AML-02: Omacetaxine With Standard-of-Care Induction With Cytarabine & Idarubicin in Newly-Diagnosed AML Patients

Study Overview
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Brief Summary
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This is a dose escalation study to evaluate Omacetaxine when given in combination with a standard induction regimen of 7+3 (cytarabine for Days 1-7 and Idarubicin for Days 1-3) in patients with newly diagnosed acute myelogenous leukemia (AML).

Detailed Description
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This is a dose escalation study to evaluate Omacetaxine when given in combination with a standard induction regimen of 7+3 (cytarabine for Days 1-7 and Idarubicin for Days 1-3) in patients with newly diagnosed acute myelogenous leukemia (AML). Omacetaxine will be given subcutaneously Q12 hours on Days 1-7. The optimally safe and active dose (OD) will be determined using the EffTox design. EffTox is a Bayesian adaptive design that seeks to determine the optimal dose for further study in Phase II by considering a trade-off between efficacy and toxicity. The EffTox design begins by treating a cohort of three patients at dose level 1. These patients' efficacy and toxicity outcomes are used to update the posterior distributions for the probability of efficacy and toxicity and identify acceptable dose levels. The study terminates if no dose levels are acceptable. Otherwise, the acceptable doses are ranked using the Euclidean distance from (1.0, 0.0) and the next cohort is treated at the dose with the minimum distance under the restriction that we may only escalate or deescalate by one dose level at a time (e.g., the second cohort can only escalate to dose level 2 or deescalate to dose level -1). The second cohort is treated at the dose with the minimum distance and posterior distributions, and the list of acceptable doses and distances are updated as before. This process continues until at least 20 subjects are enrolled in the study. The dose with the minimum distance at study completion is considered the optimal dose for further investigation. If none of the dose levels are acceptable at study completion, an optimal dose level will not be identified and the drug does not warrant further investigation. Post induction therapy will consist of standard cytarabine consolidation chemotherapy or allogeneic stem cell transplantation based on pretreatment risk assessment.

Official Title
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AML-02: Study of the Activity and Safety of the Addition of Omacetaxine to the Standard-of-Care Induction Therapy Regimen of Cytarabine and Idarubicin in Newly-Diagnosed AML Patients

Conditions
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Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: Cytarabine
* Drug: Idarubicin
* Drug: Omacetaxine mepesuccinate
* Drug: Omacetaxine mepesuccinate
* Drug: Omacetaxine mepesuccinate
* Drug: Omacetaxine mepesuccinate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Newly diagnosed, untreated patients with AML according to the WHO classification for AML. Prior short-term therapy (≤7 days) with hydroxyurea, steroids, biological or targeted therapy (e.g. FLT3 inhibitors, other kinase inhibitors, azacitidine, ATRA), or hematopoietic growth factors is allowed. A single or two-day dose of cytarabine (up to 3 g/m^2) for emergency use is also allowed as prior therapy. Patients age 18 to 70 years old who meet diagnostic criteria for AML according to the WHO classification for AML. Previously untreated AML (≥20% blasts). Note that prior short-term therapy (≤7 days) with hydroxyurea, steroids, biological or targeted therapy (e.g. FLT3 inhibitors, other kinase inhibitors, azacitidine, ATRA), or hematopoietic growth factors is allowed. A single or two-day dose of cytarabine (up to 3 g/m2) for emergency use is also allowed as prior therapy. ECOG performance status of 0-3 Adequate organ function, if not suspected to be due to AML, within 14 days of study registration, defined as: Total bilirubin ≤ 2.0 x ULN (unless due to hemolysis) AST and ALT ≤ 3 X ULN (unless believed to be due to tumor involvement) Serum Creatinine ≤ 1.5 x ULN Creatinine Clearance > 30 ml/min Negative urine or serum pregnancy test in females. Patients of reproductive potential (males and females) must consent to and practice double-barrier methods of contraception during treatment and for 12 weeks following the last dose of Omacetaxine. Adequate contraception is defined as double-barrier protection (i.e., condom plus spermicide in combination with a diaphragm, cervical/vault cap, or intrauterine device). Birth control pills, birth control patches and/or injections of hormones to prevent pregnancy are not considered an adequate method of preventing pregnancy, and double-barrier protection is required while on study and for 12 weeks after last dose. Patients will be instructed to notify the investigator if pregnancy is discovered either during or within 12 weeks of completing treatment with Omacetaxine. This also applies to male patients whose partners become pregnant while the patient is on study or within the 12 week period after the last dose of study drug. Patients must be willing and able to review, understand, and provide written consent before starting therapy. Exclusion Criteria: Acute promyelocytic leukemia. Investigational drug within 4 weeks of study entry. Cardiac insufficiency grade III or IV New York Heart Association (NYHA) Female subjects who are pregnant or breast feeding. Patients who are HIV positive. Active uncontrolled infection or severe systemic infection (enrollment is possible after control of infection). Concurrent malignancy (other than AML) with an estimated life expectancy less than two years and requiring active therapy. Psychological, familial, sociological, or geographical condition that would preclude study compliance and follow-up. Uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or medically relevant active conduction system abnormalities. Prior to study entry, any ECG abnormality at screening has to be documented by the investigator as not medically relevant. Pregnant or breastfeeding: Omacetaxine is a Pregnancy Category D medication and has caused embryo-fetal death in animals. Confirmation that the subject is not pregnant must be established by a negative urine β-human chorionic gonadotropin (β-hCG) pregnancy test result obtained during screening. Pregnancy testing is not required for post-menopausal or surgically sterilized women. Other severe acute or chronic medical or psychiatric condition, or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for enrollment in this study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1: Omacetaxine at Dose level at 0.625mg/m^2<br>Patients will receive Omacetaxine at Dose level 0.625mg/m^2, Cytarabine and Idarubicin as part of the treatment plan. Study participants will follow in outpatient clinic at least every 2 months for a total of 6 months. A final study visit will occur 6 months (+/-1 week) after the last dose of Omacetaxine. This visit will end study participation unless there is ongoing toxicity that is at least possibly related to study treatment. In this case, the patient will be followed as medically appropriate until resolution or stabilization of the adverse event. | Drug: Cytarabine<br>* Cytarabine (100mg/m^2/day) in 1000ml NS as a continuous IV infusion over 24 hours x 7 days.<br>* Other names: Cytosine arabinoside, Ara-C, Cytosar;Drug: Idarubicin<br>* Idarubicin (12 mg/m^2/day) IVPB in 100 mL NS over 15 minutes daily from Days 1 to 3.<br>* Other names: Idamycin PFS, Idamycin®;Drug: Omacetaxine mepesuccinate<br>* Omacetaxine administered subcutaneously Q12 hours Days 1 to 7. Dose level 0.625mg/m^2<br>|
| Experimental: Cohort 2: Omacetaxine at Dose level at 1.25mg/m^<br>Patients will receive Omacetaxine at Dose level 1.25mg/m^2, Cytarabine and Idarubicin as part of the treatment plan. Study participants will follow in outpatient clinic at least every 2 months for a total of 6 months. A final study visit will occur 6 months (+/-1 week) after the last dose of Omacetaxine. This visit will end study participation unless there is ongoing toxicity that is at least possibly related to study treatment. In this case, the patient will be followed as medically appropriate until resolution or stabilization of the adverse event. | Drug: Cytarabine<br>* Cytarabine (100mg/m^2/day) in 1000ml NS as a continuous IV infusion over 24 hours x 7 days.<br>* Other names: Cytosine arabinoside, Ara-C, Cytosar;Drug: Idarubicin<br>* Idarubicin (12 mg/m^2/day) IVPB in 100 mL NS over 15 minutes daily from Days 1 to 3.<br>* Other names: Idamycin PFS, Idamycin®;Drug: Omacetaxine mepesuccinate<br>* Omacetaxine administered subcutaneously Q12 hours Days 1 to 7. Dose level 1.25mg/m^2<br>|
| Experimental: Cohort 3: Omacetaxine at Dose level at 2.0mg/m^<br>Patients will receive Omacetaxine at Dose level 2.0mg/m^2, Cytarabine and Idarubicin as part of the treatment plan. Study participants will follow in outpatient clinic at least every 2 months for a total of 6 months. A final study visit will occur 6 months (+/-1 week) after the last dose of Omacetaxine. This visit will end study participation unless there is ongoing toxicity that is at least possibly related to study treatment. In this case, the patient will be followed as medically appropriate until resolution or stabilization of the adverse event. | Drug: Cytarabine<br>* Cytarabine (100mg/m^2/day) in 1000ml NS as a continuous IV infusion over 24 hours x 7 days.<br>* Other names: Cytosine arabinoside, Ara-C, Cytosar;Drug: Idarubicin<br>* Idarubicin (12 mg/m^2/day) IVPB in 100 mL NS over 15 minutes daily from Days 1 to 3.<br>* Other names: Idamycin PFS, Idamycin®;Drug: Omacetaxine mepesuccinate<br>* Omacetaxine administered subcutaneously Q12 hours Days 1 to 7. Dose level 2.0mg/m^2<br>|
| Experimental: Cohort 4: Omacetaxine at Dose level at 3.0mg/m^<br>Patients will receive Omacetaxine at Dose level 3.0mg/m^2, Cytarabine and Idarubicin as part of the treatment plan. Study participants will follow in outpatient clinic at least every 2 months for a total of 6 months. A final study visit will occur 6 months (+/-1 week) after the last dose of Omacetaxine. This visit will end study participation unless there is ongoing toxicity that is at least possibly related to study treatment. In this case, the patient will be followed as medically appropriate until resolution or stabilization of the adverse event. | Drug: Cytarabine<br>* Cytarabine (100mg/m^2/day) in 1000ml NS as a continuous IV infusion over 24 hours x 7 days.<br>* Other names: Cytosine arabinoside, Ara-C, Cytosar;Drug: Idarubicin<br>* Idarubicin (12 mg/m^2/day) IVPB in 100 mL NS over 15 minutes daily from Days 1 to 3.<br>* Other names: Idamycin PFS, Idamycin®;Drug: Omacetaxine mepesuccinate<br>* Omacetaxine administered subcutaneously Q12 hours Days 1 to 7. Dose level 3.0mg/m^2<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Optimally Tolerated Dose | The primary endpoint is determination of the optimally active and safe dose (OD) of Omacetaxine when added to the standard-of-care induction chemotherapy for AML and estimation of the efficacy and response rate. OD will be defined as a dose level at which fewer than 30% of patients experience hematologic toxicity and greater than 50% of patients achieve a CR (50% is an accepted CR rate in AML when using a single induction). | Within 50 days (duration of hematologic recovery) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Toxicity: Describe by the Adverse Events as Assessed by the CTCAE Grading | Describe the adverse events associated with Omacetaxine when administered in combination with cytarabine and Idarubicin as induction therapy for AML, using CTCAE grading | Up to 6 months after last dose of Omacetaxine | 
| Time to Hematologic Recovery | Time to Absolute Neutrophil Count > 1.0 x 10e9/L and Platelet Count > 100 x 10e9/L, whichever was later, for those patients who achieved a remission and achieved these hematologic goals. | Within 6 months of last dose of Omacetaxine | 
| Overall Participant Survival | Observed overall survival among participants (days) | 3 years | 
| Event Free Survival | Observed length of time (days) after which patients remained free of recurrence or death. | 6 months | 
| Progression Free Survival | Among the participants who achieved CR,CRi, progression free survival in number of days, i.e. the number of days participants who achieved CR/CRi remained alive and in a remission. | 3 years |