Acute Myelogenous Leukemia
Conditions
Brief summary
To evaluate the response to chemotherapy with the drug decitabine combined with rapamycin in the treatment of relapsed or refractory acute myeloid leukemia in patients of all ages, and in the treatment of newly diagnosed leukemia in those who are older than 65 when diagnosed.
Detailed description
To determine the efficacy of decitabine followed by Rapamycin in previously untreated elderly patients not able to receive standard chemotherapy or in patients with relapsed or refractory AML, through measurement of Complete Remission (CR), Complete Remission Incomplete Platelet Recovery (CRp), Partial Remission (PR), and event free and overall survival (Arm A). To determine the safety of administration of decitabine with escalating doses of Ribavirin in elderly leukemia patients or patients with relapsed/refractory disease with M4/M5 subtypes anticipated to express high eukaryotic translation initiation factor 4E (eIF4E) at diagnosis (Arm B). To establish effect of these sequential treatments on expression of phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt /mTOR) pathway proteins and on eukaryotic translation initiation factor 4E (eIF4E) activation through Western blot and phospho-flow methodologies. To correlate the clinical response with baseline expression of phospho-p70S6 Kinase/phosphorylated protein kinase B (pAKT) and with the in vitro inhibitory effects of mammalian target of rapamycin (mTOR) inhibition with rapamycin or ribavirin on the level of downstream effectors. To determine whether a leukemia stem cell phenotype is inhibited by the sequential administration of decitabine/rapamycin or decitabine/ribavirin.
Interventions
DRUGDecitabine
Sponsors
University of Rochester
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
4.1.1 Age \>/= 18 4.1.2 Diagnosis of AML according to World Health Organization (WHO) criteria except acute promyelocytic leukemia AND 4.1.3 Refractory AML defined as failure to achieve Complete Remission (CR) after 2 cycles of induction chemotherapy or persistence of \> 40% bone marrow blasts after one cycle of chemotherapy induction OR 4.1.4 Relapsed AML defined as any evidence of disease recurrence after achieving a documented first or greater Complete Remission (CR) OR 4.1.5 Relapsed AML after stem cell transplantation. 90 days (since stem cell infusion) must have elapsed between transplant and emergence of recurrent AML OR 4.1.6 Newly diagnosed AML in a patient \>65 years old not considered fit for standard 7+ 3 chemotherapy or who declines such therapy after discussion of therapeutic options available. 4.1.7 Eastern Cooperative Oncology Group (ECOG) performance status \<3
Exclusion criteria
4.2.1 Abnormal renal function as evidenced by a calculated creatinine clearance ≤ 30 ml/min (Cockcroft-Gault formula (Appendix 2) 4.2.2 Abnormal liver function: Bilirubin \>2.0 mg/dl, transaminase(s) more than 2.5x the upper limits of normal 4.2.3 Active systemic infection not responding to antibiotics 4.2.4 Known diagnosis of human immunodeficiency virus infection (HIV) 4.2.5 Patients who are post-allogeneic transplantation should not have active Graft vs. Host Disease (GVHD) greater than grade 1 of skin at time of enrollment. They may have had donor lymphocyte infusion (DLI) but not within 4 weeks of beginning the study. 4.2.6 Pregnant or breastfeeding female subjects 4.2.7 Known or suspected Central Nervous System (CNS) leukemia involvement; past involvement is not an exclusion. \-
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Median Overall Survival | 2 years |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Blast Percentage in Peripheral Blood | baseline and four weeks | bone marrow aspirate and biopsy exam |
| Mean Change in Blast Percentage in Marrow | baseline and four weeks | Complete blood count with differential. |
Countries
United States
Participant flow
Pre-assignment details
37 patients signed consent for the study and 27 patients enrolled. Reasons for non-enrollment were withdrawal of consent (3 patients), diagnosis of MDS vs. AML on screening marrow (2 patients), enrollment on an alternate clinical trial (4 patients), and expiration during screening period due to sepsis (1 patient). The first patient enrolled in March 2014 and the last in January 2020.
Participants by arm
| Arm | Count |
|---|---|
| Decitabine Followed by Rapamycin Decitabine 20 mg/M2/day will be given as an IV infusion daily for 10 consecutive days starting on day 1 of cycle 1; in subsequent cycles, decitabine will be given for five days (days 1-5). Rapamycin 6mg (loading dose) will be administered on day 6; thereafter 2 mg/day on days 11-22 in cycle 1 and on days 6-22 in subsequent cycles. (Arm A: for patients with non-morphologic M4/M5 subtypes).
Decitabine | 26 |
| Decitabine Followed by Ribavirin Decitabine 20 mg/M2/day will be given as an IV infusion daily for 10 consecutive days starting on day 1 of cycle 1; in subsequent cycles, decitabine will be given for five days (days 1-5). Ribavirin will be dosed from day 11-day 28 beginning with dose level 1 (1000mg orally twice daily). Number of patients with Dose Limiting Toxicities (DLT) at a given dose level is 0 of out of 3: enter 3 patients at the next dose level (dose Level 2- 1200mg orally twice daily; and then dose Level 3-1400 mg orally twice daily).(Arm B: For patients with morphologic M4/M5 subtypes).
Decitabine | 1 |
| Total | 27 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 1 | 1 |
| Overall Study | no marrow exam | 1 | 0 |
Baseline characteristics
| Characteristic | Decitabine Followed by Rapamycin | Total | Decitabine Followed by Ribavirin |
|---|---|---|---|
| Age, Continuous | 74 years | 74 years | 80 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 25 Participants | 25 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 3 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 23 Participants | 23 Participants | 0 Participants |
| Region of Enrollment United States | 26 participants | 27 participants | 1 participants |
| Sex: Female, Male Female | 15 Participants | 15 Participants | 0 Participants |
| Sex: Female, Male Male | 11 Participants | 12 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 25 / 26 | 1 / 1 |
| other Total, other adverse events | 26 / 26 | 1 / 1 |
| serious Total, serious adverse events | 21 / 26 | 1 / 1 |
Outcome results
Primary
Median Overall Survival
Time frame: 2 years
Population: The Ribavirin arm did not complete the study and entered hospice before 4 weeks. Median survival of the rapamycin arm included all 26 participant who started the study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Decitabine Followed by Rapamycin | Median Overall Survival | 6.9 months |
Secondary
Blast Percentage in Peripheral Blood
bone marrow aspirate and biopsy exam
Time frame: baseline and four weeks
Population: Data was not collected for two patients in the rapamycin arm and 1 patient in the ribavirin arm.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Decitabine Followed by Rapamycin | Blast Percentage in Peripheral Blood | baseline | 24.7 percentage of cells | Standard Deviation 5.9 |
| Decitabine Followed by Rapamycin | Blast Percentage in Peripheral Blood | week 4 | 14.7 percentage of cells | Standard Deviation 5.6 |
Secondary
Mean Change in Blast Percentage in Marrow
Complete blood count with differential.
Time frame: baseline and four weeks
Population: Data was not collected for two patients in the rapamycin arm and 1 patient in the ribavirin arm.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Decitabine Followed by Rapamycin | Mean Change in Blast Percentage in Marrow | -18.5 percentage of cells |