A Study for Patients With Acute Leukemia

Study Overview
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Brief Summary
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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).

Official Title
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Phase 1 Study of LY2523355 in Patients With Acute Leukemia

Conditions
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Acute Leukemia

Intervention / Treatment
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* Drug: LY2523355


Participation Criteria
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Eligibility Criteria
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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).

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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LY2523355 on Days 1, 2, and 3<br>Starting dose was 2 milligrams per meter squared (mg/m^2) administered by a 1-hour intravenous (IV) infusion on Days 1, 2, and 3 of every 21-day Cycle. | Drug: LY2523355<br>* 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.<br>|
| Experimental: LY2523355 on Days 1, 5, and 9<br>Starting dose was 8 milligrams per meter squared (mg/m^2) administered by a 1-hour IV infusion over 1 hour on Days 1, 5, and 9 of every 21-day Cycle. | Drug: LY2523355<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline up to the end of Cycle 2 (Day 42) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline up to study completion (up to 213 days) | 
| 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. | 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 | 
| 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. | 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 | 
| 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. | 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 | 
| 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. | 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 | 
| 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. | Baseline up to disease progression or discontinuation (up to 213 days) | 
| 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. | Baseline up to disease progression or discontinuation (up to 213 days) | 
| 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. | Baseline up to disease progression or discontinuation (up to 213 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acute Myelogenous Leukemia, Acute Lymphoblastic Leukemia, Chronic Myelogenous Leukemia,Blast Crisis