Sirolimus and Azacitidine in Treating Patients With High Risk Myelodysplastic Syndrome or Acute Myeloid Leukemia That is Recurrent or Not Eligible for Intensive Chemotherapy
|Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities Adult Acute Myeloid Leukemia With Del(5q) Adult Acute Myeloid Leukemia With Inv(16)(p13;q22) Adult Acute Myeloid Leukemia With t(15;17)(q22;q12) Adult Acute Myeloid Leukemia With t(16;16)(p13;q22) Adult Acute Myeloid Leukemia With t(8;21)(q22;q22) de Novo Myelodysplastic Syndromes Myelodysplastic Syndrome With Isolated Del(5q) Previously Treated Myelodysplastic Syndromes Recurrent Adult Acute Myeloid Leukemia||Drug: Sirolimus Drug: Azacitidine||Phase 2|
|Study Design:||Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
|Official Title:||A Phase II Study of Azacitidine and Sirolimus for the Treatment of High Risk Myelodysplastic Syndrome or Acute Myeloid Leukemia Refractory to or Not Eligible for Intensive Chemotherapy|
- Rate of response [ Time Frame: Up to 5 years ]
MDS: Patients meeting an erythroid response, a platelet response, or a neutrophil response will be considered responders.
AML: Patients achieving a complete remission (CR), complete response in the absence of a total platelet recovery (CRp), or partial remission (PR) will be considered responders.
- Toxicity referring to toxic events during the full course of treatment that are attributed as possibly, probably or definitely due to treatment, graded according to the National Institutes of Health (NIH) Common Toxicity Criteria (CTC) v. 4.0 [ Time Frame: Up to 30 days after completion of study treatment ]The combination of these drugs will be deemed safe if the number of adverse events is no more that 10% greater than the additive number of events of azacitidine and sirolimus if administrated separately. This will be based upon data in the original phase 2 trials of azacitidine demonstrating an 8% toxic death rate and therefore be 18% of the total number enrolled (approx. 40 x18% = 7).
- Pharmacokinetic assessment to assess levels of the drug in vivo [ Time Frame: Day 4 of course 1 ]Day 4 levels will be drawn prior to initiation of azacitidine to allow for a PK/PD correlation study
- Inhibition of mTOR signaling by sirolimus measured by intracellular flow cytometry for phosphorylation of the downstream signaling target S6 ribosomal protein as a surrogate for mTOR activity [ Time Frame: Up to day 4 before azacitidine administration ]Distributional characteristics are examined by: histograms, box plots and descriptive statistics (e.g., mean, median, standard deviation, range). Variability will be of particular interest. We will conduct within-patient comparison of baseline versus posts-treatment percentages by Student's paired t test. A nonparametric Wilcoxon signed ranks test will be employed if normality cannot be assumed or achieved by simple transformation.
- Quality of life (QOL) assessed by the European Organization for Research and Treatment of Cancer (EORTC) QOL and the Mental Health Inventory (MHI) [ Time Frame: Up to day 164 ]
|Actual Study Start Date:||July 8, 2013|
|Estimated Study Completion Date:||January 2020|
|Estimated Primary Completion Date:||June 2018 (Final data collection date for primary outcome measure)|
Experimental: Treatment (sirolimus, azacitidine)
Patients receive sirolimus PO on days 1-10 or 1-12 and azacitidine IV on days 4-8, 11, and 12 or days 4-10. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.
Other Names:Drug: Azacitidine
I. To characterize the rate of response to azacitidine and sirolimus in adults with high-risk myelodysplastic syndrome (MDS), or relapsed or refractory acute myeloid leukemia (AML) or those unable or unwilling to tolerate high dose chemotherapy.
I. To determine the pharmacodynamic effect of sirolimus on inhibition of mammalian target of rapamycin (mTOR) signaling in adults with high-risk MDS, or relapsed or refractory AML or those unable or unwilling to tolerate high dose chemotherapy.
II. To determine the safety and tolerability of sirolimus and azacitidine in adults with high-risk MDS, or relapsed or refractory AML or those unable or unwilling to tolerate high dose chemotherapy.
III. To determine the progression free survival and overall survival in adults with high-risk MDS, or relapsed or refractory AML or those unable or unwilling to tolerate high dose chemotherapy.
IV. To determine if the quality of life of patients is improved with the combination of azacitidine and sirolimus when compared to historical controls of azacitidine alone.
Patients receive sirolimus orally (PO) on days 1-10 or 1-12 and azacitidine intravenously (IV) on days 4-8, 11, and 12 or days 4-10. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 3 months.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01869114
|United States, Pennsylvania|
|Sidney Kimmel Cancer Center at Thomas Jefferson University|
|Philadelphia, Pennsylvania, United States, 19107|
|Principal Investigator:||Neil Palmisiano, MD||Sidney Kimmel Cancer Center at Thomas Jefferson University|