Study of Decitabine in Combination With Sequential Rapamycin or Ribavirin in High Risk AML Patients
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 1/Phase 2 |
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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: 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). |
Drug: Decitabine
Other Names:
|
| Experimental: 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). |
Drug: Decitabine
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Median Overall Survival [2 years]
Secondary Outcome Measures
- 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.
Eligibility Criteria
Criteria
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.
-
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | University of Rochester | Rochester | New York | United States | 14642 |
Sponsors and Collaborators
- University of Rochester
Investigators
- Principal Investigator: Jane Liesveld, MD, University of Rochester
Study Documents (Full-Text)
More Information
Publications
None provided.- 48721
- ULEU13049
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail | 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. |
| Arm/Group Title | Decitabine Followed by Rapamycin | Decitabine Followed by Ribavirin |
|---|---|---|
| Arm/Group Description | 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 | 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 |
| Period Title: Overall Study | ||
| STARTED | 26 | 1 |
| COMPLETED | 24 | 0 |
| NOT COMPLETED | 2 | 1 |
Baseline Characteristics
| Arm/Group Title | Decitabine Followed by Rapamycin | Decitabine Followed by Ribavirin | Total |
|---|---|---|---|
| Arm/Group Description | 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 | 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 | Total of all reporting groups |
| Overall Participants | 26 | 1 | 27 |
| Age (years) [Median (Full Range) ] | |||
| Median (Full Range) [years] |
74
|
80
|
74
|
| Sex: Female, Male (Count of Participants) | |||
| Female |
15
57.7%
|
0
0%
|
15
55.6%
|
| Male |
11
42.3%
|
1
100%
|
12
44.4%
|
| Ethnicity (NIH/OMB) (Count of Participants) | |||
| Hispanic or Latino |
1
3.8%
|
0
0%
|
1
3.7%
|
| Not Hispanic or Latino |
25
96.2%
|
0
0%
|
25
92.6%
|
| Unknown or Not Reported |
0
0%
|
1
100%
|
1
3.7%
|
| Race (NIH/OMB) (Count of Participants) | |||
| American Indian or Alaska Native |
0
0%
|
0
0%
|
0
0%
|
| Asian |
0
0%
|
0
0%
|
0
0%
|
| Native Hawaiian or Other Pacific Islander |
0
0%
|
0
0%
|
0
0%
|
| Black or African American |
3
11.5%
|
0
0%
|
3
11.1%
|
| White |
23
88.5%
|
0
0%
|
23
85.2%
|
| More than one race |
0
0%
|
0
0%
|
0
0%
|
| Unknown or Not Reported |
0
0%
|
1
100%
|
1
3.7%
|
| Region of Enrollment (participants) [Number] | |||
| United States |
26
100%
|
1
100%
|
27
100%
|
Outcome Measures
| Title | Median Overall Survival |
|---|---|
| Description | |
| Time Frame | 2 years |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | Decitabine Followed by Rapamycin | Decitabine Followed by Ribavirin |
|---|---|---|
| Arm/Group Description | 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 | 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 |
| Measure Participants | 26 | 0 |
| Median (95% Confidence Interval) [months] |
6.9
|
| Title | Blast Percentage in Peripheral Blood |
|---|---|
| Description | bone marrow aspirate and biopsy exam |
| Time Frame | baseline and four weeks |
Outcome Measure Data
| Analysis Population Description |
|---|
| Data was not collected for two patients in the rapamycin arm and 1 patient in the ribavirin arm. |
| Arm/Group Title | Decitabine Followed by Rapamycin | Decitabine Followed by Ribavirin |
|---|---|---|
| Arm/Group Description | 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 | 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 |
| Measure Participants | 24 | 0 |
| baseline |
24.7
(5.9)
|
|
| week 4 |
14.7
(5.6)
|
| Title | Mean Change in Blast Percentage in Marrow |
|---|---|
| Description | Complete blood count with differential. |
| Time Frame | baseline and four weeks |
Outcome Measure Data
| Analysis Population Description |
|---|
| Data was not collected for two patients in the rapamycin arm and 1 patient in the ribavirin arm. |
| Arm/Group Title | Decitabine Followed by Rapamycin | Decitabine Followed by Ribavirin |
|---|---|---|
| Arm/Group Description | 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 | 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 |
| Measure Participants | 24 | 0 |
| Mean (Full Range) [percentage of cells] |
-18.5
|
Adverse Events
| Time Frame | 2 years | |||
|---|---|---|---|---|
| Adverse Event Reporting Description | ||||
| Arm/Group Title | Decitabine Followed by Rapamycin | Decitabine Followed by Ribavirin | ||
| Arm/Group Description | 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 | 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 | ||
All Cause Mortality |
||||
| Decitabine Followed by Rapamycin | Decitabine Followed by Ribavirin | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 25/26 (96.2%) | 1/1 (100%) | ||
Serious Adverse Events |
||||
| Decitabine Followed by Rapamycin | Decitabine Followed by Ribavirin | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 21/26 (80.8%) | 1/1 (100%) | ||
| Blood and lymphatic system disorders | ||||
| Febrile neutropenia | 11/26 (42.3%) | 0/1 (0%) | ||
| decreased platelet count | 1/26 (3.8%) | 0/1 (0%) | ||
| Anemia | 1/26 (3.8%) | 0/1 (0%) | ||
| Gastrointestinal disorders | ||||
| Gastric hemorrhage | 1/26 (3.8%) | 0/1 (0%) | ||
| Diverticulitis | 1/26 (3.8%) | 0/1 (0%) | ||
| General disorders | ||||
| Chest pain | 1/26 (3.8%) | 0/1 (0%) | ||
| Multi-organ failure | 1/26 (3.8%) | 0/1 (0%) | ||
| Infections and infestations | ||||
| pneumonia | 0/26 (0%) | 1/1 (100%) | ||
| skin infection | 1/26 (3.8%) | 0/1 (0%) | ||
| Sepsis | 2/26 (7.7%) | 0/1 (0%) | ||
| Metabolism and nutrition disorders | ||||
| Failure to thrive | 1/26 (3.8%) | 0/1 (0%) | ||
| Nervous system disorders | ||||
| syncope | 0/26 (0%) | 1/1 (100%) | ||
| Intracranial hemorrhage | 3/26 (11.5%) | 0/1 (0%) | ||
| Respiratory, thoracic and mediastinal disorders | ||||
| Hemoptysis | 1/26 (3.8%) | 1/1 (100%) | ||
| Mucositis | 1/26 (3.8%) | 0/1 (0%) | ||
Other (Not Including Serious) Adverse Events |
||||
| Decitabine Followed by Rapamycin | Decitabine Followed by Ribavirin | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 26/26 (100%) | 1/1 (100%) | ||
| Blood and lymphatic system disorders | ||||
| Bleeding from central line | 3/26 (11.5%) | 0/1 (0%) | ||
| Decreased platelets | 0/26 (0%) | 1/1 (100%) | ||
| Cardiac disorders | ||||
| Sinus tachycardia | 2/26 (7.7%) | 0/1 (0%) | ||
| Gastrointestinal disorders | ||||
| Nausea | 10/26 (38.5%) | 0/1 (0%) | ||
| Constipation | 9/26 (34.6%) | 0/1 (0%) | ||
| Abdominal pain | 5/26 (19.2%) | 0/1 (0%) | ||
| Diarrhea | 5/26 (19.2%) | 0/1 (0%) | ||
| GI discomfort | 4/26 (15.4%) | 0/1 (0%) | ||
| Oral pain | 4/26 (15.4%) | 0/1 (0%) | ||
| Vomiting | 4/26 (15.4%) | 0/1 (0%) | ||
| Hemorrhoids | 3/26 (11.5%) | 0/1 (0%) | ||
| Sore throat | 3/26 (11.5%) | 0/1 (0%) | ||
| General disorders | ||||
| Fatigue | 16/26 (61.5%) | 0/1 (0%) | ||
| Edema | 7/26 (26.9%) | 0/1 (0%) | ||
| Fever | 5/26 (19.2%) | 0/1 (0%) | ||
| Chills | 4/26 (15.4%) | 0/1 (0%) | ||
| Malaise | 3/26 (11.5%) | 0/1 (0%) | ||
| Pain | 0/26 (0%) | 1/1 (100%) | ||
| Hepatobiliary disorders | ||||
| alkaline phosphatase increased | 2/26 (7.7%) | 0/1 (0%) | ||
| ALT increased | 3/26 (11.5%) | 0/1 (0%) | ||
| Immune system disorders | ||||
| Sepsis | 0/26 (0%) | 1/1 (100%) | ||
| Infections and infestations | ||||
| Infection | 2/26 (7.7%) | 0/1 (0%) | ||
| Rhinitis/sinusitis | 2/26 (7.7%) | 0/1 (0%) | ||
| Skin infection | 5/26 (19.2%) | 0/1 (0%) | ||
| Injury, poisoning and procedural complications | ||||
| Fall | 2/26 (7.7%) | 0/1 (0%) | ||
| Bruising | 4/26 (15.4%) | 0/1 (0%) | ||
| Investigations | ||||
| Aspartate aminotransferase increased | 2/26 (7.7%) | 0/1 (0%) | ||
| Metabolism and nutrition disorders | ||||
| Anorexia | 2/26 (7.7%) | 0/1 (0%) | ||
| Hypocalcemia | 3/26 (11.5%) | 0/1 (0%) | ||
| Hypokalemia | 3/26 (11.5%) | 0/1 (0%) | ||
| Musculoskeletal and connective tissue disorders | ||||
| Arthralgia | 4/26 (15.4%) | 0/1 (0%) | ||
| Back pain | 3/26 (11.5%) | 0/1 (0%) | ||
| Extremity pain | 3/26 (11.5%) | 0/1 (0%) | ||
| Nervous system disorders | ||||
| Lethargy | 2/26 (7.7%) | 0/1 (0%) | ||
| Peripheral Neuropathy | 2/26 (7.7%) | 0/1 (0%) | ||
| Presyncope | 2/26 (7.7%) | 0/1 (0%) | ||
| Headache | 6/26 (23.1%) | 0/1 (0%) | ||
| Anxiety | 3/26 (11.5%) | 0/1 (0%) | ||
| Dizziness | 3/26 (11.5%) | 0/1 (0%) | ||
| Psychiatric disorders | ||||
| Confusion | 2/26 (7.7%) | 0/1 (0%) | ||
| Hallucinations | 2/26 (7.7%) | 0/1 (0%) | ||
| Respiratory, thoracic and mediastinal disorders | ||||
| Dyspnea | 12/26 (46.2%) | 0/1 (0%) | ||
| Cough | 6/26 (23.1%) | 0/1 (0%) | ||
| Epistaxis | 4/26 (15.4%) | 0/1 (0%) | ||
| Skin and subcutaneous tissue disorders | ||||
| Pruritis | 2/26 (7.7%) | 0/1 (0%) | ||
| Rash | 2/26 (7.7%) | 0/1 (0%) | ||
| Vascular disorders | ||||
| Hypertension | 2/26 (7.7%) | 0/1 (0%) | ||
| Thromboembolic event | 2/26 (7.7%) | 0/1 (0%) | ||
| Hypotension | 5/26 (19.2%) | 1/1 (100%) | ||
Limitations/Caveats
More Information
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
| Name/Title | Jane Liesveld |
|---|---|
| Organization | University of Rochester |
| Phone | 585 - 275 - 5823 |
| Jane_Liesveld@urmc.rochester.edu |
- 48721
- ULEU13049