A Study of LY2181308 Sodium in Patients With Relapsed or Refractory Acute Myeloid Leukemia

Study Overview
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Brief Summary
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The purpose of this study is to understand the safety profile of LY2181308 sodium administered in combination with idarubicin and cytarabine to patients with relapsed or refractory acute myeloid leukemia (AML).

Official Title
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An Open-Label Phase 2 Trial of LY2181308 Sodium Administered in Combination With Idarubicin and Cytarabine to Patients With Refractory or Relapsed Acute Myeloid Leukemia

Conditions
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Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: LY2181308 sodium
* Drug: cytarabine
* Drug: idarubicin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients who have a diagnosis of acute myeloid leukemia that is relapsed or refractory to at least 1 prior treatment for leukemia, or patients with chronic myeloid leukemia (CML) who are in myeloid blast crisis which have failed at least 1 previous tyrosine kinase inhibitor (TK1). A baseline bone marrow assessment is required less than or equal to 96 hours prior to the first dose of study drug. Must have discontinued all previous therapies for cancer, including chemotherapy, radiotherapy, immunotherapy, cancer related hormone therapy, or other investigational therapy for at least 21 days for myelosuppressive agents (such as cytarabine, daunorubicin, and gemtuzumab ozogamicin) or 14 days for non-myelosuppressive agents prior to receiving study drug, and recovered from the acute effects of therapy (such as neurotoxicity, diarrhea, and mucositis) except for residual myelosuppression and alopecia. Hydroxyurea is permitted to control the peripheral blast cell count, but must be stopped at least 24 hours before study drug administration. Must have adequate organ function. Females must have a negative pregnancy test. Male and female patients must agree to use a reliable method of birth control during and for 6 months following the last dose of study drug. Patients must be at least 18 years old. Exclusion Criteria: Have received treatment within the last 30 days with a drug that has not received regulatory approval for any indication within 14 or 21 days of the initial dose of study drug for a non-myelosuppressive or myelosuppressive agent, respectively. Patients with acute promyelocytic leukemia (APML). Major surgery within 4 weeks of study enrollment. Patients with serious pre-existing medical conditions (at the discretion of the investigator). Because of the known cardiac toxicity of anthracyclines, patients with pre-existing ejection fraction (EF) less than or equal to 45% should not participate in this study. No patient should exceed the maximum exposure of anthracycline doses (for example, idarubicin greater than 120 mg/m²). Patients with a second malignancy that could affect the interpretation of the results. Patients with leukemic involvement of the central nervous system (CNS) by spinal fluid cytology or imaging. Patients with known coagulopathy or bleeding disorder, other than leukemia related thrombocytopenia. Patients with severe of life threatening bleeding refractory to platelet transfusions are also excluded. Concomitant anticoagulant therapy (with the exception of heparinized saline to maintain the patency of central venous catheters). Women who are pregnant or breast feeding. Patients with a known hypersensitivity to oligonucleotides, idarubicin, and/or cytarabine.

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LY2181308 sodium, idarubicin, cytarabine<br> | Drug: LY2181308 sodium<br>* 750 milligrams (mg) is administered as a 3-hour intravenous infusion on Days 1, 2, 3, 8, 15, 22 of Cycle 1 (28 days) and Days 1, 8, 15, 22 of Cycle 2 (28 days) until disease progression or unacceptable toxicity develops.<br>Drug: cytarabine<br>* 1.5 grams per square meter (g/m²) will be administered as a 4-hour intravenous infusion on Days 3, 4, 5 of Cycle 1 (28 days) and Days 1, 2, 3 of Cycle 2 (28 days) until disease progression or unacceptable toxicity develops.<br>Drug: idarubicin<br>* 12 milligrams per square meter (mg/m²) will be administered as a 30-minute intravenous infusion on Days 3, 4, 5 of Cycle 1 (28 days) and on Days 1, 2, 3 of Cycle 2 (28 days) until disease progression or unacceptable toxicity develops.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events (Safety Profile) | Data are presented as number of participants who experienced serious adverse events (SAE) and possibly drug-related treatment-emergent adverse events (TEAE) during the study including the 21-day follow-up period. A summary of serious adverse events and other nonserious adverse events regardless of causality is located in the Reported Adverse Events section. | Start of treatment to study completion up to 6.7 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Response to LY2181308 Sodium in Combination With Idarubicin and Cytarabine (Remission Rates) | Response is complete remission (CR) + CR with incomplete blood count recovery (CRi) + partial remission (PR) + cytoreduction. CR: fewer than 5% blasts based on a cell count of at least 200 cells from a bone marrow aspirate containing bone marrow spicules, in the setting of peripheral blood recovery to: platelets ≥100x10⁹/liter (L), neutrophils ≥10⁹/L. PR: defined as a decrease of at least 50% in blast count on the bone marrow aspirate; or cytoreduction (defined as a decrease in blast count not meeting the criteria for a PR or CR). Response rate is calculated as a total number of participants with CR or CRi or PR or cytoreduction divided by the total number of participants treated multiplied by 100. | Baseline to progression of disease or death up to 6 months | 
| Relapse-Free Survival | Relapse-Free Survival was defined as the time from first objective status assessment of complete remission (CR) or CR with incomplete blood count recovery (CRi) or partial remission (PR) or cytoreduction to the first time of disease progression or death as a result of any cause. CR: fewer than 5% blasts based on a cell count of at least 200 cells from a bone marrow aspirate containing bone marrow spicules, in the setting of peripheral blood recovery to: platelets ≥100x10⁹/liter (L), neutrophils ≥10⁹/L. PR: defined as a decrease of at least 50% in blast count on the bone marrow aspirate; or cytoreduction (defined as a decrease in blast count not meeting the criteria for a PR or CR). There were too few participants who had a documented progression of disease or death event amongst the participants with a response of CR, CRi, PR or cytoreduction to conduct the time-to-event analysis, thus the relapse-free survival was not analyzed. | Baseline to progression of disease or death up to 6 months | 
| Area Under the Curve of LY2181308 Over the Dosing Interval | Area under the curve of LY2181308 over the dosing interval | Day 3: 0,12,24,36,48,60,72,84,96,108,120,132 hours | 
| Pharmacodynamics: Number of Participants With Survivin Protein Expression | Pharmacodynamics: Number of participants with Survivin Protein Expression. | 6 Months | 
| Change From Baseline in Survivin Index at Day 2 | Data presented are the ratio of Day 2 survivin index to the baseline survivin index. Survivin is a protein expressed in tumor cells, including acute myeloid leukemia (AML), which regulates mitosis and prevents tumor cell death. Survivin index was calculated as ([blast survivin mean equivalent fluorochrome (MEFL) - blast isotypic control MEFL]/blast isotypic control MEFL). | Baseline, Day 2 |