 | Pharmacokinetics, Area Under the Concentration Versus Time Curve (AUC), Single Dose | The AUC(0-24) | 278 nanagram hours per milliliter (ng*h/mL) | Geometric Coefficient of Variation 209 |
| LY2523355 | Pharmacokinetics, Area Under the Concentration Versus Time Curve (AUC), Single Dose | The AUC(0-inf) | 229 nanagram hours per milliliter (ng*h/mL) | Geometric Coefficient of Variation 191 |
| Schedule B LY2523355 | Pharmacokinetics, Area Under the Concentration Versus Time Curve (AUC), Single Dose | The AUC(0-24) | 3420 nanagram hours per milliliter (ng*h/mL) | — |
| Schedule B LY2523355 | Pharmacokinetics, Area Under the Concentration Versus Time Curve (AUC), Single Dose | The AUC(0-inf) | 3490 nanagram hours per milliliter (ng*h/mL) | — |
| Schedule C LY2523355 | Pharmacokinetics, Area Under the Concentration Versus Time Curve (AUC), Single Dose | The AUC(0-24) | 473 nanagram hours per milliliter (ng*h/mL) | Geometric Coefficient of Variation 163 |
| Schedule C LY2523355 | Pharmacokinetics, Area Under the Concentration Versus Time Curve (AUC), Single Dose | The AUC(0-inf) | 537 nanagram hours per milliliter (ng*h/mL) | Geometric Coefficient of Variation 157 |
| Schedule A 6 mg LY2523355 | Pharmacokinetics, Area Under the Concentration Versus Time Curve (AUC), Single Dose | The AUC(0-24) | 613 nanagram hours per milliliter (ng*h/mL) | Geometric Coefficient of Variation 92 |
| Schedule A 6 mg LY2523355 | Pharmacokinetics, Area Under the Concentration Versus Time Curve (AUC), Single Dose | The AUC(0-inf) | 675 nanagram hours per milliliter (ng*h/mL) | Geometric Coefficient of Variation 86 |
| Schedule B 8 mg LY2523355 | Pharmacokinetics, Area Under the Concentration Versus Time Curve (AUC), Single Dose | The AUC(0-24) | 469 nanagram hours per milliliter (ng*h/mL) | Geometric Coefficient of Variation 22 |
| Schedule B 8 mg LY2523355 | Pharmacokinetics, Area Under the Concentration Versus Time Curve (AUC), Single Dose | The AUC(0-inf) | 608 nanagram hours per milliliter (ng*h/mL) | Geometric Coefficient of Variation 28 |
| Schedule B 10 mg LY2523355 | Pharmacokinetics, Area Under the Concentration Versus Time Curve (AUC), Single Dose | The AUC(0-inf) | 1530 nanagram hours per milliliter (ng*h/mL) | Geometric Coefficient of Variation 29 |
| Schedule B 10 mg LY2523355 | Pharmacokinetics, Area Under the Concentration Versus Time Curve (AUC), Single Dose | The AUC(0-24) | 1060 nanagram hours per milliliter (ng*h/mL) | Geometric Coefficient of Variation 31 |
| Schedule B 12 mg LY2523355 | Pharmacokinetics, Area Under the Concentration Versus Time Curve (AUC), Single Dose | The AUC(0-inf) | 970 nanagram hours per milliliter (ng*h/mL) | Geometric Coefficient of Variation 55 |
| Schedule B 12 mg LY2523355 | Pharmacokinetics, Area Under the Concentration Versus Time Curve (AUC), Single Dose | The AUC(0-24) | 746 nanagram hours per milliliter (ng*h/mL) | Geometric Coefficient of Variation 46 |
| Schedule B 14 mg 2523355 | Pharmacokinetics, Area Under the Concentration Versus Time Curve (AUC), Single Dose | The AUC(0-24) | NA nanagram hours per milliliter (ng*h/mL) | — |
| Schedule B 14 mg 2523355 | Pharmacokinetics, Area Under the Concentration Versus Time Curve (AUC), Single Dose | The AUC(0-inf) | NA nanagram hours per milliliter (ng*h/mL) | — |
| Schedule B 16 mg LY2523355 | Pharmacokinetics, Area Under the Concentration Versus Time Curve (AUC), Single Dose | The AUC(0-24) | 8770 nanagram hours per milliliter (ng*h/mL) | — |
| Schedule B 16 mg LY2523355 | Pharmacokinetics, Area Under the Concentration Versus Time Curve (AUC), Single Dose | The AUC(0-inf) | 9200 nanagram hours per milliliter (ng*h/mL) | — |
Secondary
Pharmacokinetics, Maximum Plasma Concentration (Cmax), Multiple Dose
The maximum plasma concentration (Cmax) was the maximum plasma concentration obtained from the plasma concentration versus time curves of LY2523355. Multiple dose LY2523355 plasma Cmax values are shown at each dose level for both schedules of administration (Day 3 of Cycle 1 for the Day 1, 2, and 3 schedule of administration and Day 9 of Cycle 1 for the Days 1, 5, and 9 schedule of administration). The maximum plasma concentration (Cmax) was the maximum plasma concentration obtained from the plasma concentration versus time curves of LY2523355 were calculated to assess intra and intercycle variability, depending on dosage cycle.
Time frame: Days 3 (Parts A or C) or 9 (Part B), Cycle 1: Predose, 1 hour (hr), 2 hr, 3 hr, 4 hr, 6 hr, 8, hr, 12 hr, 24 hr, 48 hr, 72 hr postdose
Population: Participants who received more than one dose of LY2523355 with evaluable pharmacokinetic data, Schedules A,B,C.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| LY2523355 | Pharmacokinetics, Maximum Plasma Concentration (Cmax), Multiple Dose | 43.1 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 46 |
| Schedule B LY2523355 | Pharmacokinetics, Maximum Plasma Concentration (Cmax), Multiple Dose | 2440 nanograms per milliliter (ng/mL) | — |
| Schedule C LY2523355 | Pharmacokinetics, Maximum Plasma Concentration (Cmax), Multiple Dose | 439 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 391 |
| Schedule A 6 mg LY2523355 | Pharmacokinetics, Maximum Plasma Concentration (Cmax), Multiple Dose | 187 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 69 |
| Schedule B 8 mg LY2523355 | Pharmacokinetics, Maximum Plasma Concentration (Cmax), Multiple Dose | 155 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 139 |
| Schedule B 10 mg LY2523355 | Pharmacokinetics, Maximum Plasma Concentration (Cmax), Multiple Dose | 283 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 23 |
| Schedule B 12 mg LY2523355 | Pharmacokinetics, Maximum Plasma Concentration (Cmax), Multiple Dose | NA nanograms per milliliter (ng/mL) | — |
| Schedule B 14 mg 2523355 | Pharmacokinetics, Maximum Plasma Concentration (Cmax), Multiple Dose | 892 nanograms per milliliter (ng/mL) | — |
Secondary
Pharmacokinetics, Maximum Plasma Concentration (Cmax), Single Dose
The maximum plasma concentration (Cmax) was the maximum plasma concentration obtained from the plasma concentration versus time curves of LY2523355 were calculated to assess intra and intercycle variability, depending on dosage cycle.
Time frame: Cycle 1(Day 1),: Predose, 1 hour (hr), 2 hr, 3 hr, 4 hr, 6 hr, 8, hr, 12 hr, 24 hr, 48 hr, 72 hr postdose
Population: Participants who received one dose of LY2523355 on Day 1 of Cycle 1(Schedule A,B,C) with evaluable pharmacokinetic data to enable determination of the LY2523355 plasma Cmax on Day 1. Schedule A,C data was combined for 5 mg, 2 participants received and incorrect dose of 6 mg and 16 mg are included in data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| LY2523355 | Pharmacokinetics, Maximum Plasma Concentration (Cmax), Single Dose | 198 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 1410 |
| Schedule B LY2523355 | Pharmacokinetics, Maximum Plasma Concentration (Cmax), Single Dose | 895 nanograms per milliliter (ng/mL) | — |
| Schedule C LY2523355 | Pharmacokinetics, Maximum Plasma Concentration (Cmax), Single Dose | 240 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 420 |
| Schedule A 6 mg LY2523355 | Pharmacokinetics, Maximum Plasma Concentration (Cmax), Single Dose | 391 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 254 |
| Schedule B 8 mg LY2523355 | Pharmacokinetics, Maximum Plasma Concentration (Cmax), Single Dose | 169 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 47 |
| Schedule B 10 mg LY2523355 | Pharmacokinetics, Maximum Plasma Concentration (Cmax), Single Dose | 354 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 66 |
| Schedule B 12 mg LY2523355 | Pharmacokinetics, Maximum Plasma Concentration (Cmax), Single Dose | 254 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 18 |
| Schedule B 14 mg 2523355 | Pharmacokinetics, Maximum Plasma Concentration (Cmax), Single Dose | NA nanograms per milliliter (ng/mL) | — |
| Schedule B 16 mg LY2523355 | Pharmacokinetics, Maximum Plasma Concentration (Cmax), Single Dose | 17,000 nanograms per milliliter (ng/mL) | — |
Secondary
Response Rate (Percentage) for Acute Lymphoblastic Leukemia Using The Revised International Working Group Criteria
Response rate for participants with acute lymphoblastic leukemia include the proportion of participants who achieved a morphologic complete remission, morphologic complete remission with incomplete blood count recovery, cytogenetic complete remission, molecular complete remission, or partial remission. The Revised International Working Group Criteria was used to determine response rate for participants with acute lymphoblastic leukemia by early treatment assessment, morphologic leukemia-free state (less than 5% blasts in an aspirate sample with marrow spicules and with a count of at least 200 nucleated cells) and morphologic complete remission (and have an absolute neutrophil count of more than 1000 per microliter and platelets of 100,000 per microliter.
Time frame: Baseline up to disease progression or discontinuation (up to 213 days)
Population: Participants with acute lymphoblastic leukemia who received at least one dose of study medication (LY2523355).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LY2523355 | Response Rate (Percentage) for Acute Lymphoblastic Leukemia Using The Revised International Working Group Criteria | 25.0 percentage of responders |
Secondary
Response Rates for Chronic Myelogenous Leukemia in Blast Crisis (Complete Hematologic Response, no Evidence of Leukemia, Return to Chronic Phase)
Response rate for participants with chronic myelogenous leukemia in blast crisis include the proportion of participants who achieved a complete hematologic response, had no evidence of leukemia, or had returned to chronic phase. The criteria outlined in Cohen 2005 (Cohen MH, Johnson JR, Pazdur R. 2005. U.S. Food and Drug Administration Drug Approval Summary: conversion of imatinib mesylate (STI571; Gleevec) tablets from accelerated approval to full approval. Clin Cancer Res. 11(1):12-19.) was used to determine response rate for participants with chronic myelogenous leukemia in blast crisis.
Time frame: Baseline up to disease progression or discontinuation (up to 213 days)
Population: Participants with chronic myelogenous leukemia in blast crisis who received at least one dose of study medication (LY2523355).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Schedule B LY2523355 | Response Rates for Chronic Myelogenous Leukemia in Blast Crisis (Complete Hematologic Response, no Evidence of Leukemia, Return to Chronic Phase) | 0 percentage of responders |
Other Pre-specified
Death of Participants on Study up to the Follow-up Period
The number of participants who died through the follow-up period of the study. This does not include the outcomes for the two participants who died while on treatment through Cycle 2 as captured in the Participant Flow Table. A summary of serious and other non-serious adverse events regardless of causality is located in the Reported Adverse Events module.
Time frame: Baseline up to end of treatment follow-up (up to 213 days)
Population: Participants who received at least one dose of study medication (LY2523355).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| LY2523355 | Death of Participants on Study up to the Follow-up Period | 1 Participants |
| Schedule B LY2523355 | Death of Participants on Study up to the Follow-up Period | 4 Participants |
| Schedule C LY2523355 | Death of Participants on Study up to the Follow-up Period | 0 Participants |