Inotuzumab Ozogamicin and Conventional Chemotherapy In Patients Aged 56 Years and Older With ALL

Study Overview
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Brief Summary
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The trial proposed to evaluate the efficacy and safety of an inotuzumab ozogamicin followed by maintenance treatment in patients with acute lymphoblastic leukemia older than 56 years

Detailed Description
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Despite recent advances especially in younger patients, the prognosis of elderly patients with ALL remains dismal with a 5-year survival rate of around 20%, even after intensive chemotherapy. Inotuzumab ozogamicin (PF-05208773; CMC-544) is an antibody-targeted intravenous (IV) chemotherapy agent composed of an anti-CD22 antibody linked to calicheamicin, a potent cytotoxic antitumor antibiotic. After a prephase treatment, induction therapy will be based on three cycles of inotuzumab ozogamicin and intrathecal therapy only. This will be followed by a conventional maintenance therapy. All patients will be followed for cytological response, minimal residual disease and safety parameters.

Official Title
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Open Label Phase II Study to Evaluate the Efficacy and Safety of Inotuzumab Ozogamicin for Induction Followed by Chemotherapy Consolidation and Maintenance Therapy In Patients Aged 56 Years and Older With Acute Lymphoblastic Leukemia (ALL)

Conditions
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Precursor Cell Lymphoblastic Leukemia

Intervention / Treatment
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* Drug: Inotuzumab ozogamicin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female patients, ≥56 years of age and contraindication for age-adapted consolidation chemotherapy due to age (≥75 years) and/or severe co-morbidities (>2 per Charlson Score). Newly diagnosed acute lymphoblastic leukemia (>25% marrow blasts, assessed by morphology; i.e. M3 marrow) Leukemic blasts must have CD22 surface expression of at least 20%, assessed by local/institutional flow cytometry of a bone marrow aspirate sample (assessment of CD22 via the reference lab for immunophenotyping is strongly recommended). In the case of an inadequate aspirate sample (dry tap), flow cytometry of peripheral blood specimen may be substituted if the patient has circulating blasts; alternatively, CD22 expression may be documented by immunohistochemistry of a bone marrow biopsy specimen No previous ALL-specific treatment with the exception of corticosteroids and/or single dose vincristine and/or a maximum of three doses of cyclophosphamide (cumulative dose of 600 mg/m2) and the standard prephase treatment With or without documented CNS involvement Adequate liver function, including total serum bilirubin < 2.0 x upper limit of normal (ULN) unless the patient has documented Gilbert syndrome, and aspartate and alanine aminotransferase (AST and ALT) < 2.5 x ULN. If organ function abnormalities are considered due to leukemic infiltration of the liver, total serum bilirubin must be < 2.5 x ULN and AST/ALT < 5 x ULN Serum creatinine <1.5 x ULN or any serum creatinine level associated with a measured or calculated creatinine clearance of >40 mL/min WHO performance status ≤ 2 Signed written inform consent Inclusion in GMALL registry Exclusion Criteria: Philadelphia-chromosome or BCR-ABL positive ALL Burkitt's or mixed phenotype acute leukemia based on the WHO 2008 criteria Peripheral absolute lymphoblast count >10,000/μL after pre-phase treatment and before start of study medication Known systemic vasculitis (e.g. , Wegener's granulomatosis, polyarteritis nodosa, systemic lupus erythematosus), primary or secondary immunodeficiency (such as HIV infection or severe inflammatory disease) Current or chronic hepatitis B or C infection as evidenced by hepatitis B surface antigen and anti-hepatitis C antibody positivity, respectively, or known seropositivity for human immunodeficiency virus (HIV) Major surgery within < 4 weeks before entry on study Unstable or severe uncontrolled medical condition (e.g., unstable cardiac function or unstable pulmonary condition) Concurrent active malignancy other than non-melanoma skin cancer, carcinoma in situ of the cervix, or localized prostate cancer that has been definitely treated with radiation or surgery; patients with previous malignancies are eligible provided that they have been disease free for >2 years Cardiac function, as measured by left ventricular ejection fraction (LVEF) that is less than 45%, or the presence of New York Heart Association (NYHA) stage III or IV congestive heart failure Myocardial infarction < 6 months before entry on study History of clinically significant ventricular arrhythmia, or unexplained syncope not believed to be vasovagal in nature, or chronic bradycardic states such as sinoatrial block or higher degrees of AV block unless a permanent pacemaker has been implanted Uncontrolled electrolyte disorders that can confound the effects of a QTc prolonging drug (e.g., hypokalemia, hypocalcemia, hypomagnesemia) History of chronic liver disease (e.g., cirrhosis) or suspected alcohol abuse History of hepatic veno-occlusive disease (VOD) or sinusoidal obstruction syndrome (SOS) Administration of live vaccine <6 weeks before entry on study Evidence of uncontrolled current serious active infection (including sepsis, bacteremia, fungemia or COVID-19 infection) or patients with a recent history (within 4 months) of deep tissue infections such as fasciitis or osteomyelitis Patients who have had a severe allergic reaction or anaphylactic reaction to any humanized monoclonal antibodies or any known hypersensitivity to the active substance or any of its excipients Pregnant females; breastfeeding females; males and females of childbearing potential (a woman is considered of childbearing potential (WOCBP) i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile e.g. after hysterectomy or bilateral ovariectomy. Please refer to chapter 12.4 Contraceptive Requirements.) not using highly effective contraception or not agreeing to continue highly effective contraception for women at least 8 months and for men at least 5 months after the last dose of investigational product 18. Participation in other studies involving investigational drug(s) (Phase I-IV) within 4 weeks before study inclusion 19. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study.

Ages Eligible for Study
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Minimum Age: 56 Years
Maximum Age: 74 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: Induction Therapy with Inotuzumab Ozogamicin<br>Patients will receive up to 3 cycles Inotuzumab with applications on day 1, 8 and 15 in each cycle. First dose will be 0.8 mg/m² on Day 1. All subsequent doses will be 0,5 mg/m². | Drug: Inotuzumab ozogamicin<br>* Patients will receive standard of care chemotherapy (only maintenance) after Inotuzumab Ozogamicin.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event free survival (EFS) at 12-months follow-up | An event is any of the following: persisting bone marrow blasts (more than 5% leukemic blasts) after two cycles of inotuzumab ozogamicin, relapse or death. | At 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete hematological remission | The rate of complete hematological remission after inotuzumab ozogamicin induction treatment | 42 days | 
| MRD response after induction treatment | The rate of patients being negative for minimal residual disease (defined by RQ-PCR for at least one leukemia-specific IG/TR gene rearrangement or leukemia specific genetic aberration with a sensitivity of at least 10-4) after induction treatment | 42 days | 
| Relapse free survival | Relapse free survival after two years | two years | 
| Molecular relapse | The proportion of patients with molecular relapse | two years | 
| Overall survival | Overall survival after two years | two years | 
| Death during induction | Death during induction | 42 days | 
| Death in complete remission | Death in complete remission | up to 2 years |