This pilot phase II trial studies whether biomarkers (biological molecules) in bone marrow samples can predict treatment response to sirolimus and chemotherapy (mitoxantrone hydrochloride, etoposide, and cytarabine \[MEC\]) in patients with acute myeloid leukemia (AML) that is likely to come back or spread (high-risk). Sirolimus inhibits or blocks the pathway that causes cancer cells to grow. Adding sirolimus to standard chemotherapy may help improve patient response. Studying samples of bone marrow from patients treated with sirolimus in the laboratory may help doctors learn whether sirolimus reverses or turns off that pathway and whether changes in biomarker levels can predict how well patients will respond to treatment.
PRIMARY OBJECTIVES: I. To test the association between biochemical response and clinical response. SECONDARY OBJECTIVES: I. To estimate complete response rate of sirolimus MEC in patients with high risk AML. II. To estimate progression free survival in this patient population. III. To collect further information on the safety, tolerability, and efficacy of sirolimus in combination with MEC in patients with relapsed or refractory myeloid malignancies. OUTLINE: Patients undergo collection of bone marrow samples prior to sirolimus dosing on day 4 and within 1 week and no later than day 45 of hematologic recovery. Patients receive sirolimus orally (PO) on days 2-9 (loading dose on day 1 only), and standard MEC chemotherapy comprising mitoxantrone hydrochloride intravenously (IV) over 15 minutes, etoposide IV over 1 hour, and cytarabine IV over 1 hour every 24 hours on day 4-8. After completion of study treatment, patients are followed up every 3 months for 2 years.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
BASIC_SCIENCE
Masking
NONE
Enrollment
39
Thomas Jefferson University
Philadelphia, Pennsylvania, United States
Biochemical Response
Defined by change in phosphorylated ribosomal protein S6 (pS6) positive blasts, measured as the % reduction in pS6 positive blasts from baseline to day 4. Biochemical response will be described by mean, median, standard deviation, range and coefficient of variation. The association between biochemical response and clinical response will be tested by Fisher's exact test.
Time frame: Baseline to day 4
Clinical Response
Clinical response was assessed at Day 45 using IWG criteria: Complete Remission (CR), CR with incomplete platelet recovery (CRp), CR with incomplete hematologic recovery (CRi), Partial Remission (PR), or No Response (NR). CR requires normalized blood counts and bone marrow blasts \<5%. CRp meets CR except platelet recovery; CRi meets CR except incomplete neutrophil/platelet recovery. PR is ≥50% reduction in marrow blasts to 5-25% with partial blood count improvement. NR indicates failure to meet these criteria. Tumor response per RECIST v1.0: CR = disappearance of all target lesions; PR = ≥30% decrease in sum of longest diameters; Overall Response = CR + PR. Progression = ≥20% increase in sum of longest diameters, measurable increase in non-target lesion, or new lesions.
Time frame: Day 45
Overall Response Rate (ORR) (Complete Response [CR], CR With Incomplete Platelet Recovery [CRp], or Partial Response)
Fraction of patients who achieve CR, CRp, or PR will be assessed. ORR and 95% exact confidence interval will be computed for all patients and for sensitive and resistant subgroups.
Time frame: Day 45
Relapse Free Survival (RFS)
RFS will be estimated by the Kaplan-Meier method. A landmark analysis of RFS by clinical response (CR+CRp, CRi, PR or no response \[NR\]) will be computed from day 45 marrow assessment. Median values and 95% confidence intervals will be calculated.
Time frame: Time from study entry to first documented progression, death, or last contact, assessed up to 2 years
Percentage of Participants by Risk Group
Overall Survival (OS) is defined as the time from study entry to death or last contact. OS will be analyzed by risk groups: Favorable, Intermediate, and Poor/Adverse, based on baseline factors such as cytogenetics, molecular markers, and clinical characteristics. These risk groups are used to predict clinical outcomes, with favorable indicating longer survival expectancy, intermediate suggesting moderate outcomes, and poor/adverse indicating more aggressive disease with lower survival rates. Results will be reported as the percentage of participants in each risk category.
Time frame: Up to 2 years
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