Study of Inotuzumab Ozogamicin Combined to Chemotherapy in Older Patients With Philadelphia Chromosome-negative CD22+ B-cell Precursor ALL

Study Overview
=================
Brief Summary
-----------------
The aim of the present EWALL-INO study is to confirm very promising results obtained with a combination of INO and mild chemotherapy in older de novo CD22+ B-ALL patients. For that purpose, safety and efficacy of a weekly INO administration combined to mild-intensity chemotherapy will be evaluated in a cohort of patients aged more than 55 years with newly diagnosed previously untreated Ph-negative (CD22+) BCP-ALL. Conversely to the MDACC miniHCVD-INO study and in order to lower the overall toxicity of the combination, INO will be given as part of the remission induction treatment phase during the first 2 treatment cycles only, in combination with corticosteroid, vincristine, cyclophosphamide and intrathecal prophylaxis only; then, all responding patients will received standard INO-free chemotherapy as consolidation and maintenance.

Detailed Description
-----------------
INO schedule of administration will be as described in the refractory/relapsed INO-VATE study for the first cycle, with sequential day 1/8/15 doses of 0.8, 0.5 and 0.5 mg/m2, respectively. Reduced dose of INO will be used for the second and last cycle (0.5 mg/m2 on day 1/8). This was retained in order: to minimize potential toxicities, including liver disorders and prolonged thrombocytopenia; and to allow delivery of subsequent chemotherapy consolidations cycles.

Official Title
-----------------
A Phase 2 Study of Inotuzumab Ozogamicin (INO) Combined to Chemotherapy in Older Patients With Philadelphia Chromosome-negative CD22+ B-cell Precursor Acute Lymphoblastic Leukemia

Conditions
-----------------
Acute Lymphoblastic Leukemia (ALL) - Philadelphia Chromosome (Ph)-Negative CD22+ B-cell Precursor (BCP)

Intervention / Treatment
-----------------
* Drug: Inotuzumab ozogamicin (INO)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients aged more than 55 years old, With confirmed diagnosis of BCP-ALL according to World Health Organisation (WHO) criteria expressing the CD22 antigen by flow cytometry (20% or more positive blast cells), Without central nervous system (CNS) involvement, Without BCR-ABL fusion by standard cytogenetics, Fluorescence In Situ Hybridization (FISH) analysis and/or RT-PCR, Previously untreated, Eligible to intensive chemotherapy, due to general health status, ECOG performance status ≤ 2, Patients must have the following laboratory values unless considered due to leukemia: AST and ALT ≤ 2.5 x upper the limit of normal (ULN); estimated GFR ≥ 50 mL/min using the MDRD equation; total and direct serum bilirubin ≤ 1.5 x ULN; electrolyte panel within normal ranges for the institution unless attributed to the underlying disease. Written informed consent obtained prior to any screening procedures. Eligible for National Health Insurance in France. Exclusion Criteria: Concurrent therapy with any other investigational agent or cytotoxic drug, Prior documented chronic liver disease, Active Hepatitis B Virus (HBV) or Hepatitis C Virus (HCV) or positive HIV serology, 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 maintenance. 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 and for 3 months following the last dose of maintenance. Any of concurrent severe and/or uncontrolled medical condition, which could compromise participation in the study.

Ages Eligible for Study
-----------------
Minimum Age: 55 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Inotuzumab ozogamicin (INO)<br> | Drug: Inotuzumab ozogamicin (INO)<br>* INO schedule of administration is as follows: First induction course: 0.8 mg/m² on day 1, 0.5 mg/m² on day 8, and 0.5 mg/m² on day 15 Second induction course: 0.5 mg/m² on day 1, and 0.5 mg/m² on day 8<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assessment of overall survival (OS) | The primary objective of the trial is to assess overall survival (OS) observed at 1 year after administration of INO and chemotherapy in older Ph-negative BCP-ALL patients. | one year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assessment of adverse events (AEs) | Type, duration and frequency of AEs up to 3 months of induction course 1 or 2 | 3 months | 
| Rate of complete remission (CR / CRp) | CR/CRp response rate after INO-based induction course 1 and 2 | 35 days | 
| Assessment of Minimal residual disease (MRD) | Flow cytometry and Ig-TCR MRD levels, after INO-based induction course 1 and 2 and impact on outcomes | 35 days | 
| Rate of early death | Early death (ED) rate at 30, 60 and 100 day from treatment initiation | 100 days | 
| Composite measure for Duration of response (DOR), Disease-free survival (DFS) and cumulative incidence of relapse (CIR) | Duration of response (DOR), Disease-free survival (DFS) and cumulative incidence of relapse (CIR) | one year |