Study of Chemotherapy in Combination With All-trans Retinoic Acid (ATRA) With or Without Gemtuzumab Ozogamicin in Patients With Acute Myeloid Leukemia (AML) and Mutant Nucleophosmin-1 (NPM1) Gene Mutation

Study Overview
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Brief Summary
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Randomized Phase-III, two-arm, open-label, multi-center study in adult patients with AML and NPM1 mutation. Before Amendment No. 4 (December 2013): Primary Efficacy Objective: Evaluation of efficacy based on event-free survival (EFS) after induction and consolidation chemotherapy plus all-trans retinoic acid (ATRA) with or without gemtuzumab ozogamicin (GO) in adult patients with acute myeloid leukemia (AML) and mutant nucleophosmin-1 (NPM1) After Amendment No. 4 (December 2013): Primary Efficacy Objective: Evaluation of efficacy based on overall survival (OS) after induction and consolidation chemotherapy plus all-trans retinoic acid (ATRA) with or without gemtuzumab ozogamicin (GO) in adult patients with acute myeloid leukemia (AML) and mutant nucleophosmin-1 (NPM1)

Official Title
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Phase III Study of Chemotherapy in Combination With ATRA With or Without Gemtuzumab Ozogamicin in Patients With Acute Myeloid Leukemia and NPM1 Gene Mutation

Conditions
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Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: Gemtuzumab Ozogamicin (Mylotarg)
* Drug: standard chemotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with confirmed diagnosis of acute myeloid leukemia according to the World Health Organization (WHO) classification. Presence of NPM1 mutation as assessed in one of the central AMLSG reference laboratories. Age ≥ 18 years. There is no upper age limit. No prior chemotherapy for leukemia except hydroxyurea to control hyperleukocytosis if needed for up to 5 days during the diagnostic screening phase. Non-pregnant and non-nursing. Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test within a sensitivity of at least 25 mIU/mL within 72 hours prior to registration. Female patients in the reproductive age and male patients must agree to avoid getting pregnant or to father a child while on therapy and within one year after the last dose of chemotherapy. Women of child-bearing potential must either commit to continued abstinence from heterosexual intercourse or begin two acceptable methods of birth control: one highly effective method (e.g., IUD, hormonal, tubal ligation, or partner's vasectomy), and one additional effective method (e.g., latex condom, diaphragm, or cervical cap). Women of childbearing potential is defined as a sexually active mature woman who has not undergone a hysterectomy or who has had menses at any time in the preceding 24 consecutive months. Men must use a latex condom during any sexual contact with women of childbearing potential, even if they have undergone a successful vasectomy. Signed written informed consent. Exclusion Criteria: AML with other recurrent genetic changes (according to WHO 2008): AML with t(8;21)(q22;q22); RUNX1-RUNX1T1 AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11 AML with t(15;17)(q22;q12); PML-RARA (or other translocations involving RARA) AML with t(9;11)(p22;q23); MLLT3-MLL (or other translocations involving MLL) AML with t(6;9)(p23;q34); DEK-NUP214 AML with inv(3)(q21q26.2) or t(3;3)(q21;q26.2); RPN1-EVI1. Performance status WHO > 2. Patients with ejection fraction < 50% by MUGA or ECHO scan within 14 days of day 1. Organ insufficiency: creatinine > 1.5x upper normal serum level bilirubin, AST or ALP > 2.5x upper normal serum level, not attributable to AML heart failure NYHA III/IV severe obstructive or restrictive ventilation disorder. Uncontrolled infection. Severe neurological or psychiatric disorder interfering with ability of giving an informed consent. Patients with a currently active second malignancy other than non-melanoma skin cancers. Patients are not considered to have a currently active malignancy if they have completed therapy and are considered by their physician to be at less than 30% risk of relapse within one year. Known positive for HIV, active HBV, HCV, or Hepatitis A infection. Bleeding disorder independent of leukemia. No consent for registration, storage and processing of the individual disease-characteristics and course as well as information of the family physician about study participation.

Ages Eligible for Study
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Minimum Age: 18 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>chemotherapy in combination with ATRA with gemtuzumab ozogamicin | Drug: Gemtuzumab Ozogamicin (Mylotarg)<br>* Induction Cycle 1, 2: GO 3mg/m² by intravenous infusion (IVI) on day 1 (total dose 3 mg/m2). Start after etoposide IVI. No dose reduction is foreseen in elderly (> 60 yrs) patients. Consolidation 1: GO 3mg/m² by intravenous infusion (IVI) on day 1 (total dose 3 mg/m2). Start after first dose of high-dose cytarabine. No dose reduction is foreseen in elderly (> 60 yrs) patients. For all patients experiencing prolonged thrombocytopenia CTC-Grade 3/4 during the first or second induction therapy, which occurs for more than day 35 after start of the cycle, the further cycles of therapy will be administered without Gemtuzumab ozogamicin. Consolidation 2, 3: no GO<br>Drug: standard chemotherapy<br>* Idarubicin, Etoposide, Cytarabine, ATRA, Pegfilgrastim<br>|
| Active Comparator: 2<br>chemotherapy in combination with ATRA without gemtuzumab ozogamicin | Drug: standard chemotherapy<br>* Idarubicin, Etoposide, Cytarabine, ATRA, Pegfilgrastim<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) |  | four years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rates of complete remission after induction therapy (CR) |  | not later than 56 days | 
| Cumulative incidences of relapse (CIR) and death in CR (CID) |  | four years | 
| Event-free survival (EFS) |  | four years | 
| Days in hospital during each cycle and during the whole intervention |  | 6 months | 
| Type, frequency, severity, timing and relatedness of AEs and laboratory abnormalities observed during different treatment cycles |  | 6 months | 
| Incidence of infection after induction and consolidation therapy |  | 6 months | 
| Duration of neutropenia and thrombocytopenia after induction and consolidation therapy |  | 6 months | 
| Quality of life assessed by the EORTC Quality of Life Core Questionnaire (QLQ-C30), supplemented by information on self-assessed concomitant diseases, late treatment effects, and demographics according to Messerer et al [49] |  | two years after completion of therapy | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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adult patients, NPM1 mutation