D-ALBA Frontline Sequential Dasatinib and Blinatumomab in Adult Philadelphia Positive Acute Lymphoblastic Leukemia

Study Overview
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Brief Summary
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This study aims at exploring the activity of a frontline approach based on dasatinib plus steroids administration as induction treatment, followed by the infusion of Blinatumomab, in adult Ph+ ALL.

Official Title
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D-ALBA Front-Line Sequential Treatment of Adult Philadelphia Chromosome Positive (Ph+) Acute Lymphoblastic Leukemia (ALL) Patients With Dasatinib and the Bispecific Monoclonal Antibody Blinatumomab

Conditions
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Acute Lymphoblastic Leukemia

Intervention / Treatment
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* Drug: Dasatinib
* Drug: Blinatumomab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Newly diagnosed adult B-precursor Ph+ ALL patients. Age greater or equal to18 years, Signed written informed consent according to ICH/EU/GCP and national local laws. ECOG Performance Status 0 or 1 and/or WHO performance status less or equal to 2. Renal and hepatic function as defined below: AST (GOT), ALT (GPT), and AP <2 x upper limit of normal (ULN). Total bilirubin <1.5 x ULN. Creatinine clearance equal or greater than 50 mL/min. Pancreatic function as defined below: Serum amylase less or equal to 1.5 x ULN Serum lipase less or equal to1.5 x ULN. Normal cardiac function. Negative HIV test, negative HBV DNA and HCV RNA. Negative pregnancy test in women of childbearing potential. Bone marrow specimen from primary diagnosis available. Exclusion Criteria: History of or current relevant CNS pathology (current ≥grade 2 epilepsy, seizure, paresis, aphasia, clinically relevant apoplexia, severe brain injuries, dementia, Parkinson's disease, organic brain syndrome, psychosis). Impaired cardiac function, including any one of the following: LVEF <45% as determined by MUGA scan or echocardiogram. Complete left bundle branch block. Use of a cardiac pacemaker. ST depression of >1mm in 2 or more leads and/or T wave inversions in 2 or more contiguous leads. Congenital long QT syndrome. History of or presence of significant ventricular or atrial arrhythmia. Clinically significant resting bradycardia (<50 beats per minute). QTc >450 msec on screening ECG (using the QTcF formula). Right bundle branch block plus left anterior hemiblock, bifascicular block. Myocardial infarction within 3 months prior to starting Dasatinib. Angina pectoris. Other clinically significant heart disease (e.g., congestive heart failure, uncontrolled hypertension, history of labile hypertension, or history of poor compliance with an antihypertensive regimen). Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of Dasatinib (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection). History of or current autoimmune disease. Systemic cancer chemotherapy within 2 weeks prior to study. Known hypersensitivity to immunoglobulins or to any other component of the study drug formulation. Active malignancy other than ALL with the exception of basal cell or squamous cell carcinoma of the skin, or carcinoma in situ of the cervix. Active infection, any other concurrent disease or medical conditions that are deemed to interfere with the conduct of the study as judged by the investigator. Nursing women or women of childbearing potential not willing to use an effective form of contraception during participation in the study and at least 3 months thereafter or male patients not willing to ensure effective contraception during participation in the study and at least three months thereafter.

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: Treatment<br>Adult Ph+ ALL (≥18 years old, with no upper age limit) patients will begin treatment with Dasatinib, 140 mg/day, from day 1 to day +84. Prednisone (PDN) will be administered from day -6 to day +0 (during which the presence of the BCR/ABL1 alteration will be established), at escalating doses up to 60 mg/m2; PDN will be continued up to day +24 and progressively tapered up to day +31. HLA typing will be performed immediately after the diagnosis for eligible patients. MRD will be evaluated by RT-PCR at fixed time points (days +22, +45, +57) during the induction and at day +85, the latter for molecular response evaluation. | Drug: Dasatinib<br>* Adult Ph+ ALL (≥18 years old, with no upper age limit) patients will begin treatment with Dasatinib, 140 mg/day, from day 1 to day +84.<br>Drug: Blinatumomab<br>* Upon induction: patients in CHR will receive Blinatumomab at a dose of 15 µg/m²/day as continuous intravenous infusion (CIVI) at a constant flow rate for four weeks, followed by a two-week infusion-free interval, defined as one treatment cycle. At least 2 cycles should be administered, up to a maximum of 5 cycles, if deemed necessary.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients who achieve Minimal Residual Disease (MRD) negativity upon treatment | In particular, after 2 cycles of blinatumomab. Minimal Residual Disease (MRD) negativity is intended as Complete Molecular Remission (CMR) | After 11 months from study entry | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients completing the 2 cycles of blinatumomab and alive in first complete hematologic remission (CHR) |  | From day +85 at 12 months | 
| Number of patients at Complete Molecular Response (CMR) |  | At day +22, +45, +57 and +85 from study entry | 
| Number of months of the CMR |  | At 12 and 24 months | 
| Number of patients in Overall Survival (OS) |  | At 12 and 24 months | 
| Number of grade >3 adverse events |  | At 12 and 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acute Lymphoblastic Leukemia, adult, dasatinib, blinatumomab