Study Impact on Outcome of Eltrombopag in Elderly Patients With Acute Myeloid Leukemia Receiving Induction Chemotherapy

Study Overview
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Brief Summary
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Phase II randomized placebo-controlled study to assess the impact on outcome of Eltrombopag administered to elderly patients with Acute Myeloid Leukemia (AML) receiving induction chemotherapy. A phase II multicenter and randomized placebo-controlled study

Detailed Description
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Subjects will be randomized 1:1 to receive Eltrombopag or matching placebo, in double blinded. To compare overall survival rate at 12 months between the two arms, with or without 200 mg of Eltrombopag daily after induction chemotherapy Arm A : Eltrombopag 200 mg (100 mg/day for east Asian heritage) once daily from day 11 of induction chemotherapy to AML response evaluation or platelets count > 100 x 10 Giga/L (maximum day 45) Arm B : Placebo once daily from day 11 of induction chemotherapy to AML response evaluation or platelets count > 100 x 10 Giga/L. (maximum day 45)

Official Title
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A Phase II Randomized Placebo-controlled Study to Assess the Impact on Outcome of Eltrombopag Administered to Elderly Patients With Acute Myeloid Leukemia Receiving Induction Chemotherapy

Conditions
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Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: Eltrombopag
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria 60 years of age. AML de novo, except AML 3 and AML 7. AML with no adverse cytogenetic according to Medical Research Council (MRC) 2010 classification. Subjects should be eligible for intensive chemotherapy by Daunorubicine, cytarabine, Lomustine. Eastern Cooperative Oncology Group (ECOG) < 3 (appendix 1). SORROR ≤ 3 (appendix 2). Adequate baseline organ function defined by the criteria below: Total bilirubin ≤ 1.5 x Upper Limit of Normal (ULN) range except cases clearly not indicative of inadequate liver function Alanine Aminotransferase (ALAT) and Aspartate Aminotransferase (ASAT) ≤ 3 x ULN Creatinin ≤ 1.5 x ULN Adequate cardiac function with Left Ventricular Ejection fraction (LVEF) ≥50% Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule. Women will be menopausal to be enrolled The patient must give written (personally signed and dated) informed consent before completing any study-related procedure which means assessment or evaluation that would not form part of the normal medical care of the patient and before the start of induction chemotherapy. Affiliated to the French Social Security (Health Insurance). Exclusion criteria Subjects with a diagnosis of acute promyelocytic (M3) or megakaryocytic leukemia (M7). AML with adverse cytogenetic according to the MRC 2010 classification. AML secondary to Myelodysplastic syndrome (MDS), Myeloproliferative neoplasm (MPN) Clinical symptoms suggesting active central nervous system leukemia, or presence of extramedullary AML. Previous exposure to anthracycline. Previous AML treatment other than hydroxyurea. Treatment with an investigational drug within 30 days or 5 half-life whichever is longer, preceding the first dose of study medication. History of thromboembolic event or other condition requiring ongoing use of anticoagulation either with warfarin or low molecular-weight heparin. History of another malignancy within the past three years except basal cell carcinoma of the skin or carcinoma in situ of the cervix. Pre-existing cardiovascular disease (including congestive heart failure, New York Heart Association (NYHA) Grade III/IV), or arrhythmia known to increase the risk of thromboembolic events (e.g. atrial fibrillation), or subjects with a QTc >450 msec (QTc >480 msec for subjects with Bundle Branch Block). Patient requiring platelets transfusion with platelets > 10 x 10 Giga/L, for whatever reason. History of treatment with romiplostim or other Thrombopoietin receptor (TPO-R) agonists. Uncontrolled active infection. Any serious medical condition, laboratory abnormality, or psychiatric illness that would place the participant at an unacceptable risk or prevent them from giving informed consent. Known active HIV, Hepatitis B or C infection. Pregnancy or breastfeeding.

Ages Eligible for Study
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Minimum Age: 60 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: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomization between 2 arms
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A<br>55 patients will be randomized in the experimental arm A. If platelets counts < 100 x 10 Giga/L, patients will be treated with Eltrombopag 200 mg/day per os from day 11 of induction chemotherapy to platelets counts > 100 x 10 Giga/L or maximum to day 45. If platelets counts ≥ 100 x 10 Giga/L on day 11, the start of IP will be delayed until platelets < 100 x 10 Giga/L. Chemotherapy administration would be performed among standard practice: Daunorubicin: 60 mg/m² D1 to D3 Cytarabine: 100 mg/m²/day, in a continuous 24h-IV infusion D1 to D7 Lomustine (CCNU): 200 mg/m² per os, at D1. 200mg = 4 Tablets of 50 mg will be done more than 2 hours before Daunorubicin and cytarabine administrations, to avoid vomiting secondary to anthracycline administration. Investigational Product (IP) will be taken at the same time daily on an empty stomach 1 hour before or 2 hours after a meal or preferably no calcium or dairy products. | Drug: Eltrombopag<br>* Eltrombopag concomitant with induction chemotherapy in patient with AML<br>* Other names: Arm experimental A;|
| Placebo Comparator: B<br>55 patients will be randomized in the comparator arm B and will received: Placebo once daily from day 11 of induction chemotherapy to AML response evaluation or platelets count > 100 x 10 Giga/L (maximum day 45) Placebo 200mg = 4 Tablets of 50 mg will be done more than 2 hours before Daunorubicin and cytarabine administrations, to avoid vomiting secondary to anthracycline administration. Chemotherapy administration would be performed among standard practice: Daunorubicin: 60 mg/m² D1 to D3 Cytarabine: 100 mg/m²/day, in a continuous 24h-IV infusion D1 to D7 Lomustine (CCNU): 200 mg/m² per os, at D1. | Drug: Placebo<br>* Placebo concomitant with induction chemotherapy patients with AML<br>* Other names: Arm B;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overal survival rate | overall survival rate at month 12 (year 1) between the two arms, with or without 200 mg of Eltrombopag daily after induction chemotherapy. | 12 months after beginning treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response rate (CR and CRi) at day 45 |  | At day 45 | 
| Leukemia Free Survival at month 12 (one year) | relapse measurement before month 12 | 12 months after beginning treatment | 
| Long-term survival | Overall survival at 2, 3 and 5 years | 2, 3 and 5 years after first treatment administration | 
| Percentage of patients with platelets count > 100 Giga/L at day 45 | platelets count >100 Giga/L | At day 45 | 
| Time to platelet transfusion independence | More than 3 days with platelets count ≥ 10 Giga/L | platelets count daily from baseline to the end of induction (day 45) and then at day 60, day 90, monthly until year 1 and finally at year 2, year 3 and year 5 |