E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Acute lymphoblastic leukemia, Philadelphia-chromosome and BCR-ABL negative disease, patient aged 56 years or older |
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E.1.1.1 | Medical condition in easily understood language |
Patients with acute lymphoblastic leukemia and aged 56 years or older |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10000845 |
E.1.2 | Term | Acute lymphoblastic leukemia |
E.1.2 | System Organ Class | 100000004864 |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Primary objective: To evaluate the efficacy of an inotuzumab ozogamicin induction therapy, defined as the number of patients being alive in first remission one year after start of induction therapy.
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E.2.2 | Secondary objectives of the trial |
To evaluate the safety of an inotuzumab ozogamicin induction therapy. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male or female patients, >56 years of age and fit for therapy 2. Newly diagnosed acute lymphoblastic leukemia (>25% marrow blasts, assessed by morphology; i.e., M2 or M3 marrow) 3. Leukemic blasts must have CD22 surface expression of a least 20%, assessed by local/institutional flow cytometry of a bone marrow aspirate sample (assessment of CD22 via the reference lab for immungenetics 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 4. 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 600mg/m2) and the standard prephase treatment 5. With or without documented CNS involvement 6. Adequate liver function, including total serum bilirubin <2.0 x 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 7. Serum creatinine <1.5 x upper limit of normal (ULN) or any serum creatinine level associated with a measured or calculated creatinine clearance of >40 mL/min 8. WHO performance status <2 9. Signed written inform consent 10. Inclusion in GMALL registry
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E.4 | Principal exclusion criteria |
1. Philadelphia-chromosome or BCR-ABL positive ALL 2. Burkitt’s or mixed phenotype acute leukemia based on the WHO 2008 criteria 3. Peripheral absolute lymphoblast count >10,000/µL after pre-phase treatment and before start of study medication 4. 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) 5. 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) 6. Major surgery within <4 weeks before entry on study 7. Unstable or severe uncontrolled medical condition (e.g., unstable cardiac function or unstable pulmonary condition) 8. 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 9. 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 10. Myocardial infarction <6 months before entry on study 11. 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 12. Uncontrolled electrolyte disorders that can confound the effects of a QTc prolonging drug (e.g., hypokalemia, hypocalcemia, hypomagnesemia) 13. History of chronic liver disease (e.g., cirrhosis) or suspected alcohol abuse 14. History of hepatic veno-occlusive disease (VOD) or sinusoidal obstruction syndrome (SOS) 15. Administration of live vaccine <6 weeks before entry on study 16. Evidence of uncontrolled current serious active infection (including sepsis, bacteremia, fungemia) or patients with a recent history (within 4 months) of deep tissue infections such as fasciitis or osteomyelitis 17. 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 18. 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 an for men at least 5 months after the last dose of investigational product 19. Participation in other studies involving investigational drug(s) (Phase I-IV) within 4 weeks before study inclusion 20. 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.
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E.5 End points |
E.5.1 | Primary end point(s) |
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. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
After 12-months follow-up |
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E.5.2 | Secondary end point(s) |
a. The rate of complete hematological remission after inotuzumab ozogamicin induction treatment b. The rate of patients being negative for minimal residual disease (defined by RQ-PCR for at least one leukemia-specific Ig/TCR gene rearrangement or leukemia specific genetic aberration with a sensitivity of at least 10-4) after induction treatment c. Relapse free survival after two years d. The proportion of patients with molecular relapse e. Overall survival after two years f. Death during induction g. Death in complete remission
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
24 months following initiation of Inotuzumab Ozogamicin |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 15 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The end of the trial is defined as latest 6 months after the last annual follow-up report of the last patient. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |