Study of Low-Dose Cytarabine and Etoposide With or Without All-Trans Retinoic Acid in Older Patients Not Eligible for Intensive Chemotherapy With Acute Myeloid Leukemia and NPM1 Mutation

Study Overview
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Brief Summary
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This is a randomized, Phase-III, two-arm, open-label, multi-center study in adult patients with AML and NPM1 mutation ineligible for intensive chemotherapy. Sample size: 144 patients Investigator's sites: 50-55 sites in Germany and Austria (2-10 patients per trial site are expected to be included into the trial) Estimated treatment duration of an individual patient: 8 months (Follow-Up period per patient will last additional 2 years)

Official Title
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Study of Low-Dose Cytarabine and Etoposide With or Without All-Trans Retinoic Acid in Older Patients Not Eligible for Intensive Chemotherapy With Acute Myeloid Leukemia and NPM1 Mutation

Conditions
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Acute Myeloid Leukemia (AML)

Intervention / Treatment
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* Drug: Cytarabine
* Drug: Etoposide
* Drug: All-trans retinoic acid (ATRA)


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 (including de novo AML, t-AML and s-AML) Presence of NPM1 mutation as assessed in one of the central AMLSG reference laboratories. Age > 60 years. There is no upper age limit. No prior chemotherapy for leukemia except hydroxyurea to control hyperleukocytosis if needed for up to 10 days during the diagnostic screening phase. Signed written informed consent Men must give their informed consent that they do not father a baby and must use a latex condom during any sexual contact with women of childbearing potential, even if they have undergone a successful vasectomy. (while on therapy and for 3 month after the last dose of chemotherapy) WHO performance status ≤ 3 Patients not eligible for intensive chemotherapy according to at least one of the following criteria HCT-CI Score >2 Patient's decision age ≥ 75 years Exclusion Criteria: The presence of any of the following will exclude a patient from study enrollment: All other AML subtypes, in particular those 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 No consent for registration, storage and processing of the individual disease-characteristics and course as well as information of the family physician and all other treating physicians about study participation Bleeding disorder independent of leukemia Uncontrolled infection Known positive for HIV, HBV or HCV 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) 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.

Ages Eligible for Study
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Minimum Age: 61 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 |
| --- | --- |
| Active Comparator: Standard arm<br>6 cycles of chemotherapy (low-dose cytarabine and etoposide) without ATRA | Drug: Cytarabine<br>* in all treatment cycles: Cytarabine 20 mg/day, s.c., bid, days 1-7; (total dose 280 mg).<br>Drug: Etoposide<br>* first treatment cycle Etoposide 50 mg/m²/day, continuously i.v., days 1-3; (total dose 150 mg/m2) treatment cycles 2 to 6 Etoposide 100 mg/day, p.o. or i.v. (over 1 hour), days 1-3; (total dose 300 mg).<br>|
| Experimental: Investigational arm<br>6 cycles of chemotherapy (low-dose cytarabine and etoposide) with ATRA (All-trans-Retinoic acid) | Drug: Cytarabine<br>* in all treatment cycles: Cytarabine 20 mg/day, s.c., bid, days 1-7; (total dose 280 mg).<br>Drug: Etoposide<br>* first treatment cycle Etoposide 50 mg/m²/day, continuously i.v., days 1-3; (total dose 150 mg/m2) treatment cycles 2 to 6 Etoposide 100 mg/day, p.o. or i.v. (over 1 hour), days 1-3; (total dose 300 mg).<br>Drug: All-trans retinoic acid (ATRA)<br>* in all treatment cycles: ATRA 45 mg/m²/day p.o., days 8-10, ATRA 15 mg/m²/day p.o., days 11-28, with or shortly after meals distributed on 3 doses per day.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| overall survival |  | 2 years and 8 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of Complete remission |  | 8 months | 
| cumulative incidence of relapse |  | 2 years and 8 months | 
| cumulative incidence of death in complete remission |  | 2 years and 8 months | 
| event-free survival |  | 2 years and 8 months | 
| Rate of early deaths (ED)/hypoplastic deaths (HD) |  | 8 months | 
| Type, frequency, severity, timing and relatedness of adverse events (AEs) and laboratory abnormalities observed during different treatment cycles | adverse events graded using the National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] Version 4.0 | 8 months | 
| Incidence of infection after each treatment cycle |  | 8 months | 
| Duration of neutropenia after each treatment cycle |  | 8 months | 
| Duration of thrombocytopenia after each treatment cycle |  | 8 months | 
| Duration of hospitalization after each treatment cycle |  | 8 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.33 | 2 years and 8 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AML, NPM1 Mutation, elderly patients (>60 years), unfit for intensive chemotherapy