Everolimus (RAD001) in Elderly Patients With Acute Myeloid Leukemia
The main goal of this study is to assess the safety and tolerability of RAD001 in combination with low-dose cytarabine in acute myeloid leukemia patients unfit for intensive chemotherapy. The secondary goals are to investigate the likely causes of drug response or failure.
|Study Design:||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||A Phase I Dose Finding Study of Everolimus (RAD001) in Elderly Patients With Acute Myeloid Leukemia (AML) Unfit for Intensive Induction Chemotherapy|
- safety & tolerability [ Time Frame: over 24 cycles of treatment ] [ Designated as safety issue: Yes ]haematological toxicities (marrow status, neutrophil recovery), non-haematological grade 4 toxicity
- clinical Response [ Time Frame: up to 3 years ] [ Designated as safety issue: No ]measure disease free survival up to 3 years
- biomarkers of response [ Time Frame: over length of treatment up to 24 cycles ] [ Designated as safety issue: No ]measure examples of biomarkers of disease response such as gene-specific methylation and phosphorylation status of mTOR targets
- patient related outcomes [ Time Frame: during treatment and in followup for up to 3 years ] [ Designated as safety issue: No ]Quality of life questionnaires and treatment related toxicities
|Study Start Date:||February 2010|
|Estimated Study Completion Date:||January 2014|
|Estimated Primary Completion Date:||July 2013 (Final data collection date for primary outcome measure)|
Experimental: Everolimus with 5-azacitidine
Everolimus increasing oral doses days 5-21 each cycle 5-azacitidine 75mg sub cutaneously 7 doses in 21 days
In this study, 5-azacitidine will be administered sc for 7 doses over 9 days in a 28 day cycle. Everolimus will be administered orally with the first dose starting on day 5 (first Friday) of each cycle and continued until day 21 of each cycle. Patients will be treated with combined azacitidine + Everolimus for a minimum of 6 cycles and until at least 2 cycles after documentation of CR. Upon cessation of azacitidine, the patient will be permitted to take Everolimus maintenance therapy until progression at the investigator's discretion.
Other Name: Everolimus
A multicentre 2-stage Phase Ib/II trial of 5-Azacitidine combined with Everolimus for AML patients over the age of 60 or relapsed AML over the age of 18. The MTD and DLT of 5-Azacitidine (7 doses over 9 days) given monthly combined with Everolimus orally for 17 days (day 5-21) each month (1 cycle) for a minimum of 6 cycles and for at least 2 cycles beyond achievement of CR and for a maximum of 12 cycles. Everolimus maintenance therapy alone may be continued at investigator's discretion until either progressive disease or dose limiting toxicity. Groups of 3 patients will be entered at each dose level. Dose escalation/stopping rules to determine the maximum tolerated dose (MTD) are as follows:
Number in cohort experiencing DLT by day 42 Action 2/3 or 3/3 No further dose escalation. Previous level is defined as MTD 0/3 Dose escalate to next level 1/3 Expand cohort to 6 patients 1/6 or 2/6 Dose escalate to next level >2/6 No further dose escalation. Previous level is defined as MTD
Note that if dose escalation is still indicated at the highest dose level, then the MTD is at or above the last dose level. If the trial stops at the first dose, then the MTD is below the first dose level. In either of the above cases, the MTD is not determined from the trial.
Once the maximum dose level has been identified, a dose expansion phase will continue recruiting patients at the MTD until a total of 40 patients for the entire study is accrued.