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

This is a phase II interventional trial to evaluate the efficacy of blinatumomab followed by high-dose chemotherapy in the first-line treatment for Ph-negative acute lymphoblastic leukemia (ALL) in adults. The aim is to increase the number of complete molecular responses after first two cycles of therapy. Early molecular response is considered to be the most powerful prognostic factor in ALL. Thus, a higher proportion of early molecular responses should translate into improved survival and fewer indications for allogeneic stem cell transplants

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.)

Eligibility Criteria:
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.