Study of LY573636-sodium in Essential Thrombocythemia and Acute Myeloid Leukemia

Study Overview
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Brief Summary
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The purpose of this study is to determine a safe dose of LY573636-sodium to be given to patients with acute myeloid leukemia and to determine any side effects that may be associated with LY573636-sodium in this patient population. Efficacy measures will also be used to assess the activity of LY573636-sodium in acute myeloid leukemia and essential thrombocythemia patients.

Official Title
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Phase 1 Study of LY573636-sodium in Patients With Essential Thrombocythemia and Acute Myeloid Leukemia

Conditions
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Acute Myeloid Leukemia, Essential Thrombocythemia

Intervention / Treatment
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* Drug: LY573636-sodium


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants who have a diagnosis of either essential thrombocythemia or acute myeloid leukemia that is relapsed or refractory to at least one prior standard treatment. If participants have acute promyelocytic leukemia, they must be resistant and/or intolerant of both all trans retinoic acid (ATRA) and arsenic trioxide. Are at least 18 years of age. Have given written informed consent approved by Lilly and the ethical review board (ERB)/institutional review board (IRB) governing the site. Must have adequate hepatic and renal function. Have discontinued all previous therapies for cancer, including chemotherapy, radiotherapy, immunotherapy, cancer-related hormonal 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. Hydroxyurea used to control peripheral blood blast count is permitted within these respective periods, but it must be stopped at least 24 hours before study drug administration. Males and females with reproductive potential must agree to use medically approved contraceptive precautions during the trial and for 6 months following the last dose of study drug. Females of child bearing potential must have had a negative serum pregnancy test less than or equal to 7 days prior to the first dose of study drug. Have a serum albumin level greater than equal to 3.0 grams/deciliter (g/L), less than or equal to 72 hour prior to dosing with LY573636-sodium. Exclusion Criteria: Have received treatment 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. Participants with myeloproliferative disorders (for example, chronic myeloid leukemia (CML), polycythemia vera and primary myelofibrosis) other than essential thrombocythemia. Have received an autologous or allogenic stem cell transplant within 75 days of the initial dose of study drug for the dose escalation phase or within 60 days of the initial dose of study drug for the dose confirmation phase. Recipients of an allogeneic stem cell transplant must have discontinued immunosuppressive therapy at least 24 hours before study drug administration with no more than Grade 1 acute graft-versus-host disease. Have previously completed or withdrawn from this study or any other study investigating LY573636 sodium. Have serious preexisting medical conditions that in the opinion of the investigator would preclude participation in this study. Have serious concomitant disorders, including active bacterial, fungal, or viral infection, incompatible with the study. Have a second primary malignancy that could affect interpretation of results. Have a known coagulopathy or bleeding disorder, other than leukemic related thrombocytopenia. Participants with severe or life-threatening bleeding refractory to platelet transfusions are also excluded from this study. Major surgery within 4 weeks of study enrollment. Are receiving warfarin (Coumadin). Females who are pregnant or breast feeding. Have known positive results of human immunodeficiency virus (HIV), hepatitis B surface antigen (HBSAg) or hepatitis C antibodies (HCAb). Have received treatment within 28 days of the initial dose of study drug with an experimental agent for noncancerous indications that has not received regulatory approval for any indication. Participants receiving amiodarone, quinidine, propofol, or clozapine. Participants receiving treatment with strong or moderate inhibitors of cytochrome P450 (CYP)2C19, including proton-pump inhibitors (PPIs). Esomeprazole or pantoprazole are allowed if not administered within 72 hours before or after LY573636 administration

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: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LY573636<br> | Drug: LY573636-sodium<br>* Individualized dose is dependent on participant's height, weight, gender and is adjusted to target a specific exposure range corrected for a participant's laboratory parameters. Dosing will be done on Day 1 of a 35-day cycle for acute myeloid leukemia (AML) and Day 1 of a 28-day cycle for essential thrombocythemia (ET) for at least one cycle. A participant may have additional cycles of LY573636 if he or she is receiving benefit from the study drug and does not fulfill any of the criteria for study discontinuation.<br>* Other names: LY573636;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recommended Phase 2 Dose of LY573636-Sodium in Participants With Relapsed or Refractory Acute Myeloid Leukemia (AML) and Essential Thrombocythemia (ET) | Recommended Phase 2 dose was determined by maximum tolerated dose (MTD). MTD is the highest dose at which no more than 1 of 6 participants experienced a dose-limiting toxicity (DLT) and level immediately below that which had ≥2 instances of DLT. A DLT is an adverse event (AE) observed during the first cycle of treatment that is believed to be related to LY573636 and fulfills any of the following: ET only , Common Terminology Criteria for AE (CTCAE, Version 3.0) Grade (Gr) 4 hematologic toxicity for ≥3 days; For all, ≥Gr 3 nonhematological toxicity except for nausea/vomiting or diarrhea unless it fits the next criteria; ≥Gr 3 nausea, vomiting, or diarrhea that persists >7 days despite maximal treatment; Gr 3 electrolyte disturbances that persist despite maximal measures; DLT can be declared if a participant experienced increasing toxicity during treatment. The primary outcome measure was not analyzed because the enrollment was stopped early before MTD was reached. | Predose up to 35 days postdose in Cycle 1 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics Area Under the Curve(AUC) of LY573636 Above the Albumin-Corrected Threshold (AUCalb) | LY573636 has been found to be highly bound to albumin. AUCalb is a surrogate measure of exposure to unbound (free) LY573636. PK sample is withdrawn at any time on days 8,14,15,21,28. | Predose,1h,2h,4h, 8d,14d,15d,21d,28d post dose | 
| Number of Participants With Bone Marrow (BM) Response | The International Working Group's revised recommendations were used to assess response in acute myeloid leukemia (AML): complete response (CR) is <5% blasts in BM and with a cell count ≥200 cells in BM, and with peripheral blood platelets ≥100x10⁹/liter (L) and absolute neutrophils ≥1x10⁹/L; CR with incomplete blood count recovery is defined as CRi; partial response (PR) is ≥5% blasts in BM but with ≥50% reduction in blast count. Number of responders for AML = CR+PR+ CRi. Result of a European Leukemia Net consensus conference was used to assess response in essential thrombocythemia (ET). CR is platelets ≤400x10⁹/L in peripheral blood, no disease-related symptoms, normal spleen size and white blood cells ≤10x10⁹/L in peripheral blood; PR has platelets ≤600x10⁹/L in peripheral blood or decrease > 50% from baseline but does not meet CR criteria. Number of responders for ET = CR+PR. | Baseline to measured progressive disease up to 70 days | 
| Pharmacokinetics: Concentration Maximum (Cmax) of LY573636 | PK sample is withdrawn at any time on days 8,14,15,21,28. | Predose,1h,2h,4h, 8d,14d,15d,21d,28d post dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acute Myeloid Leukemia, Myeloid Leukemia, Relapsed, Refractory