Randomized Phase III Study of Intensive Chemotherapy With or Without Dasatinib (Sprycel™)

Study Overview
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Brief Summary
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This is a randomized phase III open-label, multicenter trial evaluating standard induction therapy (daunorubicin [DNR] and cytarabine [Ara-C]) and consolidation therapy (high-dose cytarabine [HDAC]) with or without dasatinib in adult patients with newly diagnosed CBF-AML

Detailed Description
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This is a randomized phase III open-label, multicenter trial evaluating standard induction therapy (daunorubicin [DNR] and cytarabine [Ara-C]) and consolidation therapy (high-dose cytarabine [HDAC]) with or without dasatinib in adult patients with newly diagnosed CBF-AML; in the investigational arm, consolidation therapy is followed by a one-year maintenance therapy with dasatinib. Patients with molecular disease persistence or molecular relapse as assessed by quantitative RQ-PCR for the CBF fusion transcripts will be eligible for hematopoietic stem cell transplantation before overt hematologic relapse occurs. Primary endpoint is event-free survival. AML patients will be assessed for the CBF fusion genes in one of two AMLSG central laboratories within 48 hours of diagnosis, and only patients with CBF-AML will be enrolled.

Official Title
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Randomized Phase III Study of Intensive Chemotherapy With or Without Dasatinib (Sprycel™) in Adult Patients With Newly Diagnosed Core-Binding Factor Acute Myeloid Leukemia (CBF-AML)

Conditions
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Acute Myeloid Leukemia (AML)

Intervention / Treatment
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* Drug: Dasatinib
* Drug: Cytarabine
* Drug: Daunorubicin
* Drug: Idarubicin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Core-binding factor (CBF) AML with molecular diagnosis of RUNX1-RUNX1T1 fusion transcript resulting from t(8;21)(q22;q22.1) (or a variant form) or of CBFB-MYH11 fusion transcript resulting from inv(16)(p13.1q22)/t(16;16)(p13.1;q22) as assessed in one of the central AMLSG reference laboratories (Ulm, Hannover) Age ≥ 18; there is no upper age limit No prior chemotherapy for leukemia except hydroxyurea for up to 5 days during the diagnostic screening phase Non-pregnant and non-nursing. Due to the unknown teratogenic potential of dasatinib in humans, pregnant or nursing patients may not be enrolled. Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test within a sensitivity of at least 25 mIU/mL with-in 72 hours prior to registration. Women of child-bearing potential must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control - one highly effective method (e.g., IUD, hormonal, tubal ligation, or partner's vasectomy), and one additional effective method (e.g., latex condom, diaphragm, or cervical cap) - AT THE SAME TIME, at least four weeks before she begins dasatinib therapy. Women of childbearing potential is defined as a sexually active mature woman who has not undergone a hysterectomy or who has had menses at any time in the preceding 24 consecutive months. Men must agree not to father a child and must use a latex condom during any sexual contact with women of childbearing potential while taking dasatinib and for 3 months after therapy is stopped, even if they have undergone a successful vasectomy. Signed written informed consent. Exclusion Criteria: Performance status WHO >2 Pulmonary edema and/or pleural/pericardial effusion within 14 days of day 1. If edema/effusion resolves to CTC Grade ≤1, patients can be treated with dasatinib. Patients with ejection fraction <50% by echocardiography within 14 days of day 1 Organ insufficiency (creatinine >1.5x upper normal serum level; bilirubin, AST or AP >2.5x upper normal serum level; heart failure NYHA III/IV; severe obstructive or restrictive ventilation disorder) Uncontrolled infection Patients with a currently active second malignancy other than non-melanoma skin cancers. Patients are not considered to have a currently active malignancy, if they have completed therapy and are considered by their physician to be at less than 30% risk of relapse within one year. Severe neurological or psychiatric disorder interfering with ability of giving an informed consent Known positive for HIV, active HBV, HCV, or Hepatitis A infection Bleeding disorder independent of leukemia No consent for registration, storage and processing of the individual disease characteristics and course as well as information of the family physician and/or other physicians involved in the treatment of the patient about study participation. No consent for biobanking.

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Standard arm<br>Patients will receive induction therapy with daunorubicin 60 mg/m2/day administered on days 1-3 (when daunorubicin is not available due to supply shortage: Idarubicin 12mg²/day on days 1,3,5) and cytarabine 200 mg/m2/day administered by continuous IV infusion on days 1-7. Patients achieving PR only at the end of cycle 1 will receive a second induction cycle with daunorubicin 50 mg/m2/day (when daunorubicin is not available due to supply shortage: Idarubicin 10 mg²/day on days 1 and 3) administered on days 1-3 and cytarabine 200 mg/m2/day administered by cont. IV infusion daily on days 1-5. Patients will receive 4 cycles of consolidation therapy. Consolidation therapy consists of high-dose cytarabine 3 g/m2 (>60 years: 1 g/m2) q12h, days 1-3 administered intravenously over three hours. Follow-up period: There is no maintenance therapy in the standard arm. Patients will be closely followed, in particular for molecular disease persistence or molecular relapse. | Drug: Cytarabine<br> <br> * Other names: ARA-cell;Drug: Daunorubicin<br> <br> * Other names: Daunoblastin;Drug: Idarubicin<br> <br> |
| Experimental: Investigational arm<br>Patients will receive induction therapy with daunorubicin 60 mg/m2/day on days 1-3 (when daunorubicin is not available due to supply shortage: Idarubicin 12mg²/day on days 1,3,5) and cytarabine 200 mg/m2/day by cont. IV infusion on days 1-7. Patients will receive dasatinib 100 mg QD on days 8-21. Patients achieving PR only at the end of cycle 1 will receive a 2nd induction cycle with daunorubicin 50 mg/m2/day on days 1-3 (when daunorubicin is not available due to supply shortage: Idarubicin 10 mg²/day on days 1 and 3) and cytarabine 200 mg/m2/day by cont. IV infusion on days 1-5. Patients will receive dasatinib 100 mg QD on days 6-21. Consolidation therapy (4 cycles). Treatment consists of high-dose cytarabine 3 g/m2 (>60 years: 1 g/m2) q12h, days 1-3 iv over 3 hours. Patients will receive dasatinib 100 mg QD on days 4-21. Maintenance therapy: Patients completing consolidation therapy will continue to receive single agent dasatinib 100 mg QD for one year (or until relapse). | Drug: Dasatinib<br> <br> * Other names: Sprycel;Drug: Cytarabine<br> <br> * Other names: ARA-cell;Drug: Daunorubicin<br> <br> * Other names: Daunoblastin;Drug: Idarubicin<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-free Survival | To assess event-free survival (EFS) after intensive induction (daunorubicin and cytarabine) and consolidation (high-dose cytarabine) chemotherapy with or without dasatinib in patients with CBF-AML | 4 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cumulative incidence of relapse (CIR) |  | 4 years | 
| Cumulative incidence of death (CID) |  | 4 years | 
| overall survival |  | 4 years | 
| relapse-free survival |  | 4 years | 
| PIA analysis | Pharmacodynamic inhibition of KIT as assessed by the KIT plasma inhibitory assay (PIA) | 4 years | 
| toxicity | Type, frequency, severity (graded using the National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] version 4.03), timing and relatedness of non-hematologic toxicity observed during different treatment cycles. | 7 months (standard arm) / 19 months (investigational arm) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AML, Dasatinib, Core Binding Factor (CBF)