Combination of Sorafenib and Omacetaxine Mepesuccinate in Newly Diagnosed or Relapsed/Refractory AML Carrying FLT3-ITD

Study Overview
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Brief Summary
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The study aims to test if combination of sorafenib and omacetaxine mepesuccinate (OM, also known as homoharringtonine) results in durable composite complete remission (CRc) in patients with newly diagnosed or relapsed/refractory (R/R) acute myeloid leukemia (AML) carrying FLT3-ITD (Fms-Like Tyrosine Kinase 3 - Internal Tandem Duplication).

Detailed Description
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The type of AML being studied in this clinical trial is known as FMS-like tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD) positive AML. This type of AML has an alteration (or mutation) in genes, which may associated with high risk of relapse after conventional chemotherapy and hence an extremely poor clinical outcome. FLT3 inhibitors including sorafenib are effective in inducing remission. However, their effects are only transient. There is an unmet clinic need to enhance their effectiveness, hence clinical application. This is a Phase II single-arm open-labeled study. A total of 40 eligible patients with consent will be recruited, including 20 patients with newly diagnosed and 20 with R/R FLT3-ITD AML. For newly diagnosed patients, diagnostic bone marrow (BM) and/or peripheral blood (PB) will be evaluated by next generation sequencing (NGS) based on myeloid panel that comprises 54 myeloid genes as well as their in vitro response to sorafenib and omacetaxine mepesuccinate (OM) based on an in-house platform that was established in our laboratory. FLT3-ITD allelic burden will also be evaluated. For R/R patients, FLT3-ITD status and allelic burden will be confirmed before treatment. Both groups of patients will receive sorafenib 400 mg twice daily continuously and OM 1.5 mg/m2 daily for 7 days every 28 days until progression or allogeneic hematopoietic stem cell transplantation (HSCT). Thereafter, patients will be followed up and information about disease status and survival will be collected. BM examination will be performed on day 28 to document morphological response and FLT3-ITD allelic burden. At leukemia progression, BM and/or PB samples will be collected and their in vitro response to sorafenib and OM examined. The tyrosine kinase domain (TKD) of FLT3 will also be sequenced and FLT3-ITD allelic burden will be evaluated.

Official Title
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A Phase II Single-arm Open-labeled Study Evaluating Combination of Sorafenib and Omacetaxine Mepesuccinate in Newly Diagnosed or Relapsed/Refractory AML Carrying FLT3-ITD

Conditions
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AML, FLT3-ITD Mutation

Intervention / Treatment
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* Drug: Sorafenib
* Drug: Omacetaxine Mepesuccinate Injection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provision of written informed consent approved by the Institutional Review Board (IRB). Age ≥18 years Documented primary AML or AML secondary to myelodysplastic syndrome (MDS), as defined by World Health Organization criteria At diagnosis or in morphological relapse after an initial remission or refractory after induction chemotherapy, with or without HSCT Documentation of FLT3-ITD in BM or blood with allelic burden of ≥ 20% as determined by the study site laboratory ECOG performance score 0-2 Serum creatinine ≤1.5×upper limit of normal (ULN), or glomerular filtration rate >25 mL/min, as calculated with the Cockcroft-Gault formula. Serum potassium, magnesium, and calcium (corrected for albumin) within institutional normal limits. Subjects with electrolytes outside the normal range will be eligible if these values are corrected upon retesting following any necessary supplementation. Total serum bilirubin ≤1.5×ULN. Serum aspartate transaminase (AST) and/or alanine transaminase (ALT) ≤ 2.5×ULN. Exclusion Criteria: Acute promyelocytic leukemia (AML subtype M3) Prior treatment with any FLT3 inhibitors Known infection with human immunodeficiency virus, or active hepatitis B or C infection. Refusal of blood product transfusion. In a man whose sexual partner is a woman of childbearing potential, unwillingness or inability of the man or woman to use an acceptable contraceptive method for the entire study treatment period and for at least 3 months after study treatment completion In a heterosexually active woman of childbearing potential, unwillingness or inability to use an acceptable contraceptive method for the entire study treatment period and for at least 3 months after study treatment completion Pregnancy Female subjects must agree not to breastfeed at screening and throughout the study period, and for 45 days after the final study drug 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: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: sorafenib and Omacetaxine Mepesuccinate<br>The starting dose of sorafenib will be 400 mg twice daily. Sorafenib should be taken continuously throughout the treatment period unless there is no evidence of response at first assessment on day 28 or progressive disease at any time during the treatment. OM will be given at 1.5 mg/m2/day (maximum dose 3 mg) for 7 days (concurrently with sorafenib) in 28-day cycle. Sorafenib and OM will be continued until leukemia progression or allogeneic HSCT. Thereafter, patients will be followed up and information about disease status and survival will be collected. | Drug: Sorafenib<br>* Sorafenib a kinase inhibitor indicated for the treatment of Unresectable hepatocellular carcinoma; Advanced renal cell carcinoma<br>* Other names: NEXAVAR;Drug: Omacetaxine Mepesuccinate Injection<br>* Omacetaxine Mepesuccinate is a pharmaceutical drug substance that is indicated for treatment of chronic myeloid leukemia (CML)<br>* Other names: homoharringtonine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete remission | No increase in blasts in BM or PB (<5% of total nucleated cells), with absolute neutrophil count ≥ 1x109/L and platelet count ≥ 100 x109/L | up to 16 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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FLT3-ITD (+) Acute Myeloid Leukemia (AML)