AML1208: Everolimus MICE-regimen in Treating Older Patients With Newly Diagnosed Acute Myeloid Leukemia

Sponsor

Gruppo Italiano Malattie EMatologiche dell'Adulto (Other)

Overall Status

Unknown status

CT.gov ID

NCT01154439

Collaborator

(none)

Enrollment

Locations

Arm

Duration (Months)

3.6

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Leukemia	Drug: cytarabine Drug: etoposide Drug: everolimus Drug: idarubicin Drug: mitoxantrone hydrochloride	Phase 1

Detailed Description

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

18 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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)

Study Start Date :

Oct 1, 2010

Actual Primary Completion Date :

May 1, 2013

Anticipated Study Completion Date :

Dec 1, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Everolimus Everolimus mice-regimen	Drug: cytarabine Remission induction therapy: by short i.v. infusion on days 1 and 7. Consolidation therapy: by continuous infusion on days 1-5. Other Names: Mini-ICE regimen (idarubicin, cytarabine and etoposide). Drug: etoposide Remission induction therapy: by short i.v. infusion, on days 1-7. Consolidation therapy: by short i.v. infusion, on days 1-5. Other Names: Mini-ICE regimen (idarubicin, cytarabine and etoposide). Drug: everolimus 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. Other Names: RAD001 Drug: idarubicin Consolidation therapy: by short infusion i.c. on days 1, 3 and 5. Other Names: Mini-ICE regimen (idarubicin, cytarabine and etoposide). Drug: mitoxantrone hydrochloride Remission induction therapy: by short i.v. infusion on days 1, 3 and 5

Arm

Intervention/Treatment

Experimental: Everolimus

Everolimus mice-regimen

Drug: cytarabine

Remission induction therapy: by short i.v. infusion on days 1 and 7. Consolidation therapy: by continuous infusion on days 1-5.

Other Names:

Mini-ICE regimen (idarubicin, cytarabine and etoposide).

Drug: etoposide

Remission induction therapy: by short i.v. infusion, on days 1-7. Consolidation therapy: by short i.v. infusion, on days 1-5.

Other Names:

Mini-ICE regimen (idarubicin, cytarabine and etoposide).

Drug: everolimus

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.

Other Names:

RAD001

Drug: idarubicin

Consolidation therapy: by short infusion i.c. on days 1, 3 and 5.

Other Names:

Mini-ICE regimen (idarubicin, cytarabine and etoposide).

Drug: mitoxantrone hydrochloride

Remission induction therapy: by short i.v. infusion on days 1, 3 and 5

Outcome Measures

Primary Outcome Measures

Maximum-tolerated dose of everolimus [At one year from study entry]
MTD of RAD given in combination with the MICE regimen

Secondary Outcome Measures

Safety [At one year from study entry]
Complete remission rate [At one year from study entry]
Complete remission rate (CR + CRi) following one or two induction courses.

Eligibility Criteria

Criteria

Ages Eligible for Study:

61 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Ematologia con trapianto- AOU Policlinico Consorziale di Bari	Bari	Italy
2	Azienda Ospedaliera Universitaria - Università degli Studi di Napoli "Federico II" - Facoltà di Medicina e Chirurgia	Napoli	Italy
3	Università La Sapienza	Roma	Italy	00100
4	Università degli Studi "Sapienza" - Dip Biotecnologie Cellulari ed Ematologia - Divisione di Ematologia	Roma	Italy
5	Azienda Ospedaliera Universitaria Policlinico Tor Vergata	Rome	Italy	00133