A Study of Oral Sapacitabine in Elderly Patients With Newly Diagnosed Acute Myeloid Leukemia

Study Overview
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Brief Summary
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This Phase 3 study assesses two drug regimens as the initial treatment of patients who are at least 70 years of age and have newly diagnosed acute myeloid leukemia (AML) for whom the doctor does not recommend the use of standard intensive treatment or the patient has decided not to receive standard intensive treatment after being fully informed about its benefits and risks by his/her doctor. The two drug regimens are sapacitabine administered in alternating cycles with decitabine or decitabine alone. The purpose of the study is to learn which drug regimen is more likely to keep AML in check as long as possible.

Detailed Description
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This is a multicenter, randomized, Phase 3 study (SEAMLESS) comparing two drug regimens (arms) as the front-line treatment of elderly patients aged 70 years or older with newly diagnosed acute myeloid leukemia (AML) who are not candidates for intensive induction chemotherapy. In Arm A, sapacitabine is administered in alternating cycles with decitabine, and in Arm C decitabine is administered alone. The primary efficacy endpoint is overall survival. The study is designed to demonstrate an improvement in overall survival of Arm A versus Arm C.

Official Title
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A Phase III Randomized Study of Oral Sapacitabine in Elderly Patients With Newly Diagnosed Acute Myeloid Leukemia

Conditions
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Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: Sapacitabine
* Drug: Decitabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Newly diagnosed AML based on WHO (World Health Organization) classification Age 70 years or older for whom the treatment of choice is low-intensity therapy by investigator assessment or who has refused intensive induction therapy recommended by investigator ECOG (Eastern Cooperative Oncology Group) performance status 0-2 Adequate renal function Adequate liver function Able to swallow capsules Agree to practice effective contraception Ability to understand and willingness to sign the informed consent form Exclusion Criteria: AML is of the sub-type of acute promyelocytic leukemia or extramedullary myeloid tumor without bone marrow involvement Having received any systemic anti-cancer therapy for AML or received treatment with hypomethylating agents or cytotoxic chemotherapy for preceding myelodysplastic syndrome (MDS) or myeloproliferative disease (MPD) Known or suspected central nervous system (CNS) involvement by leukemia Uncontrolled intercurrent illness Known hypersensitivity to decitabine Known to be HIV-positive

Ages Eligible for Study
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Minimum 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: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sapacitabine-decitabine alternating<br>Arm A sapacitabine administered in alternating cycles with decitabine | Drug: Sapacitabine<br>* Oral sapacitabine capsules<br>* Other names: CYC682;Drug: Decitabine<br>* Decitabine intravenous<br>* Other names: Decitabine intravenous;|
| Active Comparator: Decitabine<br>Arm C Decitabine | Drug: Decitabine<br>* Decitabine intravenous<br>* Other names: Decitabine intravenous;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | The distribution of overall survival was estimated by the method of Kaplan and Meier. A log-rank analysis stratified by randomization stratification factors was used to compare overall survival between Arm A (decitabine/sapacitabine) versus Arm C (decitabine). Cox proportional hazards models were used to identify predictive factors for overall survival. | up to 43 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete Remission (CR) | Normalization of peripheral neutrophils to >=1000 /microliter, platelet to >=100,000/microliter within 2 weeks of bone marrow biopsy/aspirate, and bone marrow to <=5 % blasts; independent of transfusions*; and no extramedullary leukemia. * independent of transfusions refer to no platelet transfusion for 1 week prior to achieving the response | up to 43 months | 
| Complete Remission With Incomplete Platelet Count Recovery (CRp) | Normalization of bone marrow to <=5% blasts; peripheral neutrophils >=1000 /microliter, platelet <=100,000 /microliter within 2 weeks of bone marrow biopsy/aspirate; independent of transfusions*; and no extramedullary leukemia. *independent of transfusions refer to no platelet transfusion for 1 week prior to achieving the response | up to 43 months | 
| Partial Remission (PR) | Normalization of peripheral neutrophils to >=1000 /microliter, platelet to >=100,000/microliter within 2 weeks of bone marrow biopsy/aspirate, >=50% decrease in bone marrow blasts over pre-treatment but still >5%; independent of transfusions* *independent of transfusions refer to no platelet transfusion for 1 week prior to achieving the response | up to 43 months | 
| Hematological Improvement | HI with duration (HI) Erythroid response (HI-E) for patients with pre-treatment hemoglobin < 11 g/dL; Major response: >2 g/dL increase in hemoglobin; for RBC, transfusion independence* Minor response: 1 to 2 g/dL increase in hemoglobin; for RBC, a 50% decrease in transfusion requirements Platelet response (HI-P) for pre-treatment platelet count <100,000/mm3; Major response: an absolute increase of platelet count by >=30,000/mm3; stabilization of platelet counts and platelet transfusion independence* Minor response: >=50% increase in platelet count with a net increase > 10,000/mm3 but <30,000/mm3 Neutrophil response (HI-N) for absolute neutrophil count (ANC) < 1,500/mm3 before therapy; Major response: >=100% increase, or an absolute increase of >500/mm3, whichever is greater Minor response: >=100% increase, but absolute increase < 500/mm3 independent of transfusions refer to no platelet transfusion for 1 week prior to achieving the response | up to 43 months | 
| Stable Disease (SD) | Failure to achieve at least hematologic improvement (HI), but no evidence of clinically significant progression for > 16 weeks. | up to 43 months | 
| Blood Products Transfused | Number of units of packed red blood cells (PRBC) and/or platelet transfusions administered per 8-week period prior to the first dose of study drug and through the date of treatment discontinuation. | up to 43 months | 
| Hospitalized Days | In-patient days in hospital. | up to 12 months | 
| 1-year Survival | One-year survival is the percentage of patients who are alive at 1-year measured from the date of randomization. | Percentage of patients alive at 1 year after randomization (participants were assessed up to 43 months for overall survival curve estimation but this measure presents the 1 year survival rate percentage). | 
| Duration of Complete Remission (dCR) | Durations of normalization of peripheral neutrophils to >=1000 /microliter, platelet to >=100,000/microliter within 2 weeks of bone marrow biopsy/aspirate, and bone marrow to <=5 % blasts; independent of transfusions*; and no extramedullary leukemia. * independent of transfusions refer to no platelet transfusion for 1 week prior to achieving the response | up to 43 months | 
| Duration of Complete Remission With Incomplete Platelet Count Recovery (dCRp) | Duration of normalization of bone marrow to <=5% blasts; peripheral neutrophils >=1000 /microliter, platelet <=100,000 /microliter within 2 weeks of bone marrow biopsy/aspirate; independent of transfusions*; and no extramedullary leukemia. *independent of transfusions refer to no platelet transfusion for 1 week prior to achieving the response | up to 43 months | 
| Duration of Partial Remission (dPR) | Duration of normalization of peripheral neutrophils to >=1000 /microliter, platelet to >=100,000/microliter within 2 weeks of bone marrow biopsy/aspirate, >=50% decrease in bone marrow blasts over pre-treatment but still >5%; independent of transfusions* *independent of transfusions refer to no platelet transfusion for 1 week prior to achieving the response | up to 43 months | 
| Duration of Hematological Improvement (dHI) | Duration of HI Erythroid response (HI-E) for patients with pre-treatment hemoglobin < 11 g/dL; Major response: >2 g/dL increase in hemoglobin; for RBC, transfusion independence* Minor response: 1 to 2 g/dL increase in hemoglobin; for RBC, a 50% decrease in transfusion requirements Platelet response (HI-P) for pre-treatment platelet count <100,000/mm3; Major response: an absolute increase of platelet count by >=30,000/mm3; stabilization of platelet counts and platelet transfusion independence* Minor response: >=50% increase in platelet count with a net increase > 10,000/mm3 but <30,000/mm3 Neutrophil response (HI-N) for absolute neutrophil count (ANC) < 1,500/mm3 before therapy; Major response: >=100% increase, or an absolute increase of >500/mm3, whichever is greater Minor response: >=100% increase, but absolute increase < 500/mm3 independent of transfusions refer to no platelet transfusion for 1 week prior to achieving the response | up to 43 months | 
| Duration of Stable Disease (dSD) | Failure to achieve at least hematologic improvement (HI), but no evidence of clinically significant progression for > 16 weeks. | up to 43 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AML