Conditions: Acute Myelogenous Leukemia
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 27
Healthy volunteers: no

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.

Arms:
arm 1: 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). arm 2: 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).

Interventions: intervention 1: Decitabine
Intervention descriptions: intervention 1: None

Protocol document:
Prot_SAP_000.pdf: 
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A Phase I/II Study of Decitabine in Combination with Sequential 
Rapamycin or Ribavirin in High Risk AML Patients 
ULEU-13049
Clinical trials.gov # NCT02109744
Principal Investigators
Jane 
L. 
Liesveld, 
M.D.
Kristen O’Dwyer, M.D 
Co-Investigators
Frank Akwaa, M.D.
Michael W. Becker, M.D.
JJ Ifthikharuddin, M.D.
Jason Mendler, M.D., Ph.D.
Statistician:   Ollivier Hyrien, PhD.
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SYNOPSIS: 
OBJECTIVES:
1.1  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 CR, CRp, PR, and event free and overall survival 
(ArmA).
1.2 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 eIF4E at diagnosis (ArmB). 
1.3 To establish effect of these sequential treatments on expression of PI3K/Akt /mTOR pathway 
proteins and on eIF4E activation through Western blot and phospho-flow methodologies.
1.4 To correlate the clinical response with baseline expression of phospho-p70S6K/pAKT and 
with the in vitro inhibitory effects of mTOR inhibition with rapamycin or ribavirin on the level 
of downstream effectors.
1.5 To determine whether a leukemia stem cell phenotype is inhibited by the sequential 
administration of decitabine/rapamycin or decitabine/ribavirin. 
TARGET POPULATION:  Elderly (>65 years old) AML patients who are not otherwise 
candidates for standard induction chemotherapy or who refuse such therapy OR adults with 
relapsed or refractory AML.  AML may have relapsed after any number of remissions or after 
stem cell transplantation in the absence of clinically significant GVHD.  For inclusion/exclusion 
criteria, see 3.1 and 3.2.  
RATIONALE:  Decitabine, a demethylating agent, has been found to have activity in elderly 
patients with AML and in patients with high risk MDS.  mTOR inhibitors such as rapamycin 
have been found to be inhibitory to AML stem cells and to have activity in some patients with 
AML.  By combining agents, which have been shown to have potential for additive or 
synergistic effects in vitro, the response rate and safety in relapsed/refractory patients will be 
determined.  In our phase I study, it was found that a daily dose of 2 mg Rapamycin resulted in 
therapeutic levels and was safely administered. 
Rapamycin does not always effectively inhibit protein translation in AML due to inability 
to inhibit 4E-BP-1.  There is data that ribavirin, an agent which inhibits methyl 7G cap  
translation via inhibition of eIF4E can  suppress AML growth in those cases with high baseline 
expression or aberrant nuclear localization of eIF4E.  In those M4/M5 AML cases known to 
express high eIF4E expression, we will therefore examine ribavirin effects in conjunction with 
decitabine as it is anticipated that rapamycin would be less effective in these cases.
DURATION OF STUDY:  Number of cycles will be determined based on response with 
maximum of 6 cycles to be given.  See 4.1.1.
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STUDY DESIGN:  Open label single arm phase II design in arm A and standard dose escalation 
design in Arm B.  In arm A, Decitabine will be given at 20 mg/m2 for 10 days in cycle 1 
followed by rapamycin orally on days 11 to 22 at 2 mg /day after a 6 mg loading dose on day 11. 
In subsequent cycles, decitabine will be given for 5 days. This arm of the study will be 
conducted using a Simon two stage model to maximize efficacy and minimize toxicity.
In arm B, in those with high eIF4E (FAB subtypes M4/M5), after completion of the 10 
days of decitabine, ribavirin will be administered at either 1000 mg bid, 1200 mg bid, or 1400 
mg bid on days 11 through 28.   In cycles beyond the first, ribavirin will be given from days 1 
through 28, and decitabine will be given for 5 days. 
CORRELATIVE STUDIES:  Endpoints of mTOR inhibition and protein translation inhibition 
will be measured at various time points during the study.  We will also assay for inhibition of a 
leukemia initiating stem cell phenotype and functionality at defined time points during the trial.
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STUDY SCHEMA
Cycle 1
Decitabine 20 mg/m2/day for 10 
days
               (Both Arms)
Rapamycin 2 mg/day on days 11-
22 after a 6 mg loading dose 
Arm A (non-M4/M5 
AML patients)
Arm B (increased 
eIF4E—M4/M5)
Ribavirin days 11-28 (see dose 
escalation schema 
Cycles 2-6
Cycle 1
Decitabine 20 mg/m2 for 5 days 
(Both Arms)
Arm A (non-M4/M5 
AML patients)
Arm B (increased 
eIF4E—M4/M5)
Rapamycin 2 mg/day for days 
6-22 after a 6 mg loading dose
Ribavirin Days 1-28 at 
originally assigned dose cohort. 
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Outline
1.0 Study Objectives
2.0 Background
2.1 Relapsed and refractory AML/ AML in elderly
2.2 Decitabine
2.3 mTOR pathway and leukemia
2.4 Rapamycin
2.5 Ribavirin
2.6 Rationale for the combination of decitabine and an mTOR inhibitor
2.7 Rational for combination of decitabine and ribavirin
3.0 Patient Selection
3.1 Eligibility criteria
3.2 Exclusion criteria
3.3 Inclusion of women and minorities
3.4 Study duration and dates
3.5 Prior and concomitant medications
4.0 Treatment Plan
4.1 Agent administration
4.1.1
Study schema
4.1.1.1 Monitoring
4.1.2
Informed Consent
4.1.3
Registration
4.2 Supportive Care Guidelines
4.2.1
Blood transfusion
4.2.2
Platelet transfusion
4.2.3
Infectious disease prophylaxis
4.2.4
Tumor lysis prophylaxis
4.2.5
Graft versus disease management
4.3 Concomitant Therapy
4.4  Dosage calculation
4.5 Dose modification
4.5.1
Rapamycin
4.5.2
Decitabine
4.5.3
Ribavirin
4.5.4
Other dose modifications
4.6 Treatment compliance
5.0 Agent formulation and  procurement
5.1 Decitabine
5.2 Rapamycin
5.3 Ribavirin
6.0 Study Calendar
7.0 Measurement of effect
7.1 Definitions
7.2  Confirmatory measurement/Duration of response
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8.0 Feasibility of conducting correlative studies
9.0 Regulatory and reporting requirements
9.1 Adverse event definitions
9.2 Adverse event reporting
9.3 Serious adverse event recording
9.4 Definition of dose-limiting toxicity
9.5 Data & Safety Monitoring
10.0
Statistical considerations
11.0
Retention of records
12.0
Patient consent and peer judgment
13.0
Changes in protocol
14.0
Reasons for withdrawal
15.0
References
Appendix 1 Performance status criteria
Appendix 2 Cockcroft-Gault Equation
Appendix 3 Common Terminology Criteria for Adverse Events (CTCAE)
Appendix 4 Declaration of Helsinki
Appendix 5 Study Calendar
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1.0 OBJECTIVES 
1.1  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 CR, CRp, PR, and event free and overall survival.
1.2  To determine the safety and feasibility of the combination of decitabine given at a fixed dose 
with sequential rapamycin in previously untreated elderly patients not able to receive standard 
chemotherapy or in patients with relapsed or refractory acute myeloid leukemia with M4/M5 
subtypes known to express phosphorylated eIF4E at diagnosis.
1.3  To establish effect of this sequential treatment on expression of PI3K/Akt /mTOR pathway 
proteins through Western blot and phospho-flow methodologies.  In those receiving ribavirin, 
effect on levels of phospho-eIF4E expression will be measured as will effects on protein 
translation. 
1.4  To correlate the clinical response to sequential decitabine with rapamycin or ribavirin  with 
baseline expression of phospho-p70S6K/pAKT .
1.5  To determine leukemia stem cell frequency in the setting of AML relapse and in de novo 
elderly AML patients and to determine if that frequency is decreased after decitabine alone or 
after decitabine followed by rapamycin or ribavirin.
2.0  BACKGROUND
2.1  Relapsed and refractory AML and AML in the 65 years and older population
Acute myeloid leukemia (AML) is a clonal hematopoietic disorder whereby normal 
progenitor cells no longer differentiate normally or respond to regulators of proliferation, 
resulting in the accumulation of leukemic blasts in the blood, bone marrow and other 
tissues.  There are an estimated 14,000 new cases of AML diagnosed in the United States 
each year  with a median age at diagnosis of 69.1   Standard initial treatment has generally 
consisted of the combination of an anthracycline, such as daunarubicin or idarubicin, and 
cytarabine with complete remission rates in patients aged 18-60 years approaching 65% 
to 75%.2   In older patients, the complete remission rates are lower, between 40% and 
60%, with a probability of survival at 2 years between 19% and 25%.3  Therefore, there 
remains a population of patients that will either not achieve a remission after initial 
induction therapy or will relapse soon thereafter and require salvage therapy.  Regardless, 
complete remission rates and overall survival after relapse tend to be poor.
When possible, relapsed patients are offered high-dose chemotherapy or reduced 
intensity therapy with hematopoietic stem cell transplant (HSCT), which is the only 
therapy associated with a reasonable chance of durable remission after relapse. However, 
the majority of relapsed patients will be ineligible for HSCT either because of a lack of 
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donor, advanced age, or the presence of other medical co-morbidities that would increase 
the potential morbidity of the procedure. As a result, therapeutic options available to date 
remain unsatisfactory for the majority of patients with relapsed AML.  Also, relapse after 
allogeneic stem cell transplantation is usually compatible with a survival of only weeks. 
Novel therapies should be investigated for the potential to improve remission duration 
and length of survival while at the same time limiting toxicity in this population of 
patients.  
Because elderly patients often have a lower response rate to standard chemotherapy 
regimens and have a higher rate of mortality during such treatments, especially when 
diagnosed at age >70 years, other therapies are now utilized in this patient group such as 
hypomethylating agents, clofarabine, and other investigational approaches.  It is generally 
held that there is no standard of care for induction therapy in elderly AML patients 2,3.
2.2  Decitabine
2.2.1
Effects in Humans
Decitabine is a unique agent with a dual mechanism of anticancer action. 
Although the compound was first synthesized over 40 years ago, only recently has 
the dual mechanism of action been elucidated.  High doses of decitabine are 
cytotoxic while lower doses are associated with DNA hypomethylating activity. 
This information sparked clinical trials using lower doses since in the original 
studies higher doses were associated with dose-limiting myelosuppression. 
Studies using such lower dosing schedules, particularly in patients with 
hematologic malignancies, have shown significant promise for the future use of 
demethylating agents. In May of 2006 the United States Food and Drug 
Administration approved the use of decitabine (DACOGEN for Injection) for the 
treatment of MDS. The current focus for the clinical use of decitabine is for the 
treatment of hematologic malignancies, namely MDS as well as AML, as a single 
agent or in combination with other agents.
2.2.2  Rationale for the Use of Decitabine in Hematologic Malignancies 
Reports suggest frequent methylation of the p15INK4B gene promoter in leukemias, 
and it has been proposed that this methylation could be necessary for leukemic 
cells to escape inhibitory signals from the bone marrow environment by silencing 
p15 expression.4,5  p15INK4B is a regulator of the G1/S phase cell cycle transition 
which negatively regulates cell-cycle dependent kinases, the activity of which is 
necessary to activate the Retinoblastoma protein transcription factor.6 
Furthermore, several studies report increased p15 gene methylation in MDS 
patients, and this methylation pattern appears to become more apparent with MDS 
disease progression.7,8 An agent such as decitabine or 5-azacytidine, with 
documented activity of hypomethylation of DNA would then be expected to 
affect the natural history of MDS and leukemias and demonstrate clinical activity. 
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Correlative investigations of Daskalakis et al.9 explored decitabine-induced p15 
gene demethylation in bone marrow mononuclear cells collected before and 
during treatment with decitabine. Samples were collected from 23 intermediate 
/high risk MDS subjects enrolled in a decitabine Phase 2 study. In these samples, 
p15 gene hypermethylation (defined as >15% methylation) was observed in 15 of 
23 patients at baseline (median, 29%; range, 16-54%). Hypermethylation occurred 
in all FAB subtypes and thus was not limited to the presence of excess bone 
marrow blasts. Of the 23 subjects that received one or more courses of low-dose 
decitabine, 19 were evaluable for changes in p15 gene methylation. Of the 12 
subjects with p15 hypermethylation prior to decitabine treatment, 9 responded to 
treatment with at least a 25% decrease (median, 16%; range, 5 to 34%). One 
subject had a <25% decrease, and in 2 subjects, p15 methylation increased. 
Subjects without initial p15 hypermethylation showed no changes in methylation 
during continued treatment. In 10 subjects, p15 immunohistochemical staining 
was performed on serial biopsies, and in 4 of 8 cases with p15 gene 
hypermethylation, cytoplasmic p15 expression was very low or absent prior to 
treatment while in the other 4 subjects and the 2 subjects without 
hypermethylation, cytoplasmic p15 levels were comparable to normal bone 
marrow. Following 1 to 3 courses of decitabine, p15 expression was induced to 
high levels in all 4 subjects with initially low or absent expression. This was 
paralleled by hypomethylation. The study concluded that emergence of partially 
demethylated epigenotypes and re-establishment of normal p15 protein expression 
following decitabine treatment implicate pharmacologic demethylation as a 
possible mechanism of response in MDS.  Other studies have documented global 
hypomethylation with decitabine but have not been able to associate responses 
with increased expression of a given gene. 10
2.2.3. Clinical Experience with Decitabine in AML and MDS
Treatment of patients with myelodysplastic syndromes (MDS) with decitabine 
leads to transfusion independence and a longer median time to progression to 
AML or death as compared to patients treated with supportive care only11.  In 
vitro data have shown that decitabine is able to induce terminal differentiation of 
leukemic blasts, which acquire the morphological and cytologic characteristics of 
fully differentiated monocytes and macrophages.  Additionally, treated cells 
regained their innate functional ability.  Decitabine has also been shown to have 
activity in MDS patients with intermediate or high risk International Prognostic 
Scoring System (IPSS) scores.  34% of patients had normalization of bone 
marrow and peripheral counts.  A dosing scheme using 20 mg/m2 daily 
intravenously for 5 days has been found to be as efficacious as other more 
complicated dosing schedules12. Subsequent studies  have shown activity as a 
first-line treatment in all cytogenetic subgroups of older AML patients13.  
Furthermore, decitabine has been successfully and safely combined with histone 
deacetylase inhibitors (HDACs) such as valproic acid, suberoylanilide 
hydroxamic acid (SAHA) and vorinostat as well as with standard chemotherapy 
regimens.14  Recently, decitabine has been utilized in elderly patients with AML 
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with some success15as upfront therapy and response rates up to 40% have been 
noted with ten day courses in a similar dosing scheme 16.
2.3
mTOR Pathway and Leukemia
The mammalian target of rapamycin (mTOR) is a serine/threonine kinase involved in the 
regulation of synthesis of proteins involved in cell cycle progression17.  It appears to be a 
nutrient sensing protein with dual regulation by amino acid availability as well as 
mitogen activation by the upstream PI3K/AKT pathways.17  The eukaryotic initiation 
factor 4 E (eIF4E), which is downstream from mTOR, is necessary for recruitment of the 
ribosome to mRNA, the rate limiting step in protein translation.  The formation of the 
eIF4E complex is regulated by 4E-BP1 and in the unphosphorylated form it binds to 
eIF4E and inhibits its activity and protein translation is halted, while when 4E-BP1 is 
phosphorylated, there is decreased affinity for eIF4E and translation can occur.  A 
separate downstream target of mTOR, p70S6K, is also involved in protein translation.  
When activated by mTOR, it is able to phosphorylate the 40S ribosomal protein S6 that 
then allows translation to occur.18
Constitutive activation of  PI3K/AKT/mTOR signaling has been shown in leukemic 
blasts with 50-70% of patients displaying phosphorylated AKT.19  There are multiple 
possible mechanisms for this activation which include activating Ras or c-KIT mutations, 
upregulation of PI3K p110, autocrine/paractine VEGF secretion and others.19 There also 
appears to be an upregulation of this pathway not only in the bulk  AML population, but 
also in leukemia stem cells transplanted in NOD/SCID mice models. 20   Activation of 
this pathway results in disrupted control of proliferation resulting in a competitive growth 
advantage for the leukemic cells.  Inhibitors of the mTOR pathway either alone or in 
combination may block the activated signaling cascade or lead to inhibition of tumor 
growth and apoptosis.20
2.4  Rapamycin
Rapamycin is a macrolide fungicide isolated from the bacteria Streptomyces 
hygroscopicus with potent antimicrobial, immunosuppressant and antitumor activities 
and is approved for the prevention of allograft rejection following organ transplantation.  
Rapamycin binds to the immunophilin FK506 binding protein 12 (FKBP12) and forms a 
complex which then binds to mTOR and inhibits downstream signaling events.21  The 
sensitivity of various AML cell lines to increasing concentrations of rapamycin in 
clonogenic assays has been measured.  There appears to be a variable degree of 
sensitivity with UT-7EPO and UT-7GM cell lines being insensitive, K562, U937, HEL 
and HL60 being moderately sensitive and the immature KG1 and KG1a cell lines being 
strongly inhibited by low concentrations of rapamycin.22  Nine patients with relapsed, 
refractory or poor-risk AML were treated with rapamycin as a single agent, with a partial 
response ( > 50% reduction in the absolute number of blasts or at least a 50% reduction in 
the percentage of marrow blasts) occurring in 4 patients.  4 patients had progressive 
disease and one had stable disease. 22 As a single agent, rapamycin has had minimal 
activity in AML. Rapamycin has been combined with cytototoxic chemotherapy in newly 
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diagnosed patients in early phase trials23 with no positive effects on CR rates noted..  
Rapamycin has also been utilized in the therapy of ALL, and it is also used after 
allogeneic stem cell transplantation for prophylaxis of graft vs. host disease in 
combination with tacrolimus or methotrexate.
2.5  Ribavirin
One of the reasons postulated for limited impact of mTOR inhibitors in AML is that first 
generation inhibitors such as rapamycin do not inhibit the mTORC2 component of 
mTOR and they also fail to inhibit 4E-PB1 phosphoryaltion, thereby allowing translation 
initiation to occur.  Unlike rapamycin, ribavirin is a competitive inhibitor of the cap 
moiety, thereby inhibiting the mRNA export and translation function of eiF4E.  eIF4E 
activity has been found to be most elevated in M4 and M5 AML (44/44 cases), and there 
is accumulation of nuclear bodies and less eiF4E in the cytoplasm when overexpression 
occurs.  When used as a single agent in 11 M4 and M5 AML cases, there was 1 CR, 2 
PRs, 2 blast responses, 4 stable disease, and 2 progressive disease outcomes 24
2.6  Rationale for the Combination of Decitabine and an mTOR Inhibitor
Decitabine has shown efficacy in the treatment of patients with myelodysplastic 
syndrome as well as AML.  Rapamycin has also been shown to have activity in patients 
with AML.  The combination of decitabine with rapamycin will allow us to test the 
potential beneficial effect of targeting two separate pathways that appear aberrant in this 
disease. Since successful maintenance dose escalation studies with a demethylation agent 
have been reported after cytotoxic chemotherapy as well as after stem cell transplantation 
and since rapamycin has effective GVHD activity without adversely impacting donor 
chimerism, we also wish to test the combination of decitabine and rapamycin in patients 
who relapse after allografting.25  It is also anticipated that this combination may be 
synergistic in that rapamycin by itself may activate pAKT via mTORC2 and IGFR1 
mechanisms. 19
In order to test the rationale for combining a demethylating agent with an mTOR 
inhibitor preclinically, AML cell lines were exposed to 5-azacytidine at 1 to 16 uM, with 
the IC50 determined to be 4-8 uM.  5-azacytidine increased apoptosis above control 
whereas rapamycin by itself had minimal effect on apoptosis as assessed in an Annexin V 
flow cytometric assay.  Effects on proliferation at concentrations of Rapamycin up to 100 
nM were also minimal.  In the U937 cell  line, the combination index was 0.465 (10 μM 
5-azacytidine and 100 nM rapamycin), indicating synergism.  For MV411, the 
combination index was 0.736, and for KG1a, 0.118, also indicating synergism.  For 
HL60, no synergism was noted.  Exposure to the combination of 5-azacytidine and 
rapamycin resulted in greater suppression of AKT and 4EBP1 phosphorylation than did 
either agent singly.  Four days of AML cell line exposure to decitabine followed by 100 
nM Rapamycin also results in inhibition of cell proliferation.  This in vitro data 
(published only in abstract form to date26) utilizing a demethylating agent and an mTOR 
inhibitor lends support to rational combination of this regimen in vitro.
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Based on the rationale for combining a hypomethylating agent with an mTOR inhibitor 
and upon the in vitro data generated, we embarked on a phase I trial to examine the 
effects of sequential decitabine and rapamycin with the primary endpoint of safety and 
feasibility: A Phase I Study of Decitabine in Combination with Escalating Doses of 
Rapamycin in Patients with Relapsed or Refractory Acute Myeloid Leukemia (registered 
as NCT00861874 at clinical trials.gov).  13 patients were accrued to the study (7 at dose 
level 1, 3 at dose level 2, and 3 at the third dose level). The median age of the patients 
was 63 (range 46-78).  The mean blast percentage at enrollment was 35% (range 6-93%).  
Seven patients had complex  karyotype.  At the end of cycle 1, 5 patients demonstrated 
disease progression, 5 had stable blast percentage, and 4 demonstrated a decline in blast 
percentage. There was one CR on the study. Median survival was 4 months (range 1-31+ 
months).  One patient  entered on the trial after prolonged neutropenia experienced 
reversible grade 3 mucositis which was deemed a DLT; hence the additional enrollment 
on the first doing cohort.  No other significant unexpected non-hematologic toxicities 
have occurred.  On the 2 mg cohort, all patients achieved therapeutic rapamycin levels 
during the first cycle and in 5/7, this occurred within 4 days of beginning therapy.  Based 
on these rapamycin levels, we have chosen 2 mg/day after a loading dose of 6 mg as the 
dose for the phase II portion of the trial with this combination27.
2.7  Rationale for combination of decitabine and ribavirin
As noted above, while mTOR inhibitors are not always effective in inhibiting translation 
in AML, ribavirin has that potential in cases where eIF4E is activated and expressed. In 
this trial, we will therefore examine the use of ribavirin in dose escalation fashion built on 
a 10 day decitabine backbone in those M4/M5 subtype patients who express high eIF4E 
levels.
3.0 PATIENT SELECTION
3.1
Inclusion Criteria
3.1.1  Age  18
3.1.2  Diagnosis of AML according to WHO (World Health Organization) criteria  
except acute promyelocytic leukemia AND
3.1.3  Refractory AML defined as failure to achieve CR after 2 cycles of  
induction chemotherapy or persistence of > 40% bone marrow blasts after one 
cycle of chemotherapy induction OR
3.1.4  Relapsed AML defined as any evidence of disease recurrence after 
achieving a documented first or greater CR OR
3.1.5  Relapsed AML after stem cell transplantation. 90 days (since stem cell 
infusion) must have elapsed between transplant and emergence of recurrent 
AMLOR
3.1.6  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. 
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 3.1.7 ECOG  performance status <3 (Appendix 1)
3.2  Exclusion Criteria
3.2.1  Abnormal renal function as evidenced by a calculated creatinine clearance 
≤ 30 ml/min (Cockcroft-Gault formula (Appendix 2)
32.2 Abnormal liver function: Bilirubin >2.0 mg/dl, transaminase(s) more than  
2.5x the upper limits of normal
3.2.3 Active systemic infection not responding to antibiotics
3.2.4 Known diagnosis of human immunodeficiency virus infection (HIV)
3.2.5 Patients who are post-allogeneic transplantation should not have active 
GVHD greater than grade 1 of skin at time of enrollment.  They may have had 
DLI but not within 4 weeks of beginning the study.  
3.2.6 Pregnant or breast feeding female subjects
3.2.7 Known or suspected CNS leukemia involvement; past involvement is not an 
exclusion. 
  
3.3 Inclusion of Women and Minorities
Both men and women and members of all ethnic groups are eligible for this trial.
     
    
 3.4
     Study Duration and Dates
The study will commence in Winter, 2014 and should meet accrual by  Autumn , 2015, 
assuming approximately two accruals per month.  These are estimates only.  Of note, 
should a patient be found to exhibit stable or improved disease after completing 6 cycles, 
a consideration will be given to continuing maintenance treatment of decitabine, but this 
will be optional and not part of this protocol. 
3.5       Prior and concomitant medications
Patients may not have had prior exposure to decitabine, rapamycin, or ribavirin.  No other 
investigational agent may have been received within two weeks, but otherwise there are 
no exclusions on numbers and types of prior therapies for AML.  As discussed below, 
hydroxyurea and/or leukapheresis may be utilized for control of circulating blast count at 
the inception of cycle 1 and 10 days into the cycle. 
4.0 TREATMENT PLAN
4.1  Agent Administration
Treatment will be administered on an outpatient basis whenever possible.  Reported 
adverse events and potential risks for  decitabine, rapamycin, and ribavirin are described 
in Section 5. No investigational or commercial agents or therapies other than those 
described below may be administered with the intent to treat the patient's malignancy.
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4.1.1 Study schema
Note:  Those patients with morphologic M4/M5 subtypes28 will be treated on Arm B 
and all other subtypes on Arm A.  At study entry, all patients will have samples 
procured for testing of eIF4E expression but this will not determine allocation to 
arm A or B which will be made solely on the basis of FAB subtype.  M4 subtype is 
acute myelomonocytic leukemia and M5 acute monocytic leukemia. 

Decitabine (Arms A and B)

20mg/m2 will be given as an intravenous infusion daily for 10 consecutive days 
starting on day 1 of cycle 1. 

In subsequent cycles, decitabine will be given for 5 days (day 1-5)
Rapamycin (Arm A)
o
For non-M4/M5 AML cases28
o
A 6 mg loading dose will be administered on Day 11 in cycle 1 and day 6 in 
subsequent cycles.  Thereafter, 2 mg/day will be administered per schedule below. 
This may be reduced to 1 mg/day if levels are elevated (>15 ng/mL).. 
o
Toxicities will be as  defined in section 9 using NCI Common Toxicity Criteria 
for Adverse Events (CTCAE (version 4.0) Appendix 3)
o
Rapamycin will be given from day 11 to 22 in cycle 1 and on days 6 to 22 in 
subsequent cycles.
Dose Level
Rapamycin
Decitabine
Level -1
1 mg
20 mg/m2
Level 1
2 mg
20 mg/m2
The rapamycin dose for phase II of the study was chosen based on results from the phase 
I study (ULEU08049).
Ribavirin (Arm B)
For M4/M5 cases28—These patient are anticipated to have high eIF4E expression as 
expressed by Western blotting24.
In cycle 1, ribavirin will be dosed from Day 11 through Day 28.  
In subsequent cycles, ribavirin will be started on Day 1 on a continuous basis until study 
completion.  These doses were chosen based on those found effective and tolerated in 
previous studies24. 
Dose level cohorts are listed in the table below.  Subject enrollment will start at Dose 
Level 1 (1000 mg). Enrollment in subsequent dose levels (escalation to Dose level 2 and 
3, or de-escalation to Level -1 and -2) will follow the dose escalation and dose de-
escalation plans as outlined below.
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Dose Level
Ribavirin
Decitabine
Description
Level -2
600 mg bid
20mg/m2
Dose de-escalation cohort
Level -1
800 mg bid
20mg/m2
Dose de-escalation cohort
Level 1
1000 mg bid 20mg/m2
Initial cohort
Level 2
1200 mg bid
20 mg/m2
Dose escalation cohort
Level 3
1400 mg bid
20mg/m2
Dose escalation cohort
Dose Escalation Plans for Ribavirin (Arm B)
Number of patients with DLT at a given 
dose level
Escalation Decision Rule
0 out of 3
Enter 3 patients at the next dose level
≥ 2
Dose escalation will be stopped.  This dose level 
will be declared the maximally administered dose 
(highest dose administered).  Three (3) additional 
patients will be entered at the next lowest level if 
only 3 patients were treated previously at that 
dose.
1 out of 3
Enter at least 3 more patients at this dose level.  –
If 0 of these 3 patients experience DLT, proceed 
to the next dose level.
-If 1 or more of this group suffer DLT, then dose 
escalation is stopped, and this dose is declared the 
maximally administered dose.
Three (3) additional patients will be entered at the 
next lowest dose level if only 3 patients were 
treated previously at that dose. 
≤ 1 out of 6 at highest dose level below the 
maximally administered dose
This is generally the recommended phase 2 dose.  
6 patients must be entered at the recommended 
phase 2 dose before going to Phase 2.
An ad hoc confidential person will ensure that no unexpected adverse events have occurred at 
each dose level before enrollment on the next dose level commences.  This will be handled 
through the DSMB of the James P Wilmot Cancer Center.  THIS WILL REQUIRE THAT THE 
LAST PERSON ENROLLED AT THE PRIOR COHORT HAS BEEN FOLLOWED FOR 30 
DAYS FROM THE START OF THERAPY.
Dose De-escalation:  If  1000 mg bid proves to be the MTD, a cohort at 800 mg bid will be 
treated, and if that is too toxic, one at 600 mg bid will be enrolled (level -2).  No further dose de-
escalation would be planned.  Safety assessment at each cohort would be as indicated above. 
4.1.1.1
Cycle  Duration
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Cycles will begin on an every 28 day basis which may be extended to 30 days to 
account for weekends, holidays, logistics of marrow aspirate and biopsy 
scheduling. 
Routine Clinical Monitoring.
Routine CBC with differential and platelets as well as a comprehensive metabolic 
profile including renal and hepatic function will be evaluated on a twice weekly 
basis and more frequently as cytopenias or metabolic abnormalities indicate.  For 
those patients receiving rapamycin,  a trough Rapamycin level will be performed 
at day 14 and 21 of each cycle. 
Marrow Status Monitoring.
Marrow aspirate only will be obtained after the first ten days (on days 10 or 11) of 
decitabine in the first cycle.  At the end of the first cycle and third cycle or at the 
time of full peripheral blood count recovery, whichever comes first, a bone 
marrow aspirate and biopsy will also be obtained. Marrow may be obtained 
between days 22 and 26 of the 1st and 3rd cycles, and a marrow at time of 
withdrawal from study is recommended but is optional. 
Number of Cycles.
If there is no overt progression of disease (defined as doubling of the peripheral 
blood blast count) after the first cycle, the patient will proceed on study and 
receive two more cycles.  If after the third cycle there is evidence of a PR/CR or 
stable disease, the patient will remain on study for 3 more cycles.  The maximum 
number of cycles that each patient may receive is six.  As noted above, physicians 
may use maintenance decitabine, but this will be off protocol.
Long Term Follow Up
Patients will be followed for survival status every 6 months for up to 2 years after 
last date of treatment. 
4.1.2    Informed Consent
Prior to any study procedures being performed, written informed consent must be 
obtained for each patient.  Each patient will sign the IRB approved informed consent, and 
the patient will be given a copy of the signed and dated consent.  The original signed 
version will be retained in study files in the Clinical Trials Office of the University of 
Rochester Cancer Center.  Information on all patients screened for the trial will be 
recorded with indication of reasons for non-participation or non-eligibility.  All 
information will be stored in a secure place.
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4.1.3     Registration 
To register a patient, the eligibility checklist and consent form will be sent to the research 
nurse or data manager who will then register the patient. The Clinical Trials Office of the 
University of Rochester Cancer Center will register all patients by phoning 585-275-
9485. The PI will sign each registration form which will include inclusion and exclusion 
criteria.
4.2 
Supportive Care Guidelines
4.2.1
Blood Transfusion: Transfusion Parameters:
Hb ≤ 7 mg/dl or HCT <21 % in the absence of cardiopulmonary disease inpatient and 
<24% outpatient. 
HCT <27 % in presence of cardiopulmonary disease. 
4.2.2
Platelet Transfusion: Transfusion Parameters:
            Active Bleeding OR
Platelets <10,000/µL  inpatient or <15,000/µL outpatient. OR 
Platelets < 20,000/µL in the presence of infection or fever. 
4.2.3. Infectious Disease Prophylaxis 
4.2.3.1 Antibiotics: Ciproflaxcin 500mg po BID or moxifloxacin 400 mg/day may 
be used during times of neutropenia at the discretion of the treating physician. 
4.2.3.2 Antivirals: Acyclovir, Valacyclovir, or Famciclovir are permitted. 
4.2.3.3 Antifungals: Fluconazole 200mg QD prophylaxis if patient is neutropenic 
until ANC >500/uL. Dosage should be adjusted according to liver function. 
Voriconazole and posaconazole may result in elevated sirolimus levels and should 
be utilized with caution and only in the case of documented fungal infections. 
Their use is permitted for those on Arm B. 
4.2.3.4 Anti-Emetics: Use of anti-emetics will be at the discretion of the treating 
physician. 
4.2.4 Tumor-lysis prophylaxis
4.2.4.1  Allopurinol 300 mg/day po on day -1 or 0 until day 14 or WBC < 500/ul. 
Rasburicase may be utilized for extreme uric acid elevations per institutional 
standards of care.
4.2.5
Graft vs. Host Disease Management—See also 4.3.4.  For those patients who are 
S/P allografting and who have a flare of GVHD during therapy, this can be treated at the 
investigators’ discretion with steroids, mycophenylate mofetil, or photopheresis.   If a 
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calcineurin inhibitor is required, a patient on Arm A would need to be removed from trial 
based on potential interaction with Rapamycin.
 
Other supportive care will be per institutional standards of care.  This will include 
treatment of neutropenic fever, management of bleeding, nausea, mucositis, or other 
toxicities.  Neupogen will not be utilized routinely but may be used in settings of 
infection or fever at the treating physicians’ discretion.
4.3  Concomitant Therapy
4.3.1  In general, concomitant medications and therapies deemed necessary for the 
supportive care and safety of the patient are allowed provided their use is documented in 
the patient record and on the appropriate case report form. The administration of any 
other systemic anticancer agents including chemotherapy, radiation therapy or biologic 
agents including donor leukocyte infusions  is NOT permitted. Similarly, concurrent use  
of other  investigational agents or their use in the 28 days prior to enrollment is not 
allowed. 
For any patient with a WBC greater than 50,000, consideration will be given for 
pretreatment with an appropriate dose of hydroxyurea to cytoreduce prior to the first dose 
of decitabine. Decitabine will not be started until the absolute blast count is less than 
15,000/uL.  Hydroxyurea may be continued into the first cycle until appropriate 
cytoreduction has occurred and should then be discontinued.  In extreme cases of WBC 
elevation or in the presence of hyperleukostasis symptoms, leukapheresis may be 
employed for cytoreduction along with hydroxyurea. 
For those patients who relapse after allogeneic transplant, tacrolimus/cyclosporine or 
steroids should be tapered off if no GVHD occurs.  If GVHD occurs/progresses during 
therapy, it should be treated initially with steroids.  Calcineurin inhibitors should be 
avoided.  Mycophenylate mofetil may be utilized. See also 4.2.5. 
4.4   Dose Calculation
Dose of decitabine will be based on body surface area calculated on actual body weight.  No 
correction for obesity will be made.  The dose of rapamycin or ribavirin is a fixed, non-
calculated dose.
4.5
  Dose Modification
4.5.1   Rapamycin 
4.5.1.1 Dose modifications for non-hematological toxicity
Grade 2 (in accordance with the NCI CTCAE version 4.0)
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If the patient experiences a Grade 2 non-hematologic toxicity, study drug must be 
withheld until the toxicity has resolved to less than or equal to Grade 1.  
Rapamycin may then be resumed at the 2 mg daily dose.  If the grade 2 toxicity 
recurs, Rapamycin must be withheld until the toxicity has resolved to less than or 
equal to Grade 1. In those patients receiving 2 mg/day, dosing will be restarted on 
a 1 mg/day basis. If this recurs at the 1 mg dosing, rapamycin can then be dosed at 
1 mg/ qod, but this is the lowest dose allowed. 
Grade 3 or 4
If a patient experiences a Grade 3 or 4 toxicity, study drug must be withheld until 
the toxicity has resolved to less than or equal to grade 1 and the daily dose must 
be reduced to 1 mg/day from 2 mg per day,   If the Grade 3 or 4 toxicity recurs, 
Rapamycin must be withheld until the toxicity has resolved to less than or equal 
to Grade 1, and the daily dose must be reduced to 1 mg qod.  If the same toxicity 
occurs again, the drug must be stopped.
4.5.1.2 Dose modifications for hematologic toxicity
Grade 2 
No dose interruptions will be performed for grade 1 or 2 hematologic toxicity 
because it is anticipated that all patients may become pancyopenic as a result of 
treatment or from the AML itself.
Grade 3 or 4
No dose reductions will be performed for grade 3 or 4 anemia, neutropenia and 
thrombocytopenia.  Patients will receive supportive care as specified in section 
4.2. Cycles may be delayed up to a week in the event of stable disease if severe 
neutropenia and/or active infection are present until the infection is controlled and 
neutropenia stabilized or improving. 
Dose modifications for other reasons
If vomiting occurs following rapamycin administration, an extra dose will not be 
given that day and antiemetics will be prescribed to enable resumption of the next 
day’s dose.  
Grade 3 infections, fatigue, weight loss, and electrolyte imbalances are anticipated 
in relapsed AML patients and will be appropriately treated but are not deemed 
study related toxicities and will not result in dose modifications. 
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4.5.1.3 Dose modification for toxic range rapamycin level
If the rapamycin level at the time of scheduled measurement is >15 
ng/mL, the dose will be held for 5 days, and a repeat level will be drawn 
on the 5th day. If the level is still >15, the drug will be held for 5 more 
days and the level repeated.  Once the repeat level is no longer above the 
normal range, the daily dose will be reduced to 1 mg and a rapamycin 
level will be drawn 5 days after the dose adjustment has been made.  If the 
level is again  ≥ 15 ng/dL, drug will be held until levels return to the 
therapeutic range and then started again at 1 mg every other day.
4.5.2
Decitabine
No specific dose modification for hematologic toxicities.  
Schedule modifications will be based on disease status and count recovery from 
the previous cycle as follows:
Subjects with >5% blasts in marrow will proceed to a 5 day cycle.
Those with no morphological evidence of leukemia (<5% blasts )will receive a 5 
day course of decitabine
Those with no evidence of AML but who have grade 4 neutropenia (<500/uL) of 
at least 14 days duration will receive 5 days with the next cycle.  If this happens 
again in the subsequent cycle, 3 days will be administrated.  
Subjects should receive 3 cycles of treatment as discussed above before treatment 
failure is determined in the absence of obviously resistant, progressive disease.
4.5.3  Ribavirin
4.5.3.1 Dose Modifications for  Hematologic Toxicity
No dose modification for hematologic toxicity will occur.  Patients will 
receive supportive care as specified in section 4.2.  Cycles may be delayed 
up to a week in the event of stable disease if severe neutropenia and/or 
active infection are present until the infection is controlled and 
neutropenia stabilizes or is improving. 
4.5.3.2 Dose Modifications for non-hematologic toxicity
For non-hematologic toxicities thought due to ribavirin, the drug will be 
held until toxicity resolves to less than or equal to grade 1. If the 
resumption of ribavirin results in the same toxicity, dose will be lowered 
by one cohort, and for those on 1000 bid, dose may be reduced to 800 mg 
bid (dose level -1).  If toxicity occurs at that level, ribavirin will be 
redosed at 600 mg bid (dose level -2), and if toxicity occurs at that dose, 
ribavirin will be stopped. 
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Grade 3 infections, fatigue, weight loss, and electrolyte imbalances are 
anticipated in relapsed AML patients and will be appropriately treated but 
are not deemed study related toxicities and will not result in dose 
modifications
4.5.4 Other dose modifications according to standard clinical practices are to the 
discretion of the treating physician. The study coordinator and primary investigator (s) 
should be notified of such modifications.  As examples, treatment can be delayed at the 
discretion of the investigator for disease-related complications such as febrile 
neutropenia, infection, mucositis, hemorrhage, or extreme fatigue and debility.
4.6 
Treatment Compliance
All study drugs will be administered to eligible subjects under the supervision of the 
investigators.  The pharmacist will maintain records of  preparation and dispensing, 
including the applicable lot numbers, patients’ height, weight, and body surface, and total 
drug administered.  Any discrepancy between the calculated dose and dose administered 
and the reason for the discrepancy must be recorded on the data capture records and in 
the source documents.  Patients will also be given a log/diary on which to record 
rapamycin or ribavirin ingestion.
5.0 AGENT FORMULATION AND PROCUREMENT
5.1 Decitabine
Decitabine will be purchased from commercial sources. 
5.1.1
 Formulation Information
5.1.1.1 Product Identification 
The generic name is decitabine or 5-aza-2’-deoxycytidine. The trade name 
in the United States is DACOGENTM for Injection. 
5.1.1.2 Physical and Chemical Characteristics
Decitabine is a white to almost white finely crystalline powder, odorless 
substance, with a molecular formula of C8H12N4O4 and a molecular weight 
of 228.21 Daltons. The chemical structure is shown in Figure 1.
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Figure 1: Chemical Structure of Decitabine 
Decitabine is sparingly soluble in water (8 to12 mg/mL), slightly soluble 
in ethanol and virtually insoluble in chloroform. Decitabine is an analog of 
2'-deoxycytidine in which the #5-carbon atom of the pyrimidine ring has 
been replaced by a nitrogen atom. Decitabine appears in 2 configurations. 
The ß-D-anomer is the pharmacologically active form; the -D-anomer is 
almost inactive.29  The drug is most stable at pH 7 and when stored at low 
temperatures.30-33
Dacogen for Injection (decitabine) is supplied as a lyophilized 
preparation. Each 20-mL vial containing 50 mg decitabine should be 
stored at controlled room temperature per USP and is stable for at least 3 
years if unopened. 
Decitabine is a hypomethylating drug at lower doses and demonstrates 
direct cytotoxic properties at higher doses, therefore as with other 
potentially toxic compounds, caution should be exercised when handling 
and preparing decitabine. Decitabine should be aseptically reconstituted 
with 10 mL of Sterile Water for Injection (WFI); upon reconstitution, each 
mL contains approximately 5.0 mg of decitabine at pH 6.7 to 7.3. 
Immediately after reconstitution, the solution should be further diluted per 
recommended procedure with infusion fluids, such as 0.9% Sodium 
Chloride Injection, 5% Dextrose Injection, or Lactated Ringer’s Injection 
to a final drug concentration of 0.1 to 1.0 mg/mL. Unless used within 15 
minutes of reconstitution, the diluted solution must be prepared using cold 
infusion fluids (2oC to 8oC) and stored at 2°C to 8°C for a maximum of 7 
hours prior to administration.
5.1.1.3 Other Pertinent Information
In stability studies, 33 Dacogen for Injection maintains at least 95% of its 
initial potency for up to 60 minutes when a 50 mg vial is reconstituted 
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with 10 mL of either cold (2C to 8C) or room temperature water for 
injection (WFI). To assess potency, the decitabine was assayed by high-
performance liquid chromatography (HPLC).
Reconstituted Dacogen for Injection (5mg/mL in WFI) was mixed with 
each of the approved diluents (0.9% sodium chloride injection, 5% 
dextrose injection or lactated Ringer’s solution) and the stability was 
measured as above. The decitabine potency at diluted concentrations of 
0.1 mg/mL and 1.0 mg/mL at either room temperature for 3 hours or 
refrigerated (2C to 8C) for 7 hours followed by 2 hours at room 
temperature remained  90%. All admixtures of decitabine remained clear 
and colorless during storage at room temperature. Additionally, the pH of 
the solutions remained constant throughout the study.
Handling and Disposal
Procedures for proper handling and disposal of anticancer drugs should be 
applied. Several guidances on this subject have been published. There is 
no general agreement that all of the procedures recommended in the 
guidelines are necessary or appropriate.
5.1.1.4 The dosage of decitabine will be 20 mg/m2 given as an infusion on Days 
1-10 of the first cycle and 1-5 of subsequent cycles..  Decitabine must be 
infused over 1 hour.
5.1.1.5 Adverse reactions
Table 1. Common Adverse Events Reported in a Phase III Trial Comparing decitabine to 
Supportive Care33
DACOGEN (n=83)
Supportive Care (n=81)
Neutropenia
75 (90%)
58 (72%)
Thrombocytopenia
74 (89%)
64 (79%)
Anemia NOS
68 (82%)
60 (74%)
Febrile neutropenia
24 (29%)
5 (6%)
Nausea
35 (42%)
13 (16%)
Constipation
29 (35%)
11 (14%)
Diarrhea NOS
28 (34%)
13 (16%)
Pyrexia
44 (53%)
23 (28%)
Hyperglycemia NOS
27 (33%)
16 (20%)
Cough
33 (40%)
25 (31%)
Petechiae
32 (39%)
13 (16%)
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5.2  Rapamycin (from Rapamycin package insert)
Rapamycin can be obtained as Rapamune from Wyeth-Ayerst Laboratories.  It is approved for 
graft rejection prevention in kidney transplantation.  It will be purchased from commercial 
sources for this protocol.
The oral solution must be protected from light and stored under refrigeration, 2 degrees Celsius 
to 8 degrees Celsius and it is stable for 24 months under these conditions.  A slight haze may 
develop in refrigerated solutions, but the quality of the product is not affected.  After opening, 
the solution should be used in 1 month.  If necessary, it may be stored at temperatures up to 25 
degrees Celsius for several days after opening (not longer than 30 days).  Product may be stored 
in an amber syringe for a maximum of 24 hours (at room temperature or refrigerated).  Discard 
syringe after use.  Solution should be used immediately following dilution.  The tablet should be 
stored at room temperature (20 degrees Celsius to 25 degrees Celsius) and protected from light.
Absorption: Rapid
Volume of distribution: 12L/Kg (+/- 7.52L/kg)
Protein binding: 92%, primarily to albumin
Metabolism: Extensively hepatic via CYP3A3/4 and P-glycoprotien
Bioavailability: 14%
Half-life elimination: Mean: 62 hours
Time to peak: 1 – 3 hours
Excretion: Feces (91%); Urine (2.2%)
5.2.1. Adverse reactions
5.2.1.1.   Systemic >10%:  
Central nervous system: Insomnia, nervousness
Gastrointestinal: Increased appetite, indigestion, esophagitis
Dermatologic: Hirsutism
Endocrine/metabolic: Diabetes mellitus
Neuromuscular & Skeletal: Arthralgia
Ocular: Cataracts
Respiratory: Epistaxis
Metabolic:  Increased triglycerides or cholesterol
 <1% of case reports: 
Seizures, mood swings, headache, delirium, hallucinations, euphoria, skin 
atrophy, bruising, hyperpigmentation, acne, amenorrhea, sodium and 
water retention, Cushing’s syndrome, hyperglycemia, bone growth 
suppression, abdominal distention, ulcerative esophagitis, pancreatitis, 
muscle wasting, hypersensitivity reactions, pneumonitis in renal transplant 
patients, microangiopathic anemia in GVHD prophylaxis 
regimens only.
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5.2.2.   Drug Interactions
Cyclosporine may increase rapamycin concentrations due to inhibition of 
CYP3A4. In this protocol, active GVHD is an exclusion (see inclusion/exclusion 
section), so it is unlikely any patient would be on concurrent cyclosporine. 
 
It is recommended that strong inducers and strong inhibitors of CYP3A4 and P-gp 
be avoided with rapamycin.  Such agents include but are not limited to Rifampin, 
Rirabutin, Ketoconazole, Voriconazole, Itraconazole, Erythromycin, 
Telithromycin, and Clarithromycin.
 
Note: None of these are commonly used in AML patients except voriconazole, 
and it is recommended to avoid this.  (See supportive care section of protocol, 
section 4.2). If any of these agents or other weaker inducers of CYP3A4 require 
usage, these can be utilized with caution especially since rapamycin levels will be 
monitored frequently in this protocol. 
 
Grapefruit juice is to be avoided with rapamycin use. 
5.3  Ribavirin (from Ribavirin package insert)
5.3.1 Description-- Ribavirin, (COEPEGUS)  is a nucleoside analogue with antiviral 
activity. The chemical name of ribavirin is 1-β-D-ribofuranosyl-1H-1,2,4-triazole-3-
carboxamide. It  is available as a light pink to pink colored, flat, oval-shaped, film-coated 
tablet for oral administration. Each tablet contains 200 mg of ribavirin and the following 
inactive ingredients: pregelatinized starch, microcrystalline cellulose, sodium starch 
glycolate, cornstarch, and magnesium stearate. The coating of the tablet contains 
Chromatone-P® or Opadry® Pink (made by using hydroxypropyl methyl cellulose, talc, 
titanium dioxide, synthetic yellow iron oxide, and synthetic red iron oxide), ethyl 
cellulose (ECD-30), and triacetin. 
5.3.2 CLINICAL PHARMACOLOGY 
 Mechanism of Action 

Ribavirin is an antiviral drug 
 
Pharmacokinetics 

Multiple dose ribavirin pharmacokinetic data are available for HCV patients who 
received ribavirin in combination with peginterferon alfa-2a. Following 
administration of 1200 mg/day with food for 12 weeks mean±SD (n=39; body 
weight greater than 75 kg) AUC0-12hr was 25,361±7110 ng·hr/mL and Cmax 
was 2748±818 ng/mL. The average time to reach Cmax was 2 hours. 

The terminal half-life of ribavirin following administration of a single oral dose of  
is about 120 to 170 hours. The total apparent clearance following administration 
of a single oral dose of is about 26 L/h. There is extensive accumulation of 
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ribavirin after multiple dosing (twice daily) such that the Cmax at steady state was 
four-fold higher than that of a single dose. 
Effect of Food on Absorption of Ribavirin 

Bioavailability of a single oral dose of ribavirin was increased by co-
administration with a high-fat meal. 

Elimination and Metabolism 

The contribution of renal and hepatic pathways to ribavirin elimination after 
administration of is not known. In vitro studies indicate that ribavirin is not a 
substrate of CYP450 enzymes. 

Renal Impairment 

A clinical trial evaluated 50  subjects with either moderate (creatinine clearance 
30 to 50 mL/min) or severe (creatinine clearance less than 30 mL/min) renal 
impairment or end stage renal disease (ESRD) requiring chronic hemodialysis 
(HD). The apparent clearance of ribavirin was reduced in subjects with creatinine 
clearance less than or equal to 50 mL/min, including subjects with ESRD on HD, 
exhibiting approximately 30% of the value found in subjects with normal renal 
function. Pharmacokinetic modeling and simulation indicates that a dose of 200 
mg daily in patients with severe renal impairment and a dose of 200 mg daily 
alternating with 400 mg the following day in patients with moderate renal 
impairment will provide plasma ribavirin exposures similar to that observed in 
patients with normal renal function receiving the standard 1000/1200 mg daily 
dose. These doses have not been studied in patients.
5.3.3  Adverse Effects
6.3.3.1 Ribavirin  therapy should not be started unless a report of a negative 
pregnancy test has been obtained immediately prior to planned initiation of 
therapy. Extreme care must be taken to avoid pregnancy in female patients and in 
female partners of male patients. Patients should be instructed to use at least two 
forms of effective contraception during treatment and for 6 months after treatment 
has been stopped. Pregnancy testing should occur monthly during therapy and for 
6 months after therapy has stopped.
5.3.3.2 Anemia 
The primary toxicity of ribavirin is hemolytic anemia, which was observed 
in approximately 13% of all ribavirin/interferon-treated subjects in clinical 
trials. Anemia  occurs within 1 to 2 weeks of initiation of therapy. Because 
the initial drop in hemoglobin may be significant, it is advised that 
hemoglobin or hematocrit be obtained pretreatment and at week 2 and 
week 4 of therapy or more frequently if clinically indicated. This has not 
been a factor in AML trials thus far. 24 
5.3.3.3 Hepatic Failure –this has been noted only in hepatitis C patients. 
5.3.3.4 Other reported toxicities:
Pruritis
Severe acute hypersensitivity reactions .
Low calcium levels
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Low magnesium levels
Serious skin reactions including vesiculobullous eruptions, reactions in 
the spectrum of Stevens-Johnson Syndrome (erythema multiforme major) 
with varying degrees of skin and mucosal involvement and exfoliative 
dermatitis (erythroderma) have been reported in patients receiving 
PEGASYS with and without ribavirin. Patients developing signs or 
symptoms of severe skin reactions must discontinue therapy.  
 
Pulmonary Disorders 
Dyspnea, pulmonary infiltrates, pneumonitis, pulmonary hypertension, 
and pneumonia have been reported during therapy with ribavirin and 
interferon. 
 
Bone Marrow Suppression 
Pancytopenia (marked decreases in RBCs, neutrophils and platelets) and 
bone marrow suppression have been reported in the literature to occur 
within 3 to 7 weeks after the concomitant administration of pegylated 
interferon/ribavirin and azathioprine. This has been reversible and is of 
less concern in patients with hematologic malignancies. 
Pancreatitis 
Ribavirin  therapy should be suspended in patients with signs and 
symptoms of pancreatitis, and discontinued in patients with confirmed 
pancreatitis.
5.3.4 HOW SUPPLIED/STORAGE AND HANDLING 
Ribavirin is available as tablets for oral administration. Each tablet contains 200 
mg of ribavirin and is light pink to pink colored, flat, oval-shaped, film-coated, 
and engraved with RIB 200 on one side and ROCHE on the other side. They are 
packaged as bottle of 168 tablets (NDC 0004-0086-94).
5.3.5 Storage and Handling 
The bottle is stored  at 25ºC (77ºF); excursions are permitted between 15ºC and 
30ºC (59ºF and 86ºF) [see USP Controlled Room Temperature]. Keep bottle 
tightly closed.
6.0 STUDY CALENDAR (Appendix 5)
Baseline evaluations are to be conducted within 1 week prior to the start of the protocol unless 
otherwise specified.
Before beginning the treatment protocol, each patient will have the following performed:
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
Complete history and physical exam including: Demographics, past medical and surgical 
history, medications, allergies, vital signs, height, weight, systemic exam including 
neurological exam

EKG and Chest x-ray

Bone marrow aspirate/biopsy, cytogenetics, molecular diagnostic studies to assess for the 
presence of FLT-3 or NPM-1 mutations and flow cytometry within 2 weeks of treatment.  
If these studies were performed elsewhere, an aspirate only will be performed to obtain 
material to perform the baseline correlative studies that are part of the protocol. (See 
section 8).  

CBC with differential, platelet count

Chemistry including complete liver function tests, BUN/Cr, LDH and other electrolytes

Uric acid level

Urine analysis and urine pregnancy test for female patients of childbearing potential

DIC panel

Peripheral blood for correlative studies (See section 8 and  Appendix 5)
After the beginning of each cycle, each patient will have the following tests performed at the 
noted time points:

CBC with differential and platelets  twice per week

Chemistry including liver function tests, BUN/Cr and other electrolytes twice weekly

Triglycerides and cholesterol on Day 1 of each cycle for those on Arm A (rapamycin) 
only

Abbreviated physical examination and assessment of performance status

A bone marrow aspirate only will be performed on Day 10 or 11 of therapy after 
completion of the decitabine and before initiation of rapamycin or ribavirin in CYCLE 1 
ONLY for correlative studies including the phosphorylation status of mTOR effectors 
and stem cell frequency.

A trough rapamycin level (arm A only) will be drawn on day 14 and 21 of each cycle.  A 
level will also be drawn on Day 1 of Cycle 2 to assure a subtherapeutic level when 
decitabine is started in subsequent cycles only if the level on Day 21 was elevated.  

A bone marrow aspirate and biopsy will be performed after the completion of  cylces 1, 
3, and at the end of the study. This may occur on Days 22 through 26 of the cycle. 

A marrow aspirate and biopsy will also be performed at time of suspected disease 
progression and at study completion or at any other time the treating physician deems 
important for disease status determination
7.0 MEASUREMENT OF EFFECT  Responses will be assessed at the end of cycle 1 (for 
progression only) and cycle 3 and at study conclusion or patient withdrawal from study 
(See 8.2 below). 
7.1  Definitions
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7.1.1 Complete remission:  Normocellular marrow (>20%) with < 5% blasts and no 
extramedullary leukemia. Absence of dysplasia.  Normal peripheral blood counts 
– ANC>1000 and platelets > 100,000. Patients with these criteria and persistently 
abnormal cytogenetics will be judged as complete remission, but these aberrations 
will be noted.
7.1.2
Partial remission: Normocellular marrow (>20%) with 5-20% blasts and no 
extramedullary leukemia.
7.1.3    Treatment failure:  failure to achieve CR or PR.
7.1.4
Stable disease: No change in percentage of marrow blasts.
7.1.5    Relapse: The reappearance of circulating blast cells of the malignant phenotype; > 
5% blasts in the bone marrow not attributable to another cause; and/or, the 
development of extramedullary leukemia.
7.1.6  Hematologic recovery:  ANC > 1500 for 3 consecutive days; non-
transfused platelets > 100; no leukemic blasts in the peripheral blood.
7.1.7
Duration of remission/response:  defined as the time from documented           
remission/response to the time of progression.
7.2 
Confirmatory Measurement/Duration of Response
7.2.1 A bone marrow biopsy and aspirate will be obtained after cycle 3 and after each 
cycle and at the end of study at which time determination of a PR or CR will be 
made.
7.2.2 Duration of overall response 
The duration of overall response is measured from the time measurement 
criteria are met for CR or PR until the first date that recurrent or progressive 
disease is objectively documented. 
The duration of CR is measured from the time measurement criteria are 
first met for CR until the first date that recurrent disease is objectively 
documented.   Note will be made of use of maintenance decitabine. 
7.2.3 Progression-Free Survival 
PFS is defined as the duration of time from start of treatment to time of 
progression. 
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All bone marrow biopsies and aspirates will be reviewed by a hematopathologist. 
8.0 CORRELATIVE STUDIES
Assessment of eIF4E Expression—This will be done on all patients on pre-study marrow 
aspirate.  Light density marrow cells will be processed, and western blotting performed to 
determine if the AML is eIF4E positive (increased 2 to 3 Xs above normal controls).  
Immunohistochemistry will also be carried out with eIF4E and DAPI to document initial nuclear 
localization by confocal microscopy. Having this information at study entry will allow 
determination of ribavirin effects on eIF4E localization at subsequent sampling points and will 
also help us determine if some non-M4/M5 cases express this and whether this might affect 
rapamycin response.    
Documentation of mTOR inhibition
Assays will be performed to determine the feasibility of measuring whether the biologic endpoint 
of mTOR inhibition has been obtained in those receiving rapmycin and whether eIF4E has been 
inhibited in those receiving ribavirin.
To assess eIF4E, p70S6 kinase, and 4E-BP1 phosphorylation, leukemia blasts will be isolated via 
Ficoll-Hypaque density gradient centrifugation, lysed with buffer containing 50 nM Tris, pH 8.0, 
120 mM Na CL, 0.5% Nonidet P-40, and protease inhibitor cocktail (Roche).  The protein 
concentration of the lysate will be determined by using the Bradford method (Bio-rad, Hercules, 
CA).  Equal amounts of protein will be separated on a 4%-20% Tris-Glycine gel (Invitrogen) and 
transferred to a BioTrace PVDF membrane.  Blots will be probed with primary antibody to 
p70S6 kinase and to 4E-BP1 (Cell Signaling, Inc).  After washing and incubation with secondary 
antibody, immunoreactive proteins will be visualized by using the ECL Plus detection system 
(Amersham Biosciences).  Blasts will be sampled pre-study and after day 10-11 of the first cycle 
and at days 22-26  of the first and 3rd cycle.  It is anticipated that the number of blasts may be 
diminished by the latter two samplings to the point where cell numbers may become limiting in 
the assay, but we will attempt to determine that this endpoint has been met in the whole light 
density marrow population.  In those cases where aspirate is a dry tap, Western analysis will be 
performed on peripheral blood.    Antibodies for these assays will be purchased from Cell 
Signaling. 
If cell numbers and amounts of protein lysate allow, to assess AKT phosphorylation, leukemic 
blasts isolated and lysed as described above will be blotted and probed with primary antibody to 
Akt or phospho-AKT (Cell Signaling).  After washing and incubating with secondary antibody, 
immunoreactive proteins were visualized by using the ECL Plus detection system (Amersham 
Biosciences).  If cell numbers are limiting, Akt and Phospho-Akt as well as p70S6K can be 
detected with a flow cytometric assay. 23, 34
Other Correlative Studies to Assess apoptosis, cell cycle, and Leukemia Stem Cell 
Phenotype
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At days 0, 11, and 22-26 of the first cycle, at day 22-26 of the 3rd cycle, and at end of study, light 
density cells will be analyzed for cell cycle status, apoptosis, and expression of an AML 
progenitor/blast phenotype (CD34+, CD38-, CD123+) by FACS analysis. CFU-L assays will 
also be plated.  Cells will also be injected into NSG mice to determine presence of an engraftable 
leukemia stem cell.  In brief, approximately 10(6) light density marrow cells will be injected in 
sublethally irradiated NSG mice via tail vein in a final volume of 0.2mL of PBS with 0.5% FBS.  
After 6 to 8 weeks, animals will be sacrificed  and bone marrow will be analyzed for the 
presence of human cells by evaluation of human CD45 and human CD33 by flow cytometry 35, 
36.   Any remaining cells will be frozen for future molecular analysis of response and resistance 
markers.  
Timing of Correlative Studies
Pre-study marrow
a.
Cells for in vitro testing (MTT or Alamar Blue assays, apoptosis, cell cycle, viability, and 
snap and viable freeze for future molecular analysis.)
b. Western blots for p70S6K, 4EBP-1, Akt, and eIF4E expression (107 cells) and eIF4E 
localization by confocal microscopy (both arms); Gli-1 expression by Western or PCR to 
determine if this might predict for resistance to ribavirin (Arm B only). 
c.
CFU-L assay—10(6) cells
d. NSG reconstituting assay –10(7) cells
Day 11 aspirate (cycle 1)
a.
Light density cells for apoptosis, cell cycle, and viability
b. Western blots for p70S6K, 4EBP-1, Akt, and eIF4E and expression of downstream 
mediators; eIF4E localization by confocal microscopy 
c.
CFU-L assay
d. NSG reconstituting assay 
Day 28 cycle 1 (same studies)
End of cycle 3 (same studies)
End of cycle 6 (same studies)
End of study marrow (recommended but optional) (same studies)
9.0 REGULATORY AND REPORTING REQUIREMENTS
Each patient will be monitored for side effects associated with treatment. The NCI Common 
Toxicity Criteria will be used to assess toxicity 
(http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf ). 
All supportive measures consistent with optimal patient care will be given.
9.1 Adverse Event Definitions
.  
An adverse event is any untoward medical occurrence in a patient or clinical investigation 
subject administered an investigational product regardless of causality assessment. An adverse 
event can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of an investigational product, 
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whether or not related to the investigational product. An adverse event is unexpected when the 
specificity or severity is not consistent with the current Package Insert for commercial drug. 
A serious adverse event (experience) or reaction is any untoward medical occurrence that at any 
dose: results in death, is a life-threatening adverse event, requires inpatient hospitalization or 
prolongation of existing hospitalization, results in persistent or significant disability/ incapacity, 
or a congenital abnormality. The definition of serious adverse event (experience) also includes 
important medical event. Medical and scientific judgment will be exercised in deciding whether 
expedited reporting is appropriate in other situations, such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may jeopardize the 
patient or may require intervention to prevent one of the other outcomes listed in the definition 
above. These will also usually be considered serious. Examples of such events are intensive 
treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or 
convulsions that do not result in hospitalization; or development of drug dependency or drug 
abuse
9.2 Adverse Event Reporting
All adverse events occurring after the patient is assigned to a treatment group are to be recorded 
in the study records. Medical conditions/diseases present before starting study drug are only 
considered adverse events if they worsen after treatment assignment.  
9.3 Serious Adverse Event Recording
Fatal or life –threatening adverse events will be phoned to the Principal Investigator, the Cancer 
Center Data Safety Monitoring Committee Chairperson within 24 hours of notification. 
 Follow-up information may include hospital admission records, discharge summaries and 
autopsy reports, where applicable.  
The Principal Investigator (PI) shall also make an accurate and adequate report to the reviewing 
Institutional Review Board (IRB) on any serious and unexpected AE. 
9.4  Definition of Dose Limiting Toxicity and Determination of MTD
In arm B of the study, a dose limiting toxicity will be a grade 3 or 4 non-hematologic 
toxicity which is deemed probably or definitely due to study drug (ribavirin or combination of 
decitabine and ribavirin).  As noted above, in this population of  AML patients, Grade 3 
infections, fatigue, weight loss, and electrolyte imbalances will be appropriately treated but are 
not deemed study related toxicities and will not result in dose modifications.
9.5 Data and Safety Monitoring
Study Investigators will conduct continuous review of data and patient safety.  The 
Investigator will submit quarterly progress reports of these data to the Clinical Trials Monitoring 
Committee for review.  The review will include for each treatment arm/dose level:  the number 
of patients enrolled, withdrawals, significant toxicities as described in the protocol, serious 
adverse events both expected and unexpected, dose adjustments, and responses observed.  The PI 
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maintains a database of all adverse events with toxicity grade and information regarding 
treatment required complications, or sequelae.  The Investigator will submit a copy of the AE 
spreadsheet along with the Progress Report to the Clinical Trials Monitoring Committee for 
review. 

Any serious adverse event that is serious, related AND unexpected must be reported 
within 10 calendar days to both the DSMC and the RSRB (see RSRB guidelines).  

Serious adverse events that are related AND expected or unrelated AND unexpected will 
be reported to the Committee for review at the quarterly meeting.  SAE reports are 
expected to include sufficient detail so that the DSMC can determine the severity, 
toxicity grade, expectedness, treatment required, and a follow up report documenting 
resolution or if there are sequelae.  Unless otherwise specified in the protocol, serious 
adverse events that require detailed reports (but not necessarily expedited) are expected, 
related, non-hematologic toxicities of grades 3, 4 or 5.
The Data Safety Monitoring Committee provides oversight of study progress and safety by review of 
accrual and events at regularly scheduled meetings.  The frequency of review is determined by the 
size, risk and complexity of the trial, and is assigned by the Protocol Review Committee at the time of 
their initial review and approval. The Data and Safety Monitoring Committee will monitor all adverse 
event rates utilizing a cumulative spreadsheet listing of all events submitted along with progress 
reports by the PI. All serious adverse events that have occurred in the prior 3 months will be reviewed 
at the regular quarterly meeting of the DSMC in order to confirm toxicity grade, expectedness, 
relatedness, sequelae, follow up required, and risk to current or future subjects. 
Events that are serious, unexpected and related will require expedited review within 10 calendar days 
to the Safety Coordinator.  The DSMC Chair will determine whether further action is required, and 
when patient safety is of concern, an interim meeting may be called.
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11.0 STATISTICAL CONSIDERATIONS
Based on the data of Cashen15, where response rate to single agent decitabine was about 25 %, 
our null hypothesis would be that the true response rate 𝑟 to the combination therapy is less than 
25% (i.e. 𝐻0:𝑟≤0.25).  We will use Simon’s two-stage design to test this null hypothesis 
against its one-sided alternative (𝐻1:𝑟> 0.25). Assume that the true response rate in fact exceeds 
50%. A maximum of 24 evaluable patients would give 80% power to reject the null hypothesis at 
a significance level of .05.  In the first stage of the phase II study, 9 patients will be initially 
enrolled to assess the response rate to the combination therapy.  If there are 2 or fewer of the 9 
patients have responded, the phase II study is stopped for accrual and the combination therapy is 
determined not active. The probability of this early termination is 60%. If at least 3 out of the 
first 9 evaluable patients respond in the first stage, 15 additional evaluable patients will be 
accrued for a total of 24 evaluable patients. The null hypothesis is rejected if 10 or more 
responses are observed in 24 patients.  
The ribavirin dose escalation arm of this study will be a phase I dose escalation plan, so only 
tabular descriptions of toxicity and outcomes will be generated. The design of the phase I portion 
of the study is a standard 3+3 up and down design (See Section 7 for details).  A minimum of 3 
and a maximum of 6 patients will be entered at each dose level. The starting dose level as well as 
each subsequent dose increment (decrement) will be pre-specified. The first 3 patients will be 
treated at the starting dose level. If none of the 3 patients experiences dose-limiting toxicity, the 
dose will be escalated to the next higher level, and another 3 patients will be treated at the 
escalated level. However, if 1 of the first 3 patients experiences a dose-limiting toxicity, three 
more patients will be treated at the same dose level. The dose escalation continues until at least 
two patients among 3 or 6 patients experience toxicities, or until the highest prespecified dose 
level is reached. The MTD is defined as the highest dose level for which at least 5 of 6 subjects 
did not experience a DLT.  Once the MTD has been established, the study will subsequently 
expand to a phase II study at the MTD level to obtain further safety and efficacy data.  The Data 
Safety and Monitoring Board of the JP Wilmot Cancer Center will be utilized to review the data 
between cohorts and prior to escalating from phase I to a phase II portion of the study.
As noted in section 8, the correlative studies will be primarily exploratory.  We will utilize a Chi 
square method to determine a correlation between clinical response and mTOR mediator 
inhibition as assessed by p70S6 kinase expression or 4EBP1 expression.  Both response (yes/no) 
or decreased expression (yes/no) will be treated as binary variables, and decreased expression 
will be defined as at least a 25% decrease by densitometry or flow cytometric measurement.  We 
will also determine the mean decrease in expression in the responding and non-responding 
groups for further descriptive correlations.  In the treatment arm with ribavirin, similar analysis 
will be performed for eIF4E expression.
12.0 RETENTION OF RECORDS
12.1 A Case Report Form will be provided by the Clinical Trials Office and submitted once 
completed. Periodic monitoring of this CRF will be done to ascertain compliance with source 
documentation requirements. 
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U.S. FDA regulations (21 CFR 312.62]) require that records and documents pertaining to the 
conduct of this study including CRFs, consent forms, laboratory test results, and medication 
inventory records, must be retained by the Principal Investigator as required by the University of 
Rochester.
13.0 PATIENT CONSENT AND PEER JUDGEMENT
All institutional, NCI, FDA, State, and Federal regulations concerning informed 
consent and peer judgment will be fulfilled.
14.0 CHANGES IN PROTOCOL
Any change or addition to this protocol requires a written protocol amendment that must be 
approved by the investigator before implementation. Amendments significantly affecting the 
safety of subjects, the scope of the investigation or the scientific quality of the study, require 
additional approval by the RSRB of the University of Rochester. 
Amendments affecting only administrative aspects of the study do not require formal protocol 
amendments or IRB approval but the IRB of each center must be kept informed of such 
administrative changes
15.0 REASONS FOR WITHDRAWAL
A patient may withdraw from the study at any time for any reason, and patients are under no 
obligation to explain reason for withdrawal although this will be queried. Any patient may be 
discontinued from study in the event of progressive disease, unacceptable drug toxicity, patient 
refusal to continue on study, or if in the physician’s judgment discontinuation is in the best 
interest of the patient.
16.0 REFERENCES
1. National Cancer Institute. Acute myeloid leukemia. http://www.seer.cancer.gov/stat facts
2. Estey E, Dohner H. Acute myeloid leukemia. Lancet 2006; 368: 1894-907.
3. Estey E. Acute Myeloid Leukemia and Myelodysplastic syndromes in older patients. J Clin 
Oncol 2007;25:1908-15. 
4. Preisler HD, Li B, Chen H, et al. P15INK4B gene methyation and expression in normal, 
myelodysplastic, and acute myelogenous leukemia cells and in the marrow cells of cured 
lymphoma patients. Leukemia. 2001;15:1589-1595. 
5. Christiansen DH, Andersen MK, Pedersen-Bjergaard J. Methylation of p15INK4B is 
common, is associated with deletion of genes on chromosome arm 7q and predicts a poor 
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prognosis in therapy-related myelodysplastic and acute myeloid leukemia. Leukemia. 
2003;17:1813-1819.
6. Kim WY, Sharpless NE. The Regulation of INK4/ARF in Cancer and Aging. Cell. 
2006;127:265-275.
7. Chen H, Wu S. Hypermethylation of the p15(INK4B) gene in acute leukemia and 
myelodysplastic syndromes. Chin Med J. 2002;115:987-990.
8. Teofili L, Martini M, Luongo M et al. Hypermethylation of GpG islands in the promoter 
region of p15 (INK4b) in acute promyelocytic leukemia represses p15 (INK4b) expression 
and correlates with poor prognosis. Leukemia. 2003;17:919-924.
9. Daskalakis M, Nguyen TT, Nguyen C, et al. Demethylation of a hypermethylated 
P15/INK4B gene in patients with myelodysplastic syndrome by 5-Aza-2'-deoxycytidine 
(decitabine) treatment. Blood 2002;100:2957-2964.
10.  Kico JM, Spencer DH, Lamprecht Tl, et al. Genomic impact of transient low-dose decitabine 
treatment on primary AML cells. Blood 2013 121:1633-43. 
11. Kantarjian H, Issa JP, Rosenfeld CB et al. Decitabine improves patient outcomes in 
myelodysplastic syndromes: results of a phase III randomized study. Cancer 2006; 108:1794-
80.
12. Kantarjian H, Oki Y, Garcia-Manero G, Huang X, O’Brien S, Cortes J, Faderl S, Busso-
Ramos C, Ravandl F, Estrov Z, Ferrajoli A, Wierda,W, Shan J, Davis J, Giles F, Saba HI, 
Issa J-P. Results of randomized study of 3 schedules of low-dose decitabine in higher-risk 
myelodysplastic syndrome and chronic myelomonocytic leukemia. Blood 2007; 109:53-57.
13. Lubbert M, Ruter B, Claus R, et al. Continued low-dose decitabine (DAC) is an active first-
line treatment in all cytogenetic subgroups of older AML patients: results of the FR00331 
multicenter phase II study. Blood 2007; 110: 95a (abstract).
14. Blum W, Klisovic RB, Hackanson B, Liu Z, et al. Phase I study of decitabine alone or in 
combination with valproic acid in acute myeloid leukemia. J Clin Oncol 25:3884-91, 2007.
15. Cashen AF, Schiller GJ, O’Donnell MR, DiPersio JF. Multicenter, phase II study of 
decitabine for the first-line treatment of older patients with acute myeloid leukemia. J Clin 
Oncol 2010 28:556-61
16. Blum W, Garzon R, Kilsovic RB, Schwind S, Walker A, Geyuer S, Liu S, Havelange V, 
Becker H, Schaaf L, Mickle J, Deveine H, Kefauver C, Devine SM, Chan KK, Heerema NA, 
bloomfield CD, Grever MR byrd JC, Villalona-Calero M, Croce cM, and Marcucci G. 
Clinical response and miR-29b predictive significance in older AML patients treated with a 
10-day schedule of decitabine. PNAS 2010 107:7473-7478. 
17. Vignot S, Faivre S, Aguirre D et al. MTOR-targeted therapy of cancer with rapamycin 
derivatives. 2005; 16: 525-537.
18. Panwalker A, Verstovsek S, Giles F. Mammalian target of rapamycin inhibition as therapy 
for hematologic malignancies. Cancer 2004; 100: 657-666.
19. Martelli AM, Tazzari PL, Evangelisti C et al. Targeting the phosphatidylinositol 3-
kinase/AKT/Mammalian target of rapamycin module for acute myelogenous leukemia 
therapy: From bench to bedside. Current Medicinal Chemistry 2007; 14: 2009-2023.
20. 20Yilmaz OH, Valdez R, Theisen BK, Guo W, Ferguson DO, Wu H, Morrison SJ. Pten 
dependence distinguishes haematopoeitic stem cells from leukaemia-initiating cells. Nature 
2006;44:475-482.
21. 21Hidalgo M, Rowinsky E. The rapamycin-sensitive signal transduction pathway as a target 
for cancer therapy. Oncogene 2000; 19: 6680-6686.
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Version date: 09Aug2017
22. 22Recher C, Beyne-Rauzy O, Demur C. Antileukemic activity of rapamycin in acute 
myeloid leukemia. Blood 2005; 205: 2527-2534
23. Perl AE, Kasner MT, Tsai DE, Vogl DT. Loren LW, Schuster SJ, Porter DL, Stadtmaurer 
EA, Goldstein SC, Frey NV, Nasta SD, Hexner EO, Dierov JK, Swider CR, Bagg A, Gewirtz 
AM, Carroll M, and Luger SM. A phase I study of the mammalian target of rapamycin 
inhibitor sirolimus and MEC chemotherapy in relapsed and refractory acute myelogenous 
leukemia. Clin Can Res 2009; 15:6732-9.
24.  Assouline S, Culjkovic B Cocalakis e, et al. Molecular targeting of the oncogene eIF4E in 
acute myeloid leukemia (AML): a proof-of-principle clinical trial with ribavirin Blood 2009 
114:257-60. 
25. de Lima M, Ravandi F, Anderson B, et al. Long-term follow up of a phase I study of high-
dose decitabine, busulfan, and cyclophosphamide plus allogeneic transplantation for the 
treatment of patients with leukemias.  Cancer 2003: 94: 1242-7.
26. Liesveld JL, Rosell K, Lu C, Mulford D, Walker A. The mTOR inhibitor Rapamycin 
demonstrates activity against AML in combination with imatinib mesylate and with 5-
azacytidine. Blood 110:147B (abstract).
27. Liesveld JL, O’Dwyer K, Becker MW, Mulford D, Walker A, Chen R, Bechelli J, Rosell K, 
Jordan CT, Minhajuddin M, and Phillips GLII. Phase I Study of Decitabine and Rapamycin 
in Relapsed/Refractory Acute Myelogenous Leukemia   Blood 2012 120 Abstract 2549
28. Bennett JM, Catovsky D, Daniel MT et al. Proposed revised criteria for the classification of 
acute myeloid leukemia. A report of  the French-American-British Cooperative Group. Ann 
Intern Med 1985 103:620-5. 
29. Vesley J, Piskala A. Effects of the a-D-anomer of 5-aza-2’Deoxycytidine on L1210 mouse 
leukemic cells in vitro and in vivo. Cancer Res. 1984; 44:5165-5168.
30. Link T, Momparler RL, Rivard GE. High-performance liquid chromatographic analysis of 
chemical stability of 5-aza-2’deoxyxytidine. J Pharm Sci. 1981; 70: 1228-1232.
31. Tomankova H, Zyka J. A study of the dependence of the stability of 5-aza-2’deoxycytidine in 
alkaline media independence on time. MicroChem J. 1980; 25:281-288.
32. Liu Z, Marcucci G, et al. Characterization of decomposition products and preclinical and low 
dose clinical pharmacokinetics of decitabine (5-aza-2’deoxycytidine) by a new liquid 
chromatography/tandem mass spectrometry quantification method.  Rapid Communications 
in Mass Spectrometry. 2006; 20:1117-1126.
33. MGI Internal report FD-PSP-001-0600, Dacogen (decitabine) for injection clinical package 
insert reconstitution and preparation stability 2006.
34. Chow S, Patel H, Hedley. Measurement of MAP kinase activation by flow cytometry using 
popspho-specific antibodies to MEK and ERK: potential for pharmacodynamic monitoring of 
signal transduction inhibitors. Cytometry 46:72-78, 2001.
35. Guzman ML, Rossi RM, Neelakantan S, Li X, Corbett CA, Hassane DC, Becker MW, 
Bennett JM, Sullivan E, Lachowicz JL, Vaughan A, Sweeney CJ, Matthew W, Carroll M, 
Liesveld JL, Crooks PA, and Jordan CT. An orally bioavailable parthenolide analog 
selectively eradicates acute myelogenous leukemia stem and progenitor cells. Blood 2007 
110; 4427-4435.
36. Liesveld JL, Rosell KE, Lu C, Bechelli J, Phillips G, Lancet JE, et al. Acute myelogenous 
leukemia—microenvironment interactions: role of endothelial cells and proteasome 
inhibition. Hematology 2005:10:483-94.
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APPENDIX 1
Performance Status Criteria
ECOG Performance Status Scale
Karnofsky Performance Scale
Grade
Descriptions
Percent
Description
100
Normal, no complaints, no evidence 
of disease.
0
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction.
90
Able to carry on normal activity; 
minor signs or symptoms of disease.
80
Normal activity with effort; some 
signs or symptoms of disease.
1
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work).
70
Cares for self, unable to carry on 
normal activity or to do active work.
60
Requires occasional assistance, but 
is able to care for most of his/her 
needs.
2
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours.
50
Requires considerable assistance and 
frequent medical care.
40
Disabled, requires special care and 
assistance.
3
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours.
30
Severely disabled, hospitalization 
indicated.  Death not imminent.
20
Very sick, hospitalization indicated. 
Death not imminent.
4
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair.
10
Moribund, fatal processes 
progressing rapidly.
5
Dead.
0
Dead.
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APPENDIX 2
 Cockcroft-Gault Equation: (140-age)*wt/(Cr*72)
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APPENDIX 3 
Common Terminology Criteria for Adverse Events (CTCAE), version 4.0
(http://ctep.cancer.gov)
Publish Date: June 14, 2010
Pdf: http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf
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APPENDIX 4
Declaration of Helsinki 
World Medical Association Declaration of Helsinki:
Ethical Principles for Medical Research Involving Human Subjects
Adopted by the 18th WMA General Assembly Helsinki, Finland, June 1964 and amended by the 
29th WMA General Assembly, Tokyo, Japan, October 1975 35th WMA General Assembly, 
Venice, Italy, October 1983 41st WMA General Assembly, Hong Kong, September 1989 48th 
WMA General Assembly, Somerset West, Republic of South Africa, October 1996 and the 52nd 
WMA General Assembly, Edinburgh, Scotland.
A. INTRODUCTION
1. The World Medical Association has developed the Declaration of Helsinki as a statement of 
ethical principles to provide guidance to physicians and other participants in medical research 
involving human subjects.  Medical research involving human subjects includes research on 
identifiable human material or identifiable data.
2. It is the duty of the physician to promote and safeguard the health of the people.  The 
physician's knowledge and conscience are dedicated to the fulfillment of this duty.
3. The Declaration of Geneva of the World Medical Association binds the physician with the 
words, "The health of my patient will be my first consideration," and the International Code 
of Medical Ethics declares that, "A physician shall act only in the patient's interest when 
providing medical care which might have the effect of weakening the physical and mental 
condition of the patient."
4. Medical progress is based on research which ultimately must rest in part on experimentation 
involving human subjects.
5. In medical research on human subjects, considerations related to the well-being of the human 
subject should take precedence over the interests of science and society.
6. The primary purpose of medical research involving human subjects is to improve 
prophylactic, diagnostic and therapeutic procedures and the understanding of the etiology and 
pathogenesis of disease.  Even the best proven prophylactic, diagnostic, and therapeutic 
methods must continuously be challenged through research for their effectiveness, efficiency, 
accessibility and quality.
7. In current medical practice and in medical research, most prophylactic, diagnostic and 
therapeutic procedures involve risks and burdens.
8. Medical research is subject to ethical standards that promote respect for all human beings and 
protect their health and rights.  Some research populations are vulnerable and need special 
protection.  The particular needs of the economically and medically disadvantaged must be 
recognized.  Special attention is also required for those who cannot give or refuse consent for 
themselves, for those who may be subject to giving consent under duress, for those who will 
not benefit personally from the research and for those for whom the research is combined 
with care.
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9. Research Investigators should be aware of the ethical, legal and regulatory requirements for 
research on human subjects in their own countries as well as applicable international 
requirements.  No national ethical, legal or regulatory requirement should be allowed to 
reduce or eliminate any of the protections for human subjects set forth in this Declaration.
B. BASIC PRINCIPLES FOR ALL MEDICAL RESEARCH
1. It is the duty of the physician in medical research to protect the life, health, privacy, and 
dignity of the human subject.
2. Medical research involving human subjects must conform to generally accepted scientific 
principles, be based on a thorough knowledge of the scientific literature, other relevant 
sources of information, and on adequate laboratory and, where appropriate, animal 
experimentation.
3. Appropriate caution must be exercised in the conduct of research which may affect the 
environment, and the welfare of animals used for research must be respected.
4. The design and performance of each experimental procedure involving human subjects 
should be clearly formulated in an experimental protocol.  This protocol should be submitted 
for consideration, comment, guidance, and where appropriate, approval to a specially 
appointed ethical review committee, which must be independent of the investigator, the 
sponsor or any other kind of undue influence.  This independent committee should be in 
conformity with the laws and regulations of the country in which the research experiment is 
performed.  The committee has the right to monitor ongoing trials.  The researcher has the 
obligation to provide monitoring information to the committee, especially any serious 
adverse events.  The researcher should also submit to the committee, for review, information 
regarding funding, sponsors, institutional affiliations, other potential conflicts of interest and 
incentives for subjects.
5. The research protocol should always contain a statement of the ethical considerations 
involved and should indicate that there is compliance with the principles enunciated in this 
Declaration.
6. Medical research involving human subjects should be conducted only by scientifically 
qualified persons and under the supervision of a clinically competent medical person.  The 
responsibility for the human subject must always rest with a medically qualified person and 
never rest on the subject of the research, even though the subject has given consent.
7. Every medical research project involving human subjects should be preceded by careful 
assessment of predictable risks and burdens in comparison with foreseeable benefits to the 
subject or to others.  This does not preclude the participation of healthy volunteers in medical 
research.  The design of all studies should be publicly available.
8. Physicians should abstain from engaging in research projects involving human subjects 
unless they are confident that the risks involved have been adequately assessed and can be 
satisfactorily managed.  Physicians should cease any investigation if the risks are found to 
outweigh the potential benefits or if there is conclusive proof of positive and beneficial 
results.
9. Medical research involving human subjects should only be conducted if the importance of 
the objective outweighs the inherent risks and burdens to the subject.  This is especially 
important when the human subjects are healthy volunteers.
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10. Medical research is only justified if there is a reasonable likelihood that the populations in 
which the research is carried out stand to benefit from the results of the research.
11. The subjects must be volunteers and informed participants in the research project.
12. The right of research subjects to safeguard their integrity must always be respected.  Every 
precaution should be taken to respect the privacy of the subject, the confidentiality of the 
patient's information and to minimize the impact of the study on the subject's physical and 
mental integrity and on the personality of the subject.
13. In any research on human beings, each potential subject must be adequately informed of the 
aims, methods, sources of funding, any possible conflicts of interest, institutional affiliations 
of the researcher, the anticipated benefits and potential risks of the study and the discomfort 
it may entail.  The subject should be informed of the right to abstain from participation in the 
study or to withdraw consent to participate at any time without reprisal.  After ensuring that 
the subject has understood the information, the physician should then obtain the subject's 
freely-given informed consent, preferably in writing.  If the consent cannot be obtained in 
writing, the non-written consent must be formally documented and witnessed.
14. When obtaining informed consent for the research project the physician should be 
particularly cautious if the subject is in a dependent relationship with the physician or may 
consent under duress.  In that case the informed consent should be obtained by a well-
informed physician who is not engaged in the investigation and who is completely 
independent of this relationship.
15. For a research subject who is legally incompetent, physically or mentally incapable of giving 
consent or is a legally incompetent minor, the investigator must obtain informed consent 
from the legally authorized representative in accordance with applicable law.  These groups 
should not be included in research unless the research is necessary to promote the health of 
the population represented and this research cannot instead be performed on legally 
competent persons.
16. When a subject deemed legally incompetent, such as a minor child, is able to give assent to 
decisions about participation in research, the investigator must obtain that assent in addition 
to the consent of the legally authorized representative.
17. Research on individuals from whom it is not possible to obtain consent, including proxy or 
advance consent, should be done only if the physical/mental condition that prevents 
obtaining informed consent is a necessary characteristic of the research population.  The 
specific reasons for involving research subjects with a condition that renders them unable to 
give informed consent should be stated in the experimental protocol for consideration and 
approval of the review committee.  The protocol should state that consent to remain in the 
research should be obtained as soon as possible from the individual or a legally authorized 
surrogate.
18. Both authors and publishers have ethical obligations.  In publication of the results of 
research, the investigators are obliged to preserve the accuracy of the results.  Negative as 
well as positive results should be published or otherwise publicly available.  Sources of 
funding, institutional affiliations and any possible conflicts of interest should be declared in 
the publication.  Reports of experimentation not in accordance with the principles laid down 
in this Declaration should not be accepted for publication.
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C. ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH 
MEDICAL CARE
1. The physician may combine medical research with medical care, only to the extent that the 
research is justified by its potential prophylactic, diagnostic or therapeutic value.  When 
medical research is combined with medical care, additional standards apply to protect the 
patients who are research subjects.
2. The benefits, risks, burdens and effectiveness of a new method should be tested against those 
of the best current prophylactic, diagnostic, and therapeutic methods.  This does not exclude 
the use of placebo, or no treatment, in studies where no proven prophylactic, diagnostic or 
therapeutic method exists.
3. At the conclusion of the study, every patient entered into the study should be assured of 
access to the best proven prophylactic, diagnostic and therapeutic methods identified by the 
study.
4. The physician should fully inform the patient which aspects of the care are related to the 
research.  The refusal of a patient to participate in a study must never interfere with the 
patient-physician relationship.
5. In the treatment of a patient, where proven prophylactic, diagnostic and therapeutic methods 
do not exist or have been ineffective, the physician, with informed consent from the patient, 
must be free to use unproven or new prophylactic, diagnostic and therapeutic measures, if in 
the physician's judgment it offers hope of saving life, re-establishing health or alleviating 
suffering.  Where possible, these measures should be made the object of research, designed 
to evaluate their safety and efficacy.  In all cases, new information should be recorded and, 
where appropriate, published.  The other relevant guidelines of this Declaration should be 
followed.
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APPENDIX 5 (ARM A) Decitabine and Rapamycin
Days
 
Tests
Pre
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20-
22
22-26
28
EOS
Decitabine
 
X
X
X
X
X
X10
X10
X10
X10
X10
 
 
 
 
 
 
 
 
 
 
 
 
 
Rapamycin
 
 
 
 
 
 
X11
X11
X11
X11
X11
X
X
X
X
X
X
X
X
X
X
 
 
 
History & Physical
X
x
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC w/diff & plts
X
X
 
X3
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chemistries
X
X8
 
X3
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
LDH
X
 
 
 
 
X
 
X3
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urate
x
x
 
 
 
 
 
X4
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bone marrow
X
 
 
 
 
 
 
 
 
 
X1
 
 
 
 
 
 
 
 
 
 
 
X1
X1
Flow Cytometry
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X
 
 
Cytogenetic Studies
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X
 
 
DIC Panel
x
Molecular Studies14
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bone marrow for Correlative 
Studies
X540cc
 
 
 
 
 
 
 
 
 
X540cc
 
 
 
 
 
 
 
 
 
 
X540cc
 
 
Blood for correlative studies
X710cc
 
 
 
 
 
 
 
 
 
X710cc
 
 
 
 
 
 
 
 
 
 
X7 
10cc
 
 
EKG/CXR
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U/A, PT, PTT, Pregnancy
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chimerism
X2
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X2
 
Rapamycin Levels
 
X12
 
 
 
 
 
 
 
 
 
 
 
 
X9
 
 
 
 
 
X9
 
 
 
Evaluation of Response
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X6
X6
Long Term Follow Up
X13
1.
Aspirate only in cycle 1on day 10-11 and biopsy and aspirate at days 22-26 of cycles 1 and 3 for disease 
assessment, and at end of study.  Marrows may also be performed when clinically indicated at other times  
for disease assessment. Substitute peripheral blood if aspirate/marrow cannot be obtained.
2.
In those patients who have had an allogeneic transplant by chromosome (sex mismatched transplants) or      
by PCR assay.  This can be done on either blood or marrow at physicians’ choice. 
3.
Twice per week or as clinically indicated
4.
As indicated clinically
5.
40 cc aspirate in green top (heparinized) tubes; if marrow is a dry tap, substitute 40 cc blood total
6.
Cycles 1 and 3 only and at end of study or study discontinuation.
7.
10cc in green top tube.
8.
Include cholesterol and triglycerides on day 1 of each cycle only.
9.
Rapamycin levels will be drawn (trough) on days 14 and 21.  Patients will be asked to hold the daily        
dose until the level is drawn. 
10.
Decitabine is given on days 1-10 during cycle 1.  In subsequent cycles, decitabine is given days 1-5.
11.
Rapamycin starts on Day 6 starting with Cycle 2
12.
Cycle 2 Day 1 only
13.
Every 6 months for up to 2 years after date of last treatment 
14.
Molecular studies completed previously are acceptable if results are in the medical record.
All time points refer to all cycles except where noted. The window for protocol visits and assessments is +/- 3 days. 
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Correlative studies are described in Section 8 above.  Blood and marrow for correlative studies will be sent to the BMT laboratory (275-3041).  The study coordinator will contact,Jane 
Liesveld or her laboratory technician for pick up.  All are available through the paging system (275-2222 or web paging).
APPENDIX 5 (ARM B) Decitabine and Ribavirin
Days
 
Tests
Pre
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20-
22
22-26
28
EOS
Decitabine
 
X
X
X
X
X

X9
X9
X9
X9
X9
 
 
 
 
 
 
 
 
 
 
 
 
 
Ribavirin8
 
X10
X
10
X10
X10
X10
X10
X10
X10
X10
X10
X
X
X
X
X
X
X
X
X
X
 
 
 
History & 
Physical
X
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC w/diff & plts
X
X
 
X3
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chemistries
X
X8
 
X3
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
LDH
X
 
 
 
 
X
 
X3
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urate
X
X
 
 
 
 
 
X4
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bone marrow
X
 
 
 
 
 
 
 
 
 
X1
 
 
 
 
 
 
 
 
 
 
 
X1
X1
Flow Cytometry
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X
 
 
Cytogenetic 
Studies
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X
 
 
DIC Panel
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Molecular 
Studies12
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bone marrow for 
Correlative 
Studies
X540cc
 
 
 
 
 
 
 
 
 
X540cc
 
 
 
 
 
 
 
 
 
 
X5 40cc
 
 
Blood for 
correlative studies
X710cc
 
 
 
 
 
 
 
 
 
X710cc
 
 
 
 
 
 
 
 
 
 
X7 10cc
 
 
EKG/CXR
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U/A, PT, PTT, 
Pregnancy
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chimerism
X2
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X2
 
Evaluation of 
Response
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X6
X6
Long Term 
Follow Up
X11
1.
Aspirate only in cycle 1on day 10-11and biopsy and aspirate at days 22-26 of cycles 1 and 3      
for disease assessment and at end of study.  Marrows may also be performed when clinically 
indicated at other times for disease assessment. Substitution of peripheral blood may be 
acceptable  if aspirate/marrow cannot be obtained. 
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2.
In those patients who have had an allogeneic transplant by chromosome (sex mismatched 
transplants) or by PCR assay.  This can be done on either blood or marrow at physicians’ choice. 
3.
Twice per week or as clinically indicated
4.
As indicated clinically
5.
40 cc aspirate in green top (heparinized) tubes; if marrow is a dry tap, substitute 40 cc blood total 
6.
Cycles 1 and 3 only and at end of study or study discontinuation.
7.
10cc in green top tube.
8.
After cycle 1, ribavirin will begin on day 1 and will be given continuously without interruption 
unless for toxicity. 
9.
Decitabine is given days 1-10 during cycle 1.  In subsequent cycles, decitabine is given days 1-5.
10. Ribavirin is given continuously starting on day 1 of Cycle 2.
11.
Every 6 months for up to 2 years after date of last treatment 
12.
Molecular studies completed previously are acceptable if results are in the medical record.
All time points refer to all cycles except where noted. The window for protocol visits and assessments is +/- 3 days.
Correlative studies are described in Section 8 above.  Blood and marrow for correlative studies will be sent to the BMT laboratory (275-3041).  The study coordinator will contact Jane 
Liesveld or her laboratory technician for pick up.  All are available through the paging system (275-2222 or web paging).
Complion Document ID: 1248945

ICF_001.pdf: 
ULEU-13049/RSRB48721
Page 1 of 14
        version date: 2/16/2015
Consent Form
Study Title: A Phase I/II Study of Decitabine in Combination with 
Sequential Rapamycin or Ribavirin in High Risk AML Patients
Clinical trials.gov # NCT02109744
Principal Investigator: Jane Liesveld, MD
This is a clinical research study. Clinical research studies include only those patients who choose to take 
part. Please ask the study doctor or the study staff to explain any words or information that you do not 
clearly understand. Please take your time to make your decision. Discuss it with your family and with people 
who are important to you.
What is the usual approach to my leukemia? 
Acute myelogenous leukemia in those above 65 years of age can be treated with chemotherapy or other agents 
called hypomethylating agents.  Some patients choose to have no therapy at all or transfusions and 
chemotherapy by mouth only.  In younger patients, when leukemia relapses or does not respond to treatment, it 
is often treated with different types of chemotherapy or in suitable patients with well matched donors, a stem 
cell transplantation. There is no one chemotherapy regimen which is considered standard or best in this setting. 
You are being asked to take part in this study because you are older than 65 years of age and have recently been 
diagnosed with acute myelogenous leukemia OR you have previously been treated for acute myelogenous 
leukemia, and you have not had a complete response to therapy or your disease responded and has now 
returned. People who are not in a study are usually treated with other combinations of chemotherapy drugs or 
with stem cell transplantation.  Your doctor can explain why these options may or may not be appropriate or 
available to you at the present time. Previous studies that have used decitabine by itself have shown response 
rates of 25 to 40% in newly diagnosed patients. 
What are my other choices if I do not take part in this study?
If you decide not to take part in this study, you have other choices. For example:

you may choose to have the usual approach described above

you may choose to take part in a different study, if one is available

or you may choose not to be treated for leukemia,  but you may want to receive transfusion support
or comfort care to relieve symptoms.
RSRB Approval Date: 8/1/2019
Expiration Date: 8/21/2019
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ULEU-13049/RSRB48721
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 Why is this study being done?
The purpose of this study is 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 are older than 65 when diagnosed.  The safety of this 
combination has been previously studied but it  is considered investigational for the treatment of refractory or 
relapsed leukemia.  The study will determine whether this combination is not only safe but has benefit in 
reducing the amount of leukemia present in these patients. There will be up to 24 patients taking part in this 
portion of the study.  Both decitabine and rapamycin have approval from the FDA but not when used in this 
combination for leukemia. 
Because some patients who have M4 and M5 leukemia (types that are determined by the pathology doctor who 
reviewed the blood and marrow at diagnosis) may have changes in their cells that would make it more difficult 
for rapamycin to inhibit their leukemia, in those cases, we will combine decitabine with ribavirin which has also 
been shown to have ability to inhibit leukemia  cells. The purpose of this portion of the study will be to 
determine the highest dose of ribavirin that can be given safely in combination with decitabine in M4and M5 
types of leukemia. Up to 18 patients with M4 and M5 leukemia will participate in this study.  Both decitabine 
and ribavirin have approval from the FDA but not when used in this combination for leukemia. 
The study will also look at the effects of the treatment on your leukemia and other cells in your blood and bone 
marrow.  These studies will be done by researchers at the University of Rochester. As part of this study, blood 
and bone marrow samples may be frozen for experiments that cannot be done immediately but will only be used 
for studies that are related to this research study or to leukemia and other types of cancer. 
What are the study groups?
All study participants will get the same study drug, decitabine, given intravenously daily over 60 minutes for 10 
days in the first cycle and for 5 days in subsequent cycles.  The dose given will depend on your height and body 
weight.  Cycles will be repeated very 28 days. 
If your leukemia is of a subtype called M4 or M5 which will be determined by your pathology report (study 
group Arm B), after you finish decitabine, you will receive a drug called ribavirin, orally twice per day, from 
day 11 on through the duration of the study.  Different doses of the study drug will be given to several study 
participants.  The first several will receive the lowest dose, and if ribavirin does not cause serious side effects 
when given after decitabine, it will be given to other participants at a higher dose.  Three doses are planned, but 
if side effects occur, the dose will be lowered, and this part of the study will be stopped.  You will be informed 
which dose you will be receiving. M4 and M5 leukemias express a protein that may make those types more 
susceptible to ribavirin than rapamycin which other study subjects will be receiving. 
If your leukemia is not the M4 or M5 subtype as determined by your pathology report (study group Arm A), 
after you finish decitabine, you will receive a drug called rapamycin, orally, at a fixed dose of 2 mg per day 
after a dose of 6 mg on day 11.  You will take this from days 11 through 22 in the first cycle and 6 through 22 in 
subsequent cycles.  
RSRB Approval Date: 8/1/2019
Expiration Date: 8/21/2019
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ULEU-13049/RSRB48721
Page 3 of 14
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Irrespective of which arm of the study you are on, you will be asked to write down in a small note pad the 
number of pills you take each day and when, and your doctor will order the pills for you during your clinic 
visits. 
Another way to find out what will happen to you during this study is to read the chart below. Start reading at the 
left side and read across to the right, following the lines and arrows.
STUDY SCHEMA
How long will I be in this study?
You may receive decitabine followed by rapamcycin or ribavirin for up to 6 cycles of 28 days (about 6 months). 
After you finish these cycles,  your doctor will continue to watch you for side effects and follow your condition 
for up to 2 years. Your doctor may or may not continue other treatments when the 6 cycles are concluded.
What extra tests and procedures will I have if I take part in this study?
Most of the exams, tests, and procedures you will have are part of the usual approach for your leukemia. 
However, there are some extra tests or procedures that you will need to have if you take part in this study.
Before you begin the study:
You will need to have the following extra tests and procedures to find out if you can be in the study beyond 
what might be performed if you chose alternate treatments:

Blood sample (approximately 2 tablespoons) for future research purposes only
Decitabine 20 mg/m2/day for 10 
days
               (Both Arms)
Rapamycin 2 mg/day on days 
11-22 after a 6 mg loading dose
Arm A (non-M4/M5 
AML patients)
Arm B (increased 
eIF4E—M4/M5)
Ribavirin days 11-28 
Dose Levels:

Level -2: 600mg twice daily

Level -1: 800mg twice daily

Level 1: 1000mg twice daily

Level 2: 1200mg twice daily

Level 3: 1400mg twice daily
Cycles 2-6
Cycle 1
Decitabine 20 mg/m2 for 5 days 
(Both Arms)
Arm A (non-M4/M5 
AML patients)
Arm B (increased 
eIF4E—M4/M5)
Rapamycin 2 mg/day for days 
6-22 after a 6 mg loading dose
Ribavirin Days 1-28 at 
originally assigned dose cohort. 
RSRB Approval Date: 8/1/2019
Expiration Date: 8/21/2019
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
A bone marrow aspirate and biopsy (within 2 weeks prior to treatment). If you had a biopsy within 2 
weeks, only an aspirate will need to be repeated to determine baseline blasts and to obtain a sample 
for future research purposes
Blood and bone marrow collection for the study 
Blood and marrow research specimens are required for you to take part in this study because the research on the 
sample is an important part of the study.  The blood and marrow draws will be done just as they would for 
diagnosis and followup, and most would need to be done in any case to monitor the status of your leukemia.  
The extra amounts taken for research will help to understand if the decitabine and rapamycin or ribavirin are 
working on blood and marrow cells as expected but will not determine your treatment course on this study. 
Risks and side effects of blood sample collection 
Obtaining blood samples may cause pain and bruising. Fainting, and in rare cases infection, may also occur. If 
you have an indwelling central line or port, every effort will be made to use that for blood testing during the 
study. 
Risks and side effects of bone marrow aspirate and biopsy
Possible side effects of bone marrow aspirate and biopsy include bleeding, infection, bruising, discomfort at the 
biopsy site and possible side effects from the local anesthetic (pain or bruising at the site where the aspirate or 
biopsy occurs). During the bone marrow biopsy and aspiration, you may have a reaction to the local anesthetic.
Left over specimens
If there is specimen left over after the needed tests are completed, the specimen can be stored for future 
research. This is optional, and will be discussed in the section on optional studies.  Your privacy is very 
important  and the researchers will make every effort to protect it.  Your test results will be identified by a 
unique code and the list that links the code to your name will be kept separate from your sample and from your 
health care information.  The research results of individual participants will not be available to study subjects 
but will be available to study doctors, although this will not influence planned treatment on the study. 
Neither you nor your health care plan/insurance carrier will be billed for the collection of the blood and marrow 
used for this study that are not part of standard of care. 
During the study:
If the exams, tests, and procedures show that you can take part in the study, and you choose to take part, then 
you will need the following extra tests and procedures which are not part of the usual approach to your type of 
cancer. 

All study subjects will have a marrow aspirate (not biopsy) on day 10 or 11. 

For those receiving rapamyin, blood tests for rapamycin levels on days 14 and 21 and a triglyceride 
level at the start of cycles 2 through 6.

Bone marrow aspirate and biopsy when you end the study. This might be done even if you were not 
on the study but not in all cases. 
What possible risks can I expect from taking part in this study?
If you choose to take part in this study, there is a risk that:

You may lose time at work or home and spend more time in the hospital or doctor’s office than usual

 The combination of decitabine with ribavirin or rapamycin may not be better, and could possibly be 
worse, than the usual approach for your cancer.
RSRB Approval Date: 8/1/2019
Expiration Date: 8/21/2019
Complion Document ID: 1249021


ULEU-13049/RSRB48721
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The drugs used in this study may affect how different parts of your body work such as your liver, kidneys, 
heart, and blood. The study doctor will be testing your blood and will let you know if changes occur that may 
affect your health.
There is also a risk that you could have side effects from the study drug(s)/study approach.
Here are important points about side effects:

Some side effects may go away soon, some may last a long time, or some may never go away.

Some side effects may interfere with your ability to have children.

Some side effects may be serious and may even result in death.
Here are important points about how you and the study doctor can make side effects less of a problem:

Tell the study doctor if you notice or feel anything different so they can see if you are having a side 
effect.

The study doctor may be able to treat some side effects.

The study doctor may adjust the study drugs to try to reduce side effects.
The tables below show the most common and the most serious side effects that researchers know about. There 
might be other side effects that researchers do not yet know about. If important new side effects are found, the 
study doctor will discuss these with you.
Arms A and B- Possible side effects of DECITABINE, which is a usual approach for this type of cancer:
Possible Side Effects of DECITABINE
COMMON, SOME MAY BE SERIOUS
In 100 people receiving DECITABINE, more than 20 and up to 100 may have:
Changes to blood composition (including one to three of the following)

Low number of white cells: may increase the chance of infections, including pneumonia, fever of    
unknown origin, urinary tract infection, infection or irritation of the mouth, sinusitis and sepsis, a 
blood-stream infection caused by the presence of bacteria or other infectious organisms or their 
toxins in the blood.

Low number of platelets: increases the chance of bleeding; this may show up as small bleeding spots 
in the skin, bleeding from the nose or gums and, rarely, bleeding in the stomach or brain.

Low number of red cells (anemia): this may lead to pallor, fatigue, shortness of breath, dizziness or 
worsening of the function of the heart. 
Headache
Nausea 
Vomiting 
Diarrhea  
Constipation
Fever
Hyperglycemia (elevated blood sugars)
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OCCASIONAL, SOME MAY BE SERIOUS
In 100 people receiving DECITABINE, from 4 to 20 may have:

Ulceration of the tongue or lip 

Loss of appetite 

Sleeplessness

Cough

Hair loss 

Redness of skin 

Changes in liver or kidney function 

Back pain, joint pain or muscle pain
RARE, AND SERIOUS
In 100 people receiving DECITABINE, 3 or fewer may have:
Seizures 
Septic shock
Death may occur due to infection or bleeding.
ARM A: Possible side effects of rapamycin which those on this arm could expect in addition:
    Possible Side Effects of RAPAMYCIN
COMMON, SOME MAY BE SERIOUS
In 100 people receiving RAPAMYCIN, more than 20 and up to 100 may have:
Trouble sleeping 
Nervousness
Increased appetite
Indigestion
Inflammation of espophagus (food pipe)
Excess hair growth
Diabetes (blood sugar elevations)
Joint pain
Cataracts
Too much fat or cholesterol in the blood
Suppression of immune system
OCCASIONAL, SOME MAY BE SERIOUS
In 100 people receiving RAPAMYCIN, from 4 to 20 may have:
Joint pain
Cataracts
Nosebleeds
Headache
Fluid and water retention
Increased glucose levels in blood
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RARE, AND SERIOUS
In 100 people receiving RAPAMYCIN, 3 or fewer may have:
Seizures
Mood swings
Delirium or hallucinations
Thinning of skin
Bruising
Darkening of skin
Acne
Loss of menstrual periods in females
Suppression of bone growth
Swelling of the abdomen
Ulcers in the esophagus
Inflammation of the pancreas
Scarring in the lungs
Arm B- In addition to side effects outlined above, people who are in Arm B may also experience    the 
possible side effects of ribavirin listed below.
    Possible Side Effects of Ribavirin
COMMON, SOME MAY BE SERIOUS
In 100 people receiving ribavirin, more than 20 and up to 100 may have:
Anemia due to breakdown of red blood cells (seen mostly in patients with hepatitis)
OCCASIONAL, SOME MAY BE SERIOUS
In 100 people receiving ribavirin, from 4 to 20 may have:
Anemia  of other types which may require blood transfusion
Low white cell count
Low platelet count
Itching of skin
Low calcium
Low magnesium
Shortness of breath
Pneumonia
RARE, AND SERIOUS
In 100 people receiving ribavirin, 3 or fewer may have:
Liver failure (only seen in patients with hepatitis C)
Serious skin reactions
Acute allergic reaction
Increased pressure in the lungs
Inflammation of the pancreas
Let your study doctor know of any questions you have about possible side effects. You can ask the study doctor 
questions about side effects at any time.
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Expiration Date: 8/21/2019
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Reproductive risks: You should not get pregnant, breastfeed, or father a baby while in this study. Decitabine, 
rapamycin, or ribavirin  used in this study could be very damaging to an unborn baby. Check with the study 
doctor about what types of birth control, or pregnancy prevention, to use while in this study.
What possible benefits can I expect from taking part in this study?
You might not benefit from participation in this study.  The potential benefit to you from being in this study 
might be that your cancer would be controlled longer.
Can I stop taking part in this study?
Yes. You can decide to stop at any time. If you decide to stop for any reason, it is important to let the study 
doctor know as soon as possible so you can stop safely. If you stop, you can decide whether or not to let the 
study doctor continue to provide your medical information to the organization running the study.
The study doctor will tell you about new information or changes in the study that may affect your health or your 
willingness to continue in the study.
The study doctor may take you out of the study:

If your health changes and the study is no longer in your best interest

If new information becomes available

If you do not follow the study rules

If the study is stopped by the sponsor, IRB or FDA.
What are my rights in this study?
Taking part in this study is voluntary.  You are free not to take part or to withdraw at any time, for whatever 
reason.  No matter what decision you make, there will be no penalty or loss of benefit to which you are entitled.  
In the event that you do withdraw from this study, the information you have already provided will be kept in a 
confidential manner.
If we discover anything that might make you change your mind about continuing in the study, we will let you 
know.
For questions about your rights while in this study, call the University of Rochester Institutional Review Board 
at (585) 276-0005. For long-distance you may call toll-free: (877) 449-4441. 
What are the costs of taking part in this study?
The decitabine and its preparation and administration will be charged to you and/or your insurance company.  
You and/or your insurance company will be charged for rapamycin or ribavirin, both commercially available 
drugs.  
You and/or your health plan/insurance company will need to pay for all of the other costs of  caring for your 
leukemia while in this study, including the cost of tests, procedures, or medicines to manage any side effects, 
unless you are told that certain tests are supplied at no charge. Before you decide to be in the study, you should 
check with your health plan or insurance company to find out exactly what they will pay for.
You will not be paid for taking part in this study.
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What happens if I am injured or hurt because I took part in this study?
If you are directly injured by the drugs that are being studied, or by clinical procedures solely required to 
participate in the study, you may need to pay for treatment of your injuries, but you will not be required to pay 
for emergency medical treatment provided at Strong Memorial Hospital or Highland Hospital. The University 
may seek payment for this care from your health insurer or third parties. Decisions regarding care and 
compensation for any other research related injury will be made on a case-by-case basis.
Who will see my medical information?
 Confidentiality of Records and Authorization to Use and Disclose Information for Research Purposes 
The University of Rochester makes every effort to keep the information collected from you private. In order to 
do so, we will restrict access of study materials only to those personnel directly involved in the research, ensure 
all staff involved has been properly trained, and keep matierials in proper storage. Sometimes, however, 
researchers need to share information that may identify you with people that work for the University, regulators 
or the study sponsor. 
If you have never received a copy of the University of Rochester Medical Center (URMC) and Affiliates Notice 
of Privacy Practices, please ask the investigator for one.
What information may be used and given to others? 
The study doctor will get your personal and medical information. For example: 

Research records 

Records about phone calls made as part of this research 

Records about your study visits 

Past and present medical records related to the study (only if you will be collecting information from the 
medical record) 

Results of medical tests (only if you will be conducting medical testing, labs, imaging, etc.) 
Who may use and give out information about you? 

The study doctor and the study staff 

URMC and Affiliates 
Your information may be given to: 

The Department of Health and Human Services; 

The University of Rochester 

The U.S. Food and Drug Administration (FDA) may also need to inspect study records at some point 
during the study or even after it has been completed. In the event that this should occur, every effort will 
be made to keep identifying information about you private. 
Why will this information be used and/or given to others? 

to do the research, 

to study the results, and 

to see if the research was done right
If the results of this study are made public, information that identifies you will not be used. 
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What if I decide not to give permission to use and give out my health information? 
Then you will not be able to be in this research study. 
May I review or copy my information? 
Yes, but only after the research is over. 
How long will this be permission be valid? 
This permission will last indefinitely. [If you will destroy the records at a definite point that should be stated 
instead and should be consistent with what is listed in both your protocol and application.] 
May I cancel my permission to use and disclose information? 
You may cancel your permission to use and disclose your health information at any time. You do this by 
sending written notice to the study doctor. Upon receiving the written notice, the study team will no longer use 
or disclose your health information and you will not be able to stay in this study. Information that has already 
been gathered may need to be used and given to others for the validity of the study. 
May I withdraw from the study? 
Yes. If you withdraw your permission to be in the study, no new health information identifying you will be 
gathered after that date. Information that has already been gathered may still be used and given to others. 
Is my health information protected after it has been given to others? 
No. There is a risk that your information will be given to others without your permission. 
Where can I get more information?
You may visit the NCI Web site at http://cancer.gov/ for more information about studies or general information 
about cancer. You may also call the NCI Cancer Information Service to get the same information at: 1-800-4-
CANCER (1-800-422-6237).
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. Law. 
This Web site will not include information that can identify you. At most, the Web site will include a summary 
of the results. You can search this Web site at any time.
Who can answer my questions about this study?
For more information concerning this research or if you feel that your participation has resulted in any research 
related injury, emotional or physical discomfort, please contact the study doctor, Dr. Jane Liesveld, at 585-275-
5863 (24 hours).
The University of Rochester Research Subjects Review Board can also be contacted for any of the following 
reasons:

You wish to talk to someone other than the research staff about your rights as a research subject;

To voice concerns about the research;

To provide input concerning the research process;

In the event the study staff could not be reached.
The University of Rochester Research Subjects Review Board can be reached at:
University of Rochester Research Subjects Review Board
265 Crittenden Blvd., CU 420315
Rochester, NY 14642
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Expiration Date: 8/21/2019
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Telephone (585) 276-0005 or 
For long-distance you may call toll-free: (877) 449-4441 
ADDITIONAL STUDIES SECTION: 
This section is about optional studies you can choose to take part in
This part of the consent form is about optional studies that you can choose to take part in. You will not get 
health benefits from any of these studies. The researchers leading this optional study hope the results will help 
other people with cancer in the future.
The results  will not be added to your medical records and  you or your study doctor will not know the results.
You will not be billed for these optional studies. You can still take part in the main study even if you say ‘no’ to 
any or all of these studies. If you sign up for but cannot complete any of the studies for any reason, you can still 
take part in the main study.
Circle your choice of “yes” or “no” for each of the following studies.
Optional Storage and Use for Laboratory Studies and/or Biobanking for Possible Future 
Studies
Researchers are trying to learn more about cancer, diabetes, and other health problems. Much of this research is 
done using samples from your tissue, blood, urine, or other fluids. Through these studies, researchers hope to 
find new ways to prevent, detect, treat, or cure health problems.
Some of these studies may be about genes. Genes carry information about features that are found in you and in 
people who are related to you. Researchers are interested in the way that genes affect how your body responds 
to treatment. If a genetic study is being done, DNA (inherited material) will be isolated from the sample. A 
variety of tests may be used to examine the genes we think may be related to your disease or condition. The 
exact testing that will be done is not known at this time, so we cannot give you more details right now. Even if 
your samples are used for this kind of research, the results will not be put in your health records. Records about 
you and the genetic testing results will be kept in a coded fashion. We may need to contact you to obtain your 
consent to future genetic testing of your samples. If you want to obtain genetic counseling to understand more 
about what genetic testing is, please let us know so we can refer you to a genetic counselor.
For the optional studies portion of this clinical study, no extra blood or marrow material will be obtained 
beyond that required in the study itself, but if there are extra cells remaining in these samples after tests for this 
study are completed, the researchers ask your permission to store and use your samples and related health 
information (for example, your response to cancer treatment, results of study tests and medicines you are given) 
for medical research. The research that may be done is unknown at this time. Storing samples for future studies 
is called “biobanking”. The Biobank is being run by the leukemia research group at the James P. Wilmot Cancer 
Center at the University of Rochester. 
WHAT IS INVOLVED?
If you agree to take part, here is what will happen next:

It will be determined that there is leftover tissue from the samples collected for this trial and that 
they are no longer needed to assess your progress or response to the study medications. 

Your sample and some related health information may be stored in the Biobank, along with samples 
and information from other people who take part. The samples will be kept until they are used up. 
Information from your medical record will be updated from time to time.
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
Qualified researchers can submit a request to use the materials stored in the Biobanks. A science 
committee at the clinical trials organization will review each request. There will also be an ethics 
review to ensure that the request is necessary and proper. All requests will be part of an approved 
research study. Researchers will not be given your name or any other information that could directly 
identify you. 

Neither you nor your study doctor will be notified when research will be conducted or given reports 
or other information about any research that is done using your samples. 

Some of your genetic and health information may be placed in central databases that may be public, 
along with information from many other people. Information that could directly identify you will not 
be included.
WHAT ARE THE POSSIBLE RISKS?

The most common risks related to drawing blood from your arm are brief pain and possibly a bruise. 

There is a risk that someone could get access to the personal information in your medical records or 
other information researchers have stored about you.

There is a risk that someone could trace the information in a central database back to you. Even 
without your name or other identifiers, your genetic information is unique to you. The researchers 
believe the chance that someone will identify you is very small, but the risk may change in the future 
as people come up with new ways of tracing information.

In some cases, this information could be used to make it harder for you to get or keep a job or 
insurance. There are laws against the misuse of genetic information, but they may not give full 
protection. There can also be a risk in knowing genetic information. New health information about 
inherited traits that might affect you or your blood relatives could be found during a study. The 
researchers believe the chance these things will happen is very small, but cannot promise that they 
will not occur.
HOW WILL INFORMATION ABOUT ME BE KEPT PRIVATE?
Your privacy is very important to the researchers and they will make every effort to protect it. Here are just a 
few of the steps they will take:

When your sample(s) is sent to the researchers, no information identifying you (such as your name) 
will be sent. Samples will be identified by a unique code only. 

The list that links the unique code to your name will be kept separate from your sample and health 
information. Any Biobank staff or reserachers with access to the list must sign an agreement to keep 
your identity confidential.

Researchers to whom the University of Rochester sends your sample and information will not know 
who you are. They must also sign an agreement that they will not try to find out who you are.

Information that identifies you will not be given to anyone, unless required by law.

If research results are published, your name and other personal information will not be used.
WHAT ARE THE POSSIBLE BENEFITS?
You will not benefit from taking part in the optional portion of this study. 
ARE THERE ANY COSTS OR PAYMENTS?
There are no costs to you or your insurance. You will not be paid for taking part. If any of the research leads to 
new tests, drugs, or other commercial products, you will not share in any profits.
WHAT IF I CHANGE MY MIND?
If you decide you no longer want your samples to be used, you can call the study doctor, Dr. Jane Liesveld, at 
585-275-4099  who will let the researchers know. Then, any sample that remains in the bank will no longer be 
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used and related health information will no longer be collectd. Samples or related information that have already 
been given to or used by researchers will not be returned.
WHAT IF I HAVE MORE QUESTIONS?
If you have questions about the use of your samples for research, contact the study doctor, Dr. Jane Liesveld, at 
585-275-4099. 
Please circle your answer to show whether or not you would like to take part in each option (include only 
applicable questions):
LEFTOVER SAMPLES FOR THE LABORATORY STUDIES:
I agree to have my leftover specimens collected and I agree that my specimen sample(s) and related 
information may be used for the laboratory study(ies) described above.
YES
NO
I agree that my study doctor, or their representative, may contact me or my physician to see if I wish to 
learn about results from this(ese) study(ies).
YES
NO
LEFTOVER SAMPLES FOR FUTURE RESEARCH STUDIES:
My leftover samples and related information may be kept in a Biobank for use in future health research.
YES
           NO
I agree that my study doctor, or their representative, may contact me or my physician to see if I wish to 
participate in other future research related to my participation in this study.
YES
    NO
This is the end of the section about optional studies.
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My Signature Agreeing to Take Part in the Study
I have read this consent form or had it read to me. I have discussed it with the study doctor and my questions 
have been answered. I will be given a signed copy of this form. I agree to take part in the main study and any 
additional studies where I circled ‘yes’. 
Subject’s name (printed):______________________________________________
Subject’s signature:___________________________________________________
Date of signature:__________________
Person Obtaining Consent
I have read this form to the subject and/or the subject has read this form.  I will provide the subject with a 
signed copy of this consent form.  An explanation of the research was given and questions from the subject 
were solicited and answered to the subject’s satisfaction.  In my judgment, the subject has demonstrated 
comprehension of the information.  I have given the subject adequate opportunity to read the consent before 
signing.
Investigator’s (or approved designee’s) name & title (printed):___________________________________
Investigator’s (or approved designee’s) signature:_______________________________________
Date of signature:_____________
RSRB Approval Date: 8/1/2019
Expiration Date: 8/21/2019
Complion Document ID: 1249021