Everolimus MICE-regimen in Treating Older Patients With Newly Diagnosed Acute Myeloid Leukemia

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as mitoxantrone hydrochloride, cytarabine, etoposide, and idarubicin, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Everolimus may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the cancer. Giving everolimus together with combination chemotherapy may kill more cancer cells. PURPOSE: This phase I trial is studying the side effects and best dose of everolimus when given together with mitoxantrone hydrochloride, cytarabine, etoposide, and idarubicin in treating older patients with newly diagnosed acute myeloid leukemia.

Detailed Description
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OBJECTIVES: Primary To determine the maximum-tolerated dose of everolimus in combination with standard remission-induction therapy comprising mitoxantrone hydrochloride, cytarabine, and etoposide (MICE-regimen) followed by consolidation therapy comprising idarubicin, cytarabine, and etoposide in older patients with newly diagnosed acute myeloid leukemia. Secondary To determine the safety profile of this regimen in these patients. To determine the anti-leukemic activity (complete remission rate [complete remission and complete remission with incomplete blood count recovery]) following one or two induction courses. OUTLINE: This is a multicenter, dose-escalation study of everolimus. Standard remission-induction therapy: Patients receive mitoxantrone hydrochloride IV over 30 minutes on days 1, 3, and 5; cytarabine IV continuously on days 1-7; etoposide IV over 1 hour on days 1-3; and oral everolimus once a day on days 1-21. Patients with partial remission (PR) receive a second induction course, beginning 7-17 days after completion of induction course 1. Patients with complete remission or complete remission with incomplete blood count recovery (CR/CRi) after induction therapy proceed to consolidation therapy; patients who have failed to achieve PR after induction course 1 or a CR/CRi after induction course 2 are removed from study. Consolidation therapy: Beginning within 3 weeks from CR/CRi documentation, patients receive idarubicin IV over 30 minutes on days 1, 3, and 5; cytarabine IV continuously on days 1-5; etoposide IV over 1 hour on days 1-3; and oral everolimus once a day on days 1-10. Patients may receive another course of the consolidation therapy, beginning at least 4 weeks after initiation of consolidation therapy course 1. After completion of study treatment, patients are followed up once a month for 1 year, every 3 months for 1 year, and then periodically thereafter.

Official Title
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A Phase I Study Investigating the Combination of RAD001 With Standard Induction and Consolidation Therapy in Older Patients With Newly Diagnosed Acute Myeloid Leukemia (AML)

Conditions
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Leukemia

Intervention / Treatment
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* Drug: cytarabine
* Drug: etoposide
* Drug: everolimus
* Drug: idarubicin
* Drug: mitoxantrone hydrochloride


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Newly diagnosed acute myeloid leukemia (AML) (unequivocal) according to WHO diagnostic criteria (at least 20% blasts in the bone marrow), with FAB classification other than M3 (acute promyelocytic leukemia), and documented by bone marrow aspiration (or biopsy in case of dry tap) Previously untreated primary or secondary AML (including AML following antecedent myelodysplasia) No blast transformation of chronic myeloid leukemia or other myeloproliferative disorders No active CNS leukemia PATIENT CHARACTERISTICS: WHO performance status 0-2 Total serum bilirubin < 2 times upper limit of normal (ULN) Serum creatinine < 2 times ULN ALT/AST ≤ 3 times ULN (unless due to organ leukemic involvement) LVEF ≥ 50% by echocardiogram No other concurrent active malignancy No active uncontrolled infection No known active hepatitis B or C or HIV positivity No active heart disease including myocardial infarction within the past 3 months, symptomatic coronary artery disease, cardiac arrhythmias not controlled by medications, or uncontrolled congestive heart failure No medical condition that, in the opinion of the investigator, places the patient at an unacceptably high risk for toxicities No other known condition (e.g., familial, sociological, or geographical) or behavior (including drug dependence or abuse, psychological or psychiatric illness) that, in the opinion of the investigator, would make the patient a poor candidate for the trial No known hypersensitivity to everolimus, other rapamycins (e.g., sirolimus or temsirolimus), or to its excipients PRIOR CONCURRENT THERAPY: No prior standard or investigational chemotherapy for acute myeloid leukemia or myelodysplasia (including everolimus or other mTOR inhibitors) Prior hydroxyurea allowed (up to a maximum of 14 days) to control peripheral blood leukemic cell counts No prior enrollment in this trial No other concurrent anti-leukemia agents, investigational agents, or biological agents

Ages Eligible for Study
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Minimum Age: 61 Years
Maximum Age: 75 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: Everolimus<br>Everolimus mice-regimen | Drug: cytarabine<br>* Remission induction therapy: by short i.v. infusion on days 1 and 7. Consolidation therapy: by continuous infusion on days 1-5.<br>* Other names: Mini-ICE regimen (idarubicin, cytarabine and etoposide).;Drug: etoposide<br>* Remission induction therapy: by short i.v. infusion, on days 1-7. Consolidation therapy: by short i.v. infusion, on days 1-5.<br>* Other names: Mini-ICE regimen (idarubicin, cytarabine and etoposide).;Drug: everolimus<br>* Remission induction therapy: test dose once a day by mouth, on days 1-21 (21 days). Consolidation therapy: dose as defined by the cohort once a day by mouth, on days 1-10.<br>* Other names: RAD001;Drug: idarubicin<br>* Consolidation therapy: by short infusion i.c. on days 1, 3 and 5.<br>* Other names: Mini-ICE regimen (idarubicin, cytarabine and etoposide).;Drug: mitoxantrone hydrochloride<br>* Remission induction therapy: by short i.v. infusion on days 1, 3 and 5<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum-tolerated dose of everolimus | MTD of RAD given in combination with the MICE regimen | At one year from study entry | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety |  | At one year from study entry | 
| Complete remission rate | Complete remission rate (CR + CRi) following one or two induction courses. | At one year from study entry | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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secondary acute myeloid leukemia, untreated adult acute myeloid leukemia, adult acute basophilic leukemia, adult acute eosinophilic leukemia, adult erythroleukemia (M6a), adult pure erythroid leukemia (M6b), adult acute megakaryoblastic leukemia (M7), adult acute minimally differentiated myeloid leukemia (M0), adult acute monoblastic leukemia (M5a), adult acute monocytic leukemia (M5b), adult acute myeloblastic leukemia with maturation (M2), adult acute myeloblastic leukemia without maturation (M1), adult acute myelomonocytic leukemia (M4), adult acute myeloid leukemia with 11q23 (MLL) abnormalities, adult acute myeloid leukemia with inv(16)(p13;q22), adult acute myeloid leukemia with t(16;16)(p13;q22), adult acute myeloid leukemia with t(8;21)(q22;q22)