Blinatumomab Followed by High-dose Chemotherapy for Ph-negative Acute Lymphoblastic Leukemia (ALL)

Primary Objective:

To evaluate the percentage of complete molecular responses after two cycles of induction therapy composed of a single cycle of blinatumomab followed by chemotherapy. Molecular response id monitored by a patient-specific Ig/TCR rearrangements in an assay with the sensitivity of at least 10e-04.

Outline:

Run-in phase: dexamethasone 10 mg/m2 PO (day 1-7), cyclophosphamide IV 200 mg/m2 (day 3-5), vincristine 2 mg IV (day 6), daunorubicin 45 mg/m2 IV (day 6-7), G-CSF until recovery, methotrexate 15 mg IT.

Day 11: Screening to the study. Induction I: blinatumomab 9 µg/day IV continuously (day 12-19), dose step to 28 µg/day (day 19-40). Induction II: dexamethasone 10 mg/m2 PO (day 50-54), vindesine 3 mg/m2 IV (day 50), methotrexate 1.5 g/m2 IV (day 50), etoposide 250 mg/m2 IV (day 53-54), cytarabine 2x 2 g/m2 IV (day 54), G-CSF until recovery, methotrexate 15 mg + cytarabine 40 mg + dexamethasone 4 mg IT (day 60).

Week 11: Primary endpoint assessment.

• Complete Remission (CR) and Complete Remission with incomplete blood count recovery(CRi) continue with Consolidation I;
• no CR/CRi: end of study, salvage regimen upon the investigator´s decision.

Consolidation I (week 13): rituximab 375 mg/ m2 IV (day 0, if CD20+ at diagnosis), methotrexate 1.5 g/m2 IV (day 1, 15), PEG-asparaginase 2000 U/m2 IV (day 2, 16), 6-MP 60 mg/m2 PO (day 1-7, 15-21), methotrexate 15 mg + cytarabine 40 mg + dexamethasone 4 mg IT (day 1).

Week 18 assessment:

• CR/CRi and MRD <10-4: continue the protocol;
• CR/CRi and MRD ≥10-4;

• and CR/CRi on day 40 or ≥50% reduction of bone marrow blasts on day 40: 1-2 cycles of blinatumomab followed by alloSCT;
• and no CR/CRi on day 40 and <50% reduction of bone marrow blasts on day 40: 1 cycle of high dose chemotherapy followed by alloSCT;
• relapse: end of study.

Consolidation II (week 19): rituximab 375 mg/ m2 IV (day 0, if CD20+ at diagnosis), prednisone 60 mg/m2 PO (day 1-14), vindesine 3 mg/m2 IV (day 1, 7), adriamycine 50 mg/m2 IV (day 1, 7), cyclophosphamide 1000 mg/m2 IV (day 15), cytarabine 75 mg/m2 IV (day 17-20, 24-27), thioguanine 60 mg/m2 PO (day 15-28), methotrexate 15 mg + cytarabine 40 mg + dexamethasone 4 mg IT (day 1), methotrexate 15 mg IT (day 17, 24). Consolidation III+VI (week 27 and 43): rituximab 375 mg/ m2 IV (day 0, if CD20+ at diagnosis), methotrexate 1.5 g/m2 IV (day 1, 15), PEG-asparaginase 2000 U/m2 IV (day 2, 16), 6-MP 60 mg/m2 PO (day 1-7, 15-21). Consolidation IV (week 33): rituximab 375 mg/ m2 IV (day 0, if CD20+ at diagnosis), cytarabine 1000 mg/m2 IV (day 1, 3, 5), methotrexate 15 mg + cytarabine 40 mg + dexamethasone 4 mg IT (day 8). Consolidation V (week 38): rituximab 375 mg/ m2 IV (day 0, if CD20+ at diagnosis), cyclophosphamide 1000 mg/m2 IV (day 1), cytarabine 500 mg/m2 IV (day 1), methotrexate 15 mg + cytarabine 40 mg + dexamethasone 4 mg IT (day 1).

Maintenance (start at week 49, duration 12 months): 6-MP 60 mg/m2 PO daily, methotrexate 20 mg/m2 weekly.

(Doses of daunorubicin, methotrexate, cytarabine and PEG-asparaginase are reduced in patients >55 years.)

Inclusion criteria

• Age 18-65 years;
• Lymphoblasts positive for CD19;
• Eligible to intensive chemotherapy, due to general health status;
• With newly diagnosed B-precursor-ALL;
• Without BCR-ABL fusion by FISH analysis and/or RT-PCR;
• Blasts expressing the CD19 antigen by flow cytometry;
• Previously untreated;
• ECOG (Eastern Cooperative Oncology Group) performance status ≤ 2;
• Diagnostic sample of bone marrow (or peripheral blood with >50% of blasts) available for central MRD assessment
• Written informed consent obtained prior to any screening procedures.

Exclusion criteria

• History of malignancy other than ALL within 5 years prior to start of protocol-required therapy, except for:

• Malignancy treated with curative intent and with no known active disease present for 5 years before enrollment and felt to be at low risk for recurrence by the treating physician;
• Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease;
• Adequately treated cervical carcinoma in situ without evidence of disease;
• Adequately treated breast ductal carcinoma in situ without evidence of disease;
• Prostatic intraepithelial neoplasia without evidence of prostate cancer.
• History or presence of central nervous system (CNS) pathology as epilepsy, childhood or adult seizure, paresis, aphasia, stroke, severe brain injuries, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, psychosis;
• Persisting ALL in the CNS at the end of run-in period; patients with initial cerebrospinal fluid (CSF) infiltration arriving into CSF negativity after up to 4 intrathecal applications of chemotherapy within the first 10 days of therapy are allowed for the study;
• Current autoimmune disease or history of autoimmune disease with potential CNS involvement;
• Active known hepatitis B virus (HBV) or hepatitis C virus (HCV) or positive HIV serology;
• Hypersensitivity to any active substance contained in blinatumomab, including polysorbate 80;
• Vaccination with a live virus vaccine within 4 weeks prior to the study enrolment;
• Female patients who are pregnant or breast feeding or patients of childbearing potential not willing to use a double barrier method of contraception during the study and for 3 months following the last dose of study drug;
• Male patients whose sexual partner(s) are women of childbearing potential who are not willing to use a double barrier method of contraception, one of which includes a condom, during the study;
• Any of concurrent severe and/or uncontrolled medical condition, which could, in the opinion of the investigator, compromise participation in the study;
• Concurrent participation in another clinical study with an investigational medical product.