Conditions: Myelodysplastic Syndromes
Keywords: de novo myelodysplastic syndromes previously treated myelodysplastic syndromes
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 54
Healthy volunteers: no

Brief summary:
RATIONALE: Drugs used in chemotherapy, such as decitabine, work in different ways to stop the growth of myelodysplastic cells, either by killing the cells or by stopping them from dividing. Tretinoin and decitabine may help myelodysplastic cells become more like normal cells, and to grow and spread more slowly. Giving decitabine together with tretinoin may be an effective treatment for myelodysplastic syndromes.

PURPOSE: This phase I/II trial is studying the side effects and best dose of tretinoin when given together with decitabine in treating patients with myelodysplastic syndromes.

Detailed description:
OBJECTIVES:

Primary

* Determine the hematologic and nonhematologic toxicities of decitabine in combination with tretinoin in patients with myelodysplastic syndromes. (Phase I)
* Determine the maximum tolerated dose of tretinoin when administered with decitabine in these patients. (Phase I)
* Determine the clinical remission rate (complete and partial remission) in patients treated with this regimen. (Phase II)
* Determine the rate of hematologic improvement in these patients. (Phase II)

Secondary

* Determine the efficacy of this regimen, in terms of improved bone marrow function, by monitoring frequency of transfusion, bleeding, and infection, as well as changes in bone marrow morphology and cytogenetics in these patients.
* Assess differentiation by morphology and flow cytometry and apoptosis by flow cytometry in patients treated with this regimen.
* Determine if gene expression changes in these patients are induced by this regimen.
* Determine the efficacy of this regimen, in terms of inducing demethylation of specific genes, in these patients.
* Correlate clinical response with gene expression, demethylation of specific genes, and flow cytometric indicators of differentiation and apoptosis.

OUTLINE: This is a phase I, dose-escalation study of tretinoin followed by a phase II, open-label study.

* Phase I: Patients receive decitabine IV over 1 hour once daily on days 1-5 followed by oral tretinoin twice daily on days 10-19. Treatment repeats every 28 days for a minimum of 4 courses in the absence of disease progression or excessive toxicity. Patients who achieve a partial or complete response after completing 6 courses of treatment may receive 4 additional courses up to a total of 10 courses. Patients with stable disease or hematologic improvement are removed from study.

Cohorts of 3-6 patients receive escalating doses of tretinoin until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity attributable to tretinoin at any dose level during course 1. A total of 6 patients are treated at the MTD.

* Phase II: Patients receive decitabine as in phase I and tretinoin at the MTD. Patients undergo blood and bone marrow collection periodically during study for correlative demethylation and gene profiling studies and for evidence of differentiation and apoptosis. Samples are examined by flow cytometry, cytogenetics, histochemistry, and array-based whole genome methylation analysis.

After completion of study treatment, patients are followed at 30 days.

PROJECTED ACCRUAL: A total of 50 patients will be accrued for this study.

Arms:
arm 1: Decitabine and All-Trans Retonoic Acid (Tretinoin)

Interventions: intervention 1: decitabine intervention 2: tretinoin intervention 3: DNA methylation analysis intervention 4: cytogenetic analysis intervention 5: microarray analysis intervention 6: flow cytometry intervention 7: immunohistochemistry staining method
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None intervention 4: None intervention 5: None intervention 6: None intervention 7: None

Protocol document:
Prot_SAP_000.pdf: 
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MSK PROTOCOL COVER SHEET 
 
Phase I/II Study of Decitabine and All-Trans  Retinoic Acid (Tretinoin) for Patients With 
Myelodysplastic Syndromes 
 
Principal  Investigator/Department:  Raajit Rampal, MD, PhD/Medicine 


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Table of Contents 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA .................................................................. 1 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS .......................................................................... 2 
3.0 
BACKGROUND AND RATIONALE ............................................................................... 3 
4.1 
OVERVIEW OF STUDY DESIGN/INTERVENTION ...................................................... 7 
4.2 
DESIGN .......................................................................................................................... 7 
4.3 
INTERVENTION .......................................................................................... 8 
5.1 
THERAPEUTIC/DIAGNOSTIC AGENTS ......................................................................... 8 
5.2 
DECITABINE (5-AZA-2’-DEOXYCYTIDINE) ................................................... 8 
5.3 
ALL-TRANS RETINOIC ACID (TRETINOIN) ................................................. 10 
6.1 
CRITERIA FOR SUBJECT ELIGIBILITY ....................................................................... 11 
6.2 
SUBJECT INCLUSION CRITERIA ...................................................................... 11 
6.3 
SUBJECT EXCLUSION CRITERIA ..................................................................... 11 
7.0 
RECRUITMENT PLAN ................................................................................................... 12 
8.1 
PRETREATMENT EVALUATION .................................................................................. 12 
8.2 
PRE-STUDY EVALUATION (ELIGIBILITY ASSESSMENT) ......................... 12 
8.3 
BASELINE EVALUATIONS ................................................................................ 12 
9.0 
TREATMENT/INTERVENTION PLAN ................................................................................ 13 
10.1 
EVALUATION DURING TREATMENT ....................................................................... 14 
10.2 
SAFETY MONITORING .................................................................................... 14 
10.3 
TESTS FOR DISEASE RESPONSE ................................................................... 14 
10.4 
RESEARCH SAMPLES ...................................................................................... 15 
10.5 
RESEARCH TESTS .............................................................................................. 15 
11.1 
TOXICITIES/SIDE EFFECTS ....................................................................................... 16 
11.2 
EXPECTED SIDE EFFECTS OF DECITABINE .............................................. 16 
11.3 
EXPECTED SIDE EFFECTS OF TRETINOIN ................................................. 16 
11.4 
ADVERSE EVENT REPORTING ........................................................................ 16 
11.5 
SERIOUS ADVERSE EVENT (SAE) REPORTING ......................................... 16 
11.6 
ESTABLISHMENT OF MAXIMUM TOLERATED DOSE (MTD) ................. 18 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ................ 17 
13.0 
CRITERIA FOR REMOVAL FROM STUDY ................................................................ 20 
14.0 
BIOSTATISTICS ................................................................................................................... 20 
15.1 
PATIENT REGISTRATION AND RANDOMIZATION PROCEDURES ...................... 22 
15.2 
PATIENT REGISTRATION ................................................................................. 22 
16.1 
DATA  MANAGEMENT ISSUES .................................................................................. 23 
16.2 
QUALITY ASSURANCE ..................................................................................... 23 
16.3 
DATA AND SAFETY MONITORING ............................................................... 23 
17.1 
PROTECTION OF HUMAN SUBJECTS ............................................................................ 24 
17.2 
PRIVACY .................................................................................................................... 25 
18.1 
INFORMED CONSENT PROCEDURES .......................................................................... 26 
18.2 RESEARCH AUTHORIZATION...... ERROR! BOOKMARK NOT DEFINED. 
19.0 
REFERENCES ....................................................................................................................... 28 
20.0 
APPENDICES ........................................................................................................................... 31 


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1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
 
TITLE: Phase I/II Study of Decitabine  and All-Trans  Retinoic  Acid (Tretinoin)  for Patients with 
Myelodysplastic  Syndromes 
 
OBJECTIVE:  To determine  whether the combination of decitabine  with tretinoin is safe and 
efficacious  in the treatment  of Myelodysplastic  Syndromes. 
 
PATIENT POPULATION:  Adults (greater than 18 years) with a confirmed  diagnosis  of MDS 
(based on the FAB MDS diagnostic  criteria  (1)) and an International Prognostic  Scoring System 
(2) score of 0.5 or greater (IPSS Intermediate-1, Intermediate-2, and High-Risk  categories. For 
IPSS schema, see Appendix 1). 
 
STUDY DESIGN: This is a single-center,  open label, phase I/II study of the combination of 
decitabine  (DAC) and All-Trans  Retinoic  Acid (Tretinoin)  in patients with Myelodysplastic 
Syndromes. 
 
STUDY DRUG AND DOSE: Eligible  patients will receive decitabine intravenously  at a dose of 
20 mg/m2 daily for five days for a total dose per cycle of 100 mg/m2.  Decitabine  will be 
administered  as an outpatient  at MSKCC. Beginning on day 10 of each cycle, patients will  
receive tretinoin orally for 10 days as an outpatient  (See Figure 1.1 for study design schema). 
Three successive  tretinoin dose levels  will be evaluated:  45 mg/m2/day,  65 mg/m2/day,  and 85 
mg/m2/day given over two doses each day. A standard dose escalation scheme will be followed 
with cohorts of 3 to 6 patients treated at each dose level (section 14.0). A dose-limiting toxicity 
is defined as in section 11.5. If a DLT is seen at 45 mg/m2/day,  a dose de-escalation schema will 
be applied (See section 9.0). If no DLT is seen amongst  the three patients treated at a dose under 
consideration for MTD, then an additional 3 patients will be treated at this dose level to confirm 
this dose as the maximal tolerated dose. 
 
The phase II study will have a 2-stage design. In the first stage of this design, twenty seven 
patients will be treated. Patients treated at the tretinoin MTD (6 patients) in the phase I portion of 
the study will be carried over and counted among the patients in stage 1 of the phase II portion of 
the study. If two or fewer responses (CR or PR) are seen among the first 27 patients, the study 
will be closed for lack of efficacy.  If at least three responses are seen in the first stage, then an 
additional 13 patients will be accrued in the second stage. 
 
Treatment  will be recycled every 4 weeks, provided there is adequate recovery from non– 
hematologic  toxicities.  The effects of decitabine and escalating doses of tretinoin on markers of 
differentiation and apoptosis, and on expression of key genes will be assessed. 
 
 
 
 
FIGURE 1.1: Study Design 


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Treatment Period   → 
Cycle # 1   → 
Cycle #2, #3, #4, etc.    → 
End of 
Study 
Decitabine 
X 
X 
Tretinoin 
X 
X 
Treatment 
Days (D) 
D1 - D5 
D 6 – D 9 
D10 - D19 
D 20 – D 28 
D 1 - D 5 
D 6 – D 9 
D 10 – D 19 
D 20 - D 28 
Day X 
 
 
Patients will receive treatment for a minimum of 4 cycles, barring removal for progression of 
disease or excessive toxicity.  Patients must achieve hematologic  improvement  (HI) or Bone 
Marrow PR/CR by the completion of cycle #6. Patients achieving HI or bone marrow PR/CR by 
the completion of cycle #6 may receive up to a total of 10 cycles of therapy, barring excessive 
toxicity.  If the best response after cycle #6 is Stable Disease, these patients will be removed from 
study. Patients in the phase I study will continue  at the study entry dose. Treatment  will be 
interrupted  for grade III or IV non-hematologic  toxicity attributable  to tretinoin or decitabine. 
Therapy may be resumed with the next cycle of treatment as long as the toxicity has decreased to 
< grade 2 within 8 weeks of the last treatment administration.  However, these patients will 
receive a 25% dose reduction in tretinoin or decitabine  (which ever treatment  is suspected or 
both if the attribution is unknown)  when treatment resumes.  All patients will be followed  for 
Serious Adverse Events (SAEs) for 30 days after the completion of the last cycle of therapy 
(each cycle is 4 weeks). 
 
TIME TO COMPLETION:  It is anticipated  the study will complete accrual in 18–24 months. 
 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS 
Primary  Endpoint: 
Phase I:  Define the hematologic  and non-hematologic  toxicities  of combining a 
hypomethylating agent (Decitabine,  DAC) with escalating doses of the transcriptional modifying 
agent tretinoin (All Trans Retinoic  Acid), and define the MTD of tretinoin in combination with 
decitabine. 
 
Phase II:  Determine  the clinical remission rate (rate of Complete Remission,  Partial Remission) 
of the combination of decitabine  and tretinoin  in patients with myelodysplastic  syndromes, and 
determine  the rate of Hematologic  Improvement. 
 
 
 
 
Se condary Endpoints  (Phase I and Phase II): 


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1. Evaluate the ability of decitabine and tretinoin to affect bone marrow function by monitoring 
frequency of transfusions, frequency of bleeding and infection, and changes in bone marrow 
morphology and cytogenetics. 
2. Evaluate differentiation (using morphology and flow cytometry) and apoptosis (using flow 
cytometry) induced by treatment with decitabine and tretinoin. 
3. Perform gene profiling studies to determine if gene expression changes are induced by decitabine 
and tretinoin. 
4. Evaluate the ability  of decitabine and tretinoin to cause demethylation of specific genes. 
5. Correlate clinical response with gene expression, demethylation of specific genes, and flow 
cytometric indicators of differentiation and apoptosis. 
 
 
3.0 
BACKGROUND AND RATIONALE 
The M ye lodysplastic Syndrome s: 
The Myelodysplastic  Syndromes (MDS) are typically characterized  by refractory cytopenias  in 
patients with a hypercellular,  dysplastic  bone marrow, who have a variable propensity to 
progress to acute myelogenous  leukemia  (AML). “Low risk” MDS can be distinguished  from 
“high-risk” MDS by examining bone marrow cytogenetics,  the severity and number of 
cytopenias, and the bone marrow blast percentage.  These three parameters have been shown to 
correlate with survival and the likelihood  of progression to AML in the International Prognostic 
Scoring System (2) (See Appendix 1 for the IPSS). Low risk patients, with an IPSS score of “0” 
have a median survival of 5.7 years, and a low risk of progression to AML. In contrast, patients 
with an IPSS score of 0.5 or greater have a lower survival  (as low as 0.4 years) due to more 
rapidly progressive  bone marrow failure  and/or a greater risk of transformation to AML. 
 
The standard of care for MDS is supportive  care, which includes  blood product transfusions  and 
treatment of infectious  complications.  Growth factors are also used (rHuEPO, G-CSF), and in 
some patients, these agents can temporarily ameliorate  the effects of some cytopenias  that 
complicate  the course of patients with MDS. In 2004, 5-azacytidine  was approved for treatment 
of MDS, and although 5-azacytidine  responders had an improved quality  of life and delay in time 
to progression to AML, the overall response rate (CR, PR) was 23% with a CR rate of only 7% 
(3). Allogeneic  stem cell transplantation can cure a minority of patients who are young and 
healthy enough to undergo such a procedure, and who have an available  stem cell donor. 
 
Aberrant differentiation and proliferation are hallmarks  of MDS and AML. Agents that restore 
normal hematopoietic  differentiation and induce appropriate apoptosis would likely improve  the 
bone marrow function in patients with MDS. 
 
 
Hypome thylating  Age nts in M DS: Rationale 
DNA methylation patterns are frequently altered in malignancy including global demethylation 
and gene-specific  hypermethylation of promoter CpG islands. Hypermethylation of promoter 
CpG islands  generally result in decreased gene expression, as DNA 5-methylcytosine 


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formation results in a chromatin configuration that blocks the binding of transcription factors to 
the DNA. The genes affected by this process include  a variety of tumor suppressor genes, 
including genes involved  with cell cycle regulation(4-6). 
 
Inhibition of DNA methyltransferase  activity has been associated with cellular  differentiation in 
numerous  hematopoietic  cell systems  (7-10). Differentiation has also been correlated with 
clinical responses in MDS patients receiving decitabine.  However, if demethylation of key 
regulatory gene promoters is responsible  for the clinical  activity of demethylating agents, the 
exact genes involved  have yet to be identified. 
 
Transforming Growth factor-βs (TGF-β) are molecules  that normally inhibit  hematopoietic 
proliferation,  initiate  appropriate apoptosis, and regulate differentiation  (11). Growth inhibition 
of leukemia  ce lll      lines by transforming growth factor β (TGFβ) is associated with activation of 
p15INK4b, a cell cycle regulator  involved  with the inhibition of progression from G1 to S phase. 
Inactivation of p15INK4b is associated with methylation of the 5’ CpG island of the promoter 
region in AML cases (6, 12, 13) and in MDS patients (12, 14)(11/15 patients with MDS and 
blasts > 10%; Quesnel, 1998. 16/32 MDS patients, unknown blast counts; Uchida, 1997). 
Methylation and inactivation of the p15INK4b gene may be a mechanism for hematopoietic  cell 
escape from the G1 regulatory effect of TGFβ, and clinical responses to decitabine  in MDS 
patients have been associated with p15INK4b transcriptional activation  (15). However, it is not 
clear that pharmacologic  demethylation of p15INK4b was responsible for the observed in vivo 
clinical activity,  since other patients responded without  demethylation of p15INK4b, and all 
responders do not have hypermethylated  p15INK4b at baseline. 
 
Other CDKIs may affect the ability of TGFβ to induce G1 arrest, including the CDKI p27Kip1 
(11). In recent in vitro work, decreased p27 levels or abnormal localization of p27 to the 
cytoplasm results in unresponsiveness  of fresh AML blasts and hematopoietic  cell lines, 
respectively,  to TGFβ-mediated cell cycle arrest (16). The methylation status of the p27 
promoter in MDS and AML is not well characterized.   However, given the importance  of TGF-β 
in hematopoietic  differentiation and growth regulation,  p27 deregulation may be important  to 
study in MDS, and methylation is one method of dysregulation that could potentially be altered 
by decitabine.   Another CDKI, p57 (kip2), is methylated  in patients with a variety of leukemia 
and lymphoma  including AML. We have shown the importance  of p57 in the G1 growth arrest 
induced by TGFB in primary human hematopoietic  cells (17). We have also found methylation 
of the p57 promoter in patients with AML and others have reported this in other hematologic 
malignancies.  Decitabine  was able to induce re-expression of p57 in B-cells. The methylation 
status of p57 in MDS warrants further  study. 
 
Other genes involved  in the pathogenesis  of MDS may be abnormally methylated  and can 
potentially be reactivated by demethylation,  including genes involved  in the differentiation 
program of hematopoietic  cells. Genes affecting apoptosis pathways may also be affected by the 
demethylating effect of decitabine.  However, the effect of decitabine  on apoptosis in MDS 
patients has not been well characterized  to date. Since abnormal proliferation is a prominent 
feature of the MDS phenotype, it would be desirable to determine  if apoptosis is induced in 
responding patients. We have recently demonstrated the effects of the histone  deacetylase 


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inhibitor,  depsipeptide, on apoptosis using flow cytometry to detect 7-AAD staining  (18). This 
analysis  can similarly be applied to patients receiving 
hypomethylating agents. 
 
Hypome thylating  Age nts in M DS: Clinical Data 
5-Azacitidine  was FDA approved based on a randomized,  phase III trial comparing 5-azacitidine 
(n=99) to supportive  care (n=92); 7% of patients who received 5-azacitidine  had a complete 
response (CR), 16% had a partial response (PR), and 37% showed evidence of hematologic 
improvement  (HI) (3) (Response criteria  used was less stringent  than the IWG). Patients who 
received 5-azacitidine  appeared to have an increased time to AML progression (22 months  vs. 12 
months). 
 
In three European multi-center,  phase II trials and one MSKCC phase II trial, decitabine  was 
given to 177 elderly patients (median  age 70) at a dose of 45-50 mg/m2/day for three days every 
6-8 weeks. Across those studies, the overall response rate was 49%, including a CR rate of 24%. 
The median response duration was 9 months  (19). Decitabine  was subsequently compared to 
supportive  care in a multi-center,  randomized,  phase III trial in North America  (20). In the phase 
III trial, decitabine  was given as an inpatient,  15 mg/m2  IV every eight hours for 9 consecutive 
doses (135 mg/m2/cycle)  every 6 weeks, which was the same dose and schedule given to the 
majority of the decitabine  phase II participants.  The overall response rate (CR + PR) was (15%) 
compared with a 0% ORR in the supportive  care arm, with an 8% CR rate (IWG Response 
Criteria). The median time to death or AML progression (composite  endpoint) overall was 491 
days vs. 274 days, and survival  was prolonged in responders (657 days) compared to non- 
responders (384 days).  Patients with IPSS High-Risk  disease and Intermediate-2  Risk were 
shown to have a statistically significant  prolongation in the time to AML progression or death 
(12 months vs. 6.8 months, p= .03), the primary endpoint  of this phase III trial. The difference 
was even greater when IPSS High-Risk  cohort was analyzed  and the treatment  arm was 
compared to supportive care (time to AML progression or death 9.3 months vs. 2.8 months, p = 
.01). In another sub-group analysis,  clinical response (PR + CR), a secondary endpoint, was 
significantly improved for the Intermediate-2  Risk group (21% vs. 0%, p = .005). The response 
rate for IPSS High-Risk  patients was 13% (p = .234). 
 
In a more recent three-arm, phase II study, 100 mg/ m2 decitabine  was given every 4 weeks 
using three different  outpatient  schedules: 1) 20 mg/m2/day intravenously for 5 consecutive 
days; 2) 10 mg/m2 per day for ten days; 3) 20 mg/m2  subcutaneously for five days (21). The 5- 
day intravenous  schedule produced a complete response rate (modified  IWG criteria)  of 40%, 
which represents a potential substantial  improvement  in the response rate seen for the three day 
schedule used previously in the bulk of the phase II studies and in the randomized  phase III trial. 
 
All-Trans  Re tinoic Acid (Tre tinoin) 
MSKCC has played a major role in demonstrating that the administration of tretinoin to patients 
with APL greatly improves  survival.  In APL, retinoic  acid (RA) can usually de-repress 
promoters of RA target genes by blocking transcriptional  inhibition caused by the PML/RARα 
fusion protein.  Repression by PML/RARα is due to the recruitment  of co-repressor 


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complexes, which contain histone deacetylases (HDACs), and DNA methyltransferases.  With 


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tretinoin treatment,  the block to granulocytic  maturation is relieved,  and granulocytic  maturation 
proceeds normally. 
 
Tretinoin can induce cell-cycle  arrest of myeloid,  non-APL leukemia  cells. When 9 of 13 primary  
blast cultures  were exposed to tretinoin >95% growth inhibition was seen (22).  In this        
report, sensitivity to tretinoin correlated significantly with an increase in tretinoin- induced  RARβ 
receptor expression.  In other studies, tretinoin induced apoptotic cell death of non-M3 AML 
blasts at a concentration of 10e6 mol/l, which is clinically achievable  at a dose of 45 mg/m2/day 
(23), over a 72 hour exposure time   (24). 
 
Anecdotal reports of non-M3 AML patients with clinical responses to tretinoin monotherapy 
with associated terminal  differentiation suggest that some patients with MDS and AML may 
respond to tretinoin either alone or in combination with other agents as a result of a 
differentiation effect (25).  There are also anecdotal reports of MDS patients responding to 
tretinoin monotherapy. 
 
De citabine in combinatio n  with Tre tinoin 
Decitabine  was shown to activate the expression of the RARβ receptor gene in DLD-1 colon 
cancer ce llls, and more recently,  to inhibit  methylation at two specific  RARβ promoter CpG sites 
in colon and breast cancer cells (26, 27).  Reversal of RARβ gene promoter methylation has been 
studied in non-M3 AML cell lines (28). In these studies, Di Croce et. al. showed that RARβ2 
promoter methylation decreased to a greater degree (75%) with the combination of decitabine 
and tretinoin,  compared to tretinoin or decitabine  alone (~ 50%) (28). The demethylation and 
increased RARβ2 expression was associated with morphologic  evidence of differentiatio n. 
 
This effect was also demonstrated in non-M3 AML by Trus, et al. (29). Tretinoin alone induced 
little  or no evidence of differentiation or RARβ upregulation,  but when OCI/AML-2 cells and 
non-M3 primary cultures  were incubated with decitabine  before exposure to tretinoin, 
differentiation was seen (upregulation of CD11b and Cd14), as was upregulation of RARβ. 
Similarly,  Niitsu et. al. studied the response of three non-M3 AML cell lines to tretinoin alone, or 
tretinoin combined with decitabine.  All three non-M3 AML cell lines  studied were effectively 
induced to differentiate  by the combination.30   The combination  of tretinoin and decitabine  may 
therefore induce additive  or synergistic  differentiation activity. 
 
Tretinoin has also been shown to induce apoptosis in in vitro systems (see Section 3.0, 
“Tretinoin” sub-section) and demethylation of tretinoin-responsive  (30) after tretinoin,  then any 
apoptosis induced by tretinoin may abrogate the demethylating and cytotoxic  effects of 
decitabine,  which require S-phase and, at least for the demethylation effect, a minimum  of 3-5 
days (31-33). With the exception of Oki, et al., the “kinetics” of decitabine-induced 
demethylation has primarily been studied in in vitro systems, as cited above. Interestingly,  the 
data presented by Oki et al. indicate  that the maximal demethylating activity in patient samples 
after decitabine  administration may be closer to 12 days, since demethylation was tested in 
patient samples at 5, 12, and 26 days after decitabine monotherapy was started, and the relative 
decrease in demethylation was greatest at day #12. These data appear to support the need for 
decitabine  treatment to precede the start of tretinoin by possibly up to 12 days. 


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Although these effects have largely been explored in AML cell lines and AML primary cultures, 
it is possible that in MDS, upregulation of the RARβ receptor by demethylation may enhance the 
sensitivity of blast cells to the growth inhibitory or differentiation effects of tretinoin.  In this  
way, decitabine may induce a more “permissive” environment  for the effects of tretinoin by 
activating genes required for differentiating or apoptosis “programs”,  and a lllowing access of 
transcriptional regulatory complexes  to DNA. 
 
 
 
4.1 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
4.2 
De sign 
 
This is a phase I/II study designed to evaluate  the safety, biologic  effects, and preliminary 
clinical efficacy of the combination of decitabine  and tretinoin.  Approximately 45 eligible 
patients with a myelodysplastic  syndrome  will receive the combination of decitabine and 
tretinoin.  Decitabine  will be administered  at a dose of 20 mg/m2/day for five days every 4 
weeks. Tretinoin will be administered  from days 10-19 of each cycle in escalating doses to 
determine  the MTD of Tretinoin in combination with decitabine. 
 
The initial dose level will be 45 mg/m2/day,  which is 30% of the MTD for Tretinoin in MDS 
patients (MTD = 150 mg/m2)(34), and is a dose that has been shown to produce apoptosis in 
non-M3 AML(23), and differentiation  in APL. This is also the standard dose of tretinoin that has 
been administered  safely to patients with acute promyelocytic  leukemia  in combination with 
cytotoxic  chemotherapy.  Three dose levels will be tested, with the maximum  dose being 85 
mg/m2/day.  The rationale  for this design is that tretinoin given at doses of 90 mg/m2/day or 
greater is more likely to produce side effects (primarily skin and mucosal toxicity)  that we wish 
to avoid in this generally elderly patient population.  Also, decitabine  is expected to induce 
myelosuppression,  and infection risk may be increased by compromised  mucosal integrity.  If 2 
patients experience DLT at 45 mg/m2/day,  a dose de-escalation scheme will be employed to 
determine  the MTD below 45 mg/m2/day.  Once the MTD is established,  additional patients (to 
equal 6 patients) will be treated to confirm the MTD. If dose escalation proceeds to 85 
mg/m2/day,  and no DLT is seen in three patients, an additional 3 patients will be treated at this 
dose level to confirm this dose as the maximal tolerated dose. Once the tretinoin MTD is 
determined,  the phase II portion of the study will proceed with tretinoin at the MTD in 
combination with decitabine. 
 
The phase II study will have a 2-stage design. In the first stage of this design, twenty seven 
patients will be treated with decitabine  (20 mg/m2/day x 5 days) and tretinoin,  using the tretinoin 
MTD established  during the phase I portion of the study. Patients treated at the tretinoin MTD (6 
patients) in the phase I portion of the study will be carried over and counted among the patients  
in stage 1. If two or fewer responses (CR or PR) are seen among the first 27 patients, the study 
will be closed for lack of efficacy.  If at least three responses are seen in the first stage, then an 
additional 13 patients will be accrued in the second stage. 


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Prior to treatment,  blood and bone marrow samples will be obtained for baseline research 
studies. At defined time points after the start of the treatment,  blood and bone marrow samples 
will be obtained for research studies as well. Research studies (at all time points) will include 
flow cytometry to analyze  for evidence of differentiation and apoptosis. In addition, gene 
promoter methylation studies and Affymetrix gene profiling will also be performed. Patients will 
be monitored  for clinical  response.  Clinical responses will be correlated with the laboratory 
studies. 
4.3 
Inte rve ntion 
 
Decitabine  will be administered  by intravenous  infusion,  at a dose of 20 mg/m2 per day for 5 
days as an outpatient.  Beginning on day 10 of each cycle, tretinoin will be self-administered 
daily for 10 days. Tretinoin will be given using a dose escalation scheme to determine  the MTD 
of tretinoin in combination with decitabine during the phase I portion of the study. Tretinoin and 
decitabine  are commercially available  and the cost of this medication will be charged to the 
patient and/or their insurance  company. 
 
The rationale  for this intervention is that the addition of tretinoin,  an established  differentiating 
agent, may enhance the differentiation effects seen with decitabine  alone, and possibly increase 
the response rate over decitabine  alone and/or decrease the time to response. Tretinoin may also 
induce apoptosis based on in vitro studies, and therefore, will be started on day 10. It is 
anticipated  that any apoptotic effect of tretinoin (if this effect is seen) will be induced after 
maximal demethylation has been achieved. Demethylation and/or re-expression of specific  
genes, and/or flow cytometric  evidence of differentiation and apoptosis may be surrogate  
markers for clinical response and these parameters will be studied after exposure to decitabine 
and again after treatment  with tretinoin.  Correlation of these analyses  with clinical responses will 
assist in gaining a better understanding of the mechanism of action of decitabine  and tretinoin in 
MDS patients. 
 
 
 
 
5.1 
THERAPEUTIC/DIAGNOSTIC  AGENTS 
 
5.2 
De citabine (5-aza-2’-de oxycytidine ) 
 
De scription: 5-aza-2’-deoxycytidine  is an analog of 2’-deoxycytidine  with a nitrogen atom 
substituted  for carbon at the 5-position of the ring. 
 
Other names: 
Dacogen (™) 
DAC 
Deoxyazacitidine 


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Drug supply and distributio n: Decitabine  is formulated  and commercially  supplied  by MGI 
Pharma. 
 
 
How supplied: Lypholized  powder for injection,  50 mg in 20 ml vials. 
 
Storage:  Unopened vials are to be stored at controlled  room temperature per USP and are stable 
for 3 years.  Reconstituted  decitabine  should be stored for no longer than 7 hours at 2-8 °C. 
 
Solution Preparation: Each vial is reconstituted  with 10 ml of Sterile Water for Injection,  USP. 
One ml of reconstituted  solution will contain 5 mg of decitabine  at a pH of 6.8-7.0. This 
reconstituted  solution can be further diluted  to the desired concentration using infusion fluids 
such as 0.9% Sodium Chloride, 5% Dextrose Injection,  or Lactated Ringers  to a final drug 
concentration of 0.1-1.0 mg/ml.   Unless used within 15 minutes  upon reconstitution,  the diluted 
solution must be prepared using cold infusion fluids  and stored at 2-8°C (36-47°F) for a 
maximum  of 7 hours prior to administration. 
 
Stability: The concentration of decitabine decreases over time once the lyophilized preparation is 
reconstituted. Therefore, the sterile water used to reconstitute the lyophilized preparation and the 
0.9% Sodium Chloride (or 5% Dextrose or Lactated Ringer’s)  diluent  should be between 2-8 °C 
to minimize  decomposition.  Reconstituted  decitabine  should be stored at refrigerator 
temperatures  for no longer than 7 hours prior to administration. 
 
Decitabine  will be administered  intravenously  at a dose of 20 mg/m2  daily for 5 days. The 
infusion period is over one hour (no greater than 3 hours for solution that has been kept at 2-8 °C 
for 7 hours or less). 
 
Precautions: Skin contact with the solution should be avoided and protective gloves should be 
worn. Spilled drug can be inactivated  by a 2 M sodium hydroxide  solution.  Exposed skin can be 
treated with a borax buffer solution pH 10, to be followed  by a thorough washing with soap and 
water. 
 
M e chanism of Action: Decitabine  is a cytosine  nucleoside  analog that induces inhibition of 
DNA methylation.  This effect was first demonstrated by Jones and Taylor in 1980 (7). More 
recent investigations  have determined  that this effect appears to be brought about by the trapping 
of DNA methyltransferases  (DNMT) (35). After the DNMTs are trapped, they are degraded. 
DNA hypomethylation has been linked to activation of gene transcription in many human and 
animal cell systems. Moreover, inhibition of DNA methylation has been associated with cellular 
differentiation in studies of hematopoietic  cell systems (7-9). 
 
The MTD for 5-aza-2’deoxycytidine  was established  in phase I studies to be 1,500 – 2,250 
mg/m2   per cycle. At these higher  doses, there was significant  myelosuppression and infectious 
complications,  which proved to be dose-limiting.  In addition to the apparent cytotoxicity that 
causes myelosuppression,  a cytotoxic  effect was also noted in various  in vitro systems as well 
(36), where, at minimal  cytotoxic concentrations,  greater cell kill was seen with sustained 


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exposure to 5-aza-2’deoxycytidine  (37, 38). Therefore, a second mechanism of action may be 
cytotoxicity,  even at the lower doses proposed for this study. The cytotoxic effect follows  the 
incorporation of the drug into newly synthesized  DNA, and therefore, appears to be S-phase 
specific.  Interestingly,  5-aza-2’deoxycytidine  does not block the progression of cells from G1 
into S-phase (in contrast to cytosine arabinoside  and 5-azacytidine),  suggesting that its cytotoxic 
activity is not self-limiting  (39). 
 
5.3 
All-Trans Re tino ic Ac id (Tre tinoin) 
 
De scription:  Tretinoin  is a retinoid  derived from naturally occurring all-trans-retinol  (Vitamin 
A1). The compound is formed in vivo from retinol and can be detected at nanogram levels  in 
normal and human plasma (40). Tretinoin binds to serum albumin,  is not stored in the liver, and 
probably enters cells by diffusion.  In the cytoplasm,  Tretinoin binds to cellular  retinoic  acid 
binding proteins (CRABPs) and is transported to the nucleus  (41), where it is released and binds 
to nuclear  RARs. The signaling pathway after ligand-RAR  binding is poorly characterized. 
Isomers of tretinoin including 9-cis RA and 13-cis RA, as well as vitamin A, -carotene and 
various synthetic  retinoids,  have been clinically studied for anticancer  and /or cancer 
chemoprevention activity. 
 
Other names: Vesanoid ® 
 
Drug supply and distributio n:  Tretinoin is manufactured  and distributed  by Hoffman LaRoche. 
 
How supplied:  10 mg capsules 
 
Storage:  Store at 15 to 30 degrees Celsius (59 to 86 degrees F) and protect from light. 
 
Precautions:  Tretinoin is teratogenic  and fetotoxic  in rats at doses 1000 and 500 times the topical 
human dose, respectively.  Tretinoin is contraindicated  in persons sensitive  to parabens, vitamin 
A, and other retinoids. 
 
M e chanism of Action:  Numerous reports have documented tretinoin induced differentiation of 
APL cell in vitro. Retinoids  are known to induce granulocytic  differentiation and inhibition of 
clonal growth in the HL-60 cell line (42). Both tretinoin and 13-cis-RA isomers are active in HL- 
60 at approximately 10-6 M. Response to retinoids  in other leukemia  cell lines has been less 
consistent.  KG-1 cells showed growth inhibition at 10-9 M but exhibited  no morphologic, 
histochemical  or functional differentiation  (43). K-562 cells treated with 10-6 M tretinoin 
displayed a normal growth pattern. U937 cells underwent monocytoid  differentiation at 10-6 M 
and THP-1 cells showed functional  (but not morphologic)  differentiation at 10-9 M (43). 
Tretinoin has produced dramatic clinical  benefit in patients with APL, and as a single  agent has 
significantly survival  in this disease (44). The drug is commercially approved for this indication. 


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6.1 
CRITERIA FOR SUBJECT ELIGIBILITY 
 
6.2 
Subje ct Inclusion Crite ria 
 
• Diagnosis  of a myelodysplastic  syndrome according to the FAB classification system, 
which has been confirmed  at MSKCC 
• Age greater than or equal to 18 years 
• IPSS score of greater than or equal to 0.5. 
• Performance  Status of > 60 % (Karnofsky) 
• Serum total bilirubin  < 2.5 
• SGOT and SGPT should be < 2 times the upper limit  of normal. 
• Serum creatinine  should be < 1.5 x ULN, or 24 hour creatinine  clearance must be > 60 
cc/min. 
• Negative pregnancy test for women with child-bearing potential. 
• Female patients with child-bearing potential or male patients who are sexually active 
must agree to use an accepted form of contraception. 
• Signed informed  consent 
• Transplant  ineligible  prior to therapy 
• Prior 5-azacytindine  recipients  are eligible  regardless of prior response to 5-azacytidine. 
• Prior decitabine  recipients  must have had a response (HI or better per IWG Response 
Criteria), followed  by POD (POD after decitabine  was discontinued). 
• Patients will be eligible  for entry if they have IPSS Intermediate-1, Intermediate-2 or 
High Risk disease. 
 
6.3 
Subje ct Exclusion Crite ria 
 
• Pregnant or lactating women. Patients with childbearing potential will be required to 
practice an accepted mode of birth control. 
• Cytotoxic chemotherapy or radiotherapy within 4 weeks of starting treatment 
• Experimental therapy within 4 weeks of starting treatment 
• Medical condition which, in the opinion of the treating physician,  would put the patient at 
excessive risk of toxicity from the treatment 
• Inability to adhere to treatment or monitoring schedule 
• Unwillingness  to provide research specimens  as outlined  in the protocol 
• Presence of another malignancy which will likely require systemic  chemotherapy within 
4 months of starting decitabine and tretinoin. 
• Decitabine  refractory MDS 
• Allergy to parabens, vitamin A, or retinoids 


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7.0 
RECRUITMENT PLAN 
 
The study will be conducted at MSKCC. The study will accrue approximately 45 evaluable 
patients. Approximately 200 new patients with a diagnosis  of MDS are seen annually by 
physicians  on the Hematology,  Leukemia  and Allogeneic  Bone Marrow Transplant  Services. It is 
estimated that 2.0 years will be required to accrue ~ fifty eligible  patients. Efforts will be made 
to enroll women and minorities onto this trial. It is expected that the sex and racial breakdown of 
patients entered into this trial will reflect the overall referral patterns seen at MSKCC. However, 
because of the small number of patients entered into this trial, an absolutely representative cohort 
may not be accrued. 
 
 
8.1 
PRETREATMENT EVALUATION 
 
8.2 
Pre -study Evaluation (Eligibility  Asse ssme nt) 
 
Eligibility  evaluations  to be performed within 30 days of starting therapy with decitabine  and 
tretinoin will include  the following: 
 
• Bone marrow aspirate for histology,  cytogenetics,  flow cytometry,  and a bone marrow 
biopsy. 
• Baseline  bone marrow aspirate will also be obtained for research studies. Therefore 
patients will be consented prior to their baseline bone marrow procedure. 
• Physical exam with review of systems, medical history, Karnofsky performance  status, , 
FAB classification,  history of prior medications,  prior MDS treatments, history of 
transfusions  requirements  for two months prior to registration. 
• Determination of elements  of IPSS (bone marrow aspirate and complete blood count), 
which produces IPSS score of 0.5 or greater. 
• Electrocardiogram (EKG) 
• Comprehensive  metabolic  panel, CBC with differential  and smear review, reticulocyte 
count, pregnancy test for women with child-bearing potential. 
• Assessment  of ability of the patient to comply with the requirements  of the protocol. 
 
8.3 
Base line e valuations 
 
Baseline  evaluations  to be performed within 7 days of starting therapy with decitabine  and 
tretinoin will include  the following: 
 
• Interim medical history including review of systems, height,  weight,  vital signs, and 
calculation of body surface area, medications,  transfusion requirements,  Karnofsky 
performance  status. 


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• Comprehensive  metabolic  panel, CBC with differential  and smear review, reticulocyte 
count, PT, PTT, pregnancy test for women with child-bearing potential. 
• Patients must meet all eligibility criteria  at the time of the baseline evaluation. 
 
 
 
9.0 
TREATMENT/INTERVENTION  PLAN 
 
Eligible  patients will receive Decitabine  at a dose of 20 mg/m2  daily for 5 days as an outpatient 
and will receive a total dose per cycle of 100mg/m2. Beginning on day 10 of each cycle, patients 
will self-administer  tretinoin for 10 days (See Figure 1.1). Treatment  will be recycled every 28 
days. The tretinoin dose will be escalated within the range of 45 mg/m2/day to 85 mg/m2/day to 
determine  the MTD within that range. Although unlikely,  if DLT is seen in two patients at 45 
mg/m2/day,  a dose de-escalation  scheme will be employed to explore the safety of 30 
mg/m2/day and 15 mg/m2/day. 
The tretinoin dose escalation will proceed as follows:  Three patients will receive 45 mg/m2/day 
given over two doses each day (standard dose used for acute promyelocytic  leukemia  alone or in 
combination with cytotoxic  chemotherapy).  If no dose-limiting toxicity is observed (see section 
11.5 for definition of DLT) after completion of one cycle of therapy, three additional patients 
will receive 65 mg/m2/day given over two doses each day. If no dose-limiting toxicity is 
observed after one cycle of therapy, three additional patients will receive 85 mg/m2/day given 
over two doses each day. Doses above 85 mg/m2/day will not be tested in this trial. Based on 
prior studies with tretinoin monotherapy,  toxicity that is unacceptable  for the planned patient 
population is expected at or beyond a daily dose of 90 mg/m2, and biological effects of tretinoin 
can be expected as doses lower than 85 mg/m2/day.  A DLT in one patient at any of the three 
dose levels  tested will require the addition of three patients at that dose level. If DLT recurs in a 
second patient (2/6), the next lower dose level will be considered the MTD. If no DLT is seen 
amongst the three patients treated at the highest  tretinoin dose tested (85 mg/m2), an additional 3 
patients will be treated at this dose level to confirm this dose as the maximal tolerated dose. 
If required, the tretinoin dose de-escalation schema will proceed as follows: If two patients 
experience DLT at 45 mg/m2/day during the first cycle of therapy, and the toxicities  are likely 
attributable  to tretinoin,  patients will be enrolled  to receive tretinoin at a dose of 30 mg/m2/day, 
and 15 mg/m2/day if 30 mg/m2/day is not tolerated (if 2/6 patients experience  DLT). If 
15/mg/m2  is not tolerated (2/6 patients experience DLT), the study will be terminated  due to 
excessive toxicity of the regimen. 
 
Once the MTD is established,  patients will be accrued to the phase II portion of the study which 
will evaluate the efficacy of decitabine in combination with the MTD of tretinoin.  The phase II 
study will have a 2-stage design. In the first stage of this design, twenty seven patients will be 
treated. Patients treated at the tretinoin MTD (6 patients) in the phase I portion of the study will 
be carried over and counted among the patients in stage 1. If two or fewer responses (CR or PR) 
are seen among the first 27 patients, the study will be closed for lack of efficacy.  If at least three 
responses (CR or PR) are seen in the first  stage, then an additional 13 patients will be accrued in 
the second stage. To qualify as a non-responder, patients must undergo disease re-evaluation 
studies (bone marrow and complete blood counts) after completing four cycles of therapy. 


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Treatment  will be recycled every 28 days, provided there is adequate recovery from non- 
hematologic  toxicities.  The start of cycle #1, or subsequent cycles may be delayed for up to 2 
weeks in the event of 1) uncontrolled  infection,  or 2) other abnormalities  that would preclude 
patient eligibility (see sections 6.1 and 6.2). 
 
Patients will receive treatment for a minimum of 4 cycles, barring removal for progression of 
disease or excessive toxicity.  Patients must achieve hematologic  improvement  (HI) or Bone 
Marrow PR/CR by the completion of cycle #6. Patients achieving HI or bone marrow PR/CR by 
the completion of cycle #6 may receive up to a total of 10 cycles of therapy, barring excessive 
toxicity.  If the best response after cycle #6 is Stable Disease, these patients will be removed from 
study. Patients in the phase I study will continue  at the study entry dose. Treatment  will be 
interrupted  for grade III or IV non-hematologic  toxicity attributable  to tretinoin or decitabine. 
Therapy may be resumed with the next cycle of treatment as long as the toxicity has decreased to 
< grade 2 within 8 weeks of the last treatment administration.  However, these patients will 
receive a 25% dose reduction in tretinoin or decitabine  (which ever treatment  is suspected or 
both if the attribution is unknown)  when treatment resumes.  All patients will be followed  for 
Serious Adverse Events (SAEs) for 30 days after completion of the last cycle of therapy (each 
cycle is 28 days). 
 
Effects of decitabine and tretinoin on markers of differentiation and apoptosis, and on the 
methylation and expression of various  genes will also be assessed. 
 
Myeloid growth factors will only be allowed in the setting of febrile  neutropenia  according to 
established  guidelines  for use (45). 
 
10.1 
EVALUATION  DURING TREATMENT 
 
10.2 
Safe ty M onitoring: 
 
Weekly while on study: Complete blood count (including differential) 
 
Within 7 days of starting each cycle: CBC, Comprehensive  metabolic  panel, pregnancy test for 
patients with child-bearing potential,  physical exam, assessment of performance  status, 
medications  and adverse events. Patients will be asked to maintain a symptom diary each cycle, 
which will be reviewed prior to starting each subsequent cycle. Patients will keep a tretinoin 
administration log, which will be reviewed with the patient. A pill count will be performed and 
correlated with the patient’s tretinoin administration log to assess compliance  with tretinoin 
administration.  Physical exam and toxicity assessments  may be required more frequently if 
clinically indicated. 
 
10.3 
Te sts for Dise ase Response: 
 
Complete blood count with differential  and smear review prior to start of all treatment  cycles. 


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Bone marrow aspirate and biopsy after even-numbered  cycles (eg., 2, 4, 6, etc). Bone marrow 
aspirate studies for disease assessments  will include  flow cytometry,  cytogenetics,  and 
histochemistry. 
 
10.4 
Re se arch Sample s: 
 
Research samples will be obtained on patients treated in the phase I and the phase II portion of 
this study at the following time points: 
 
(1) Prior to treatment  (during the screening period when screening baseline bone marrow and 
bloodwork is obtained), blood (30 cc in heparin) and bone marrow aspirate (10 cc in heparin) 
will be obtained. 
 
(2) During cycle #1 and cycle # 2, on days 10 and 19, blood (30 cc in heparin) will be obtained 
for research purposes only (blood to be drawn with weekly routine  blood work). 
 
(3) During cycle #1 only, on days 10 and 19, bone marrow aspirate (10 cc in heparin)  will be 
taken for research purposes only. 
 
(4) At the time of scheduled disease assessments  done after cycles 2 and 4, blood (30 cc in 
heparin) and bone marrow aspirate (10 cc in heparin) will be obtained. 
 
10.5 
Re se arch Te sts: 
 
The following research studies will be performed at the time points indicated  in 10.3 when 
feasible: 
 
(1) Bone marrow aspirate and peripheral blood mononuclear  cells will be assessed for the extent 
of DNA methylation using  array-based whole genome methylation analysis(N imbleGen)  (46). 
The expression and methylation status of specific  genes will be analyzed,  focusing on, but not 
necessarily restricted to the following genes involved  in the TGFB signaling pathway: p57, p 21, 
p73,   p15INK4b, TGFβRII, RARβ, and JunB. 
 
(2) Bone marrow aspirate and peripheral blood mononuclear  cells will be analyzed  using gene 
profiling (Affymetrix)  which will be performed by the Core Facility Laboratory. 
 
(3) Bone marrow aspirates and peripheral blood mononuclear  cells will be analyzed  by flow 
cytometry for evidence of differentiation using fluorescein isothiocyanate  (FITC) - conjugated  or 
phycoerythrin  (PE)-conjugated  monoclonal antibodies:  CD16, CD11b, CD33, CD13, HLA-DR, 
CD34, CD45 and CD14. Combinations  to be examined  to assess for differentiation include 
CD33-PE and CD34-FITC, CD33-PE and CD11b-FITC, CD13-PE and CD34-FITC or CD11b- 
PE and CD34-FITC. Apoptosis will be assayed using flow cytometry and dual staining with 
Annexin V-PE and 7-AAD. 


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11.1 
TOXICITIES/SIDE  EFFECTS 
 
11.2 
Expe cte d Side Effe cts of De citabine 
 
Common – Myelosuppression,  nausea, vomiting. 
Uncommon  – Diarrhea, fever, anorexia,  abdominal pain, mucositis,  alopecia. 
Rare – Death. 
 
11.3 
Expe cte d Side Effe cts of Tre tinoin 
 
Common – Headache; dryness, scaling or flaking of skin; dry mouth and mucous membranes; 
cracking of lips; hyperlipidemia. 
Uncommon  – Increase in hepatic transaminases;  hypercalcemia;  nausea and vomiting; 
Rare – Pancreatitis 
 
11.4 
Adve rse Eve nt Re porting 
 
Adverse events will be followed  after the patient has received their first dose of therapy on this 
trial, and will continue  until 30 days after the completion of the last cycle of therapy. Toxicity 
will be graded and recorded using the NCI Common Toxicity  Criteria version 2.0, to allow the 
use of the “leukemia” scale for grading hematologic  toxicity. 
 
Clinically significant  adverse events will be noted and compared to the baseline  condition. 
Adverse events that will be noted will include  expected side effects, and any other clinically 
significant  symptom or laboratory value. An assessment will be made concerning the severity of 
the event, and if the event appears to be related to the study drug(s). Adverse events, toxicity 
grading,  and attributions  will be recorded in the CRDB by the RSA after review of the data by 
the Principal Investigator.  Hematologic  toxicity willl      be graded using the “leukemia” grading 
scale in the NCI CTC version 2.0. 
 
11.5 
Se rious Adve rse Eve nt (SAE) Re porting 
 
An SAE is defined as any adverse effect occurring in a patient receiving the study drug(s) that 
results in the following: 


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• Death 
• A life-threatening illness  or abnormality 
• Hospital admission or prolongation of pre-existing hospitalization 
• Persistent or debilitating  disability 
• Birth defect 
Please refer to Section 17.2 and 17.2 for further SAE reporting guidelines. 
 
11. 5 
Establishment of Maximum Tolerated Dose (MTD) 
 
In the phase I portion of this study, the MTD of tretinoin will be determined  (within the range of 
15 mg/m2  - 85 mg/m2) when given in combination with decitabine. At least three patients will 
be treated at each dose level, starting with 45 mg/m2/day,  which is 30% of the MTD (in a phase I 
MTD of tretinoin monotherapy in MDS patients, the MTD was 150 mg/m2/day when given daily 
for 6 weeks (34)). Additional dose levels will be tested as follows: 65 mg/m2/day and 85 
mg/m2/day. 
 
A dose-limiting toxicity is defined as a grade III or IV non-hematologic  toxicity (NCI CTC, ver. 
2.0). If at any dose level one patient experiences grade III or IV non-hematologic  toxicity 
(according to the NCI CTC version 2.0) attributable  to tretinoin,  three additional patients will be 
added to that dose level. If a second patient experiences grade III or IV non-hematologic  toxicity, 
the dose level below will be considered the MTD, which is defined as the dose level below that 
which produces Grade III/IV non-hematologic  toxicity in ≥ 33% of patients. 
 
If a DLT is experienced at 45 mg/m2/day and is attributable  to tretinoin,  a dose de-escalation 
schema will be employed (see section 9.0) to determine  the MTD below 45 mg/m2/day. 
 
If no DLT is seen after the 85 mg/m2/day dose level is complete, the phase II portion will 
proceed using tretinoin at a dose of 85 mg/m2/day.  However, once the MTD is established,  a 
total of 6 patients will be treated at that level to confirm the MTD before proceeding to the phase 
II portion of the study. 
 
 
 
12.1 
CRITERIA FOR THERAPEUTIC  RESPONSE/OUTCOME  ASSESSMENT 
 
Response will be determined  by the MDS International Working Group criteria  (47). 
 
12.2 
Comple te Re mission (CR) 
 
Bone marrow evaluation:  Repeat bone marrow showing  5% or less myeloblasts  with 


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normal maturation of all cell lines.  Persistent  dysplasia will be noted. (*) 
 
Peripheral Blood:  Absolute values must last at least 1 months. In some circumstances,  protocol 
therapy may require the initiation of further treatment  before the 1 month period. Such patients 
can be included  in the response criteria  into which they fit at the time therapy is started. 
Transient cytopenias during repeated chemotherapy courses should not be considered as 
interrupting durability of response, as long as they recover to the improved counts of the 
pervious course. 
 
Hgb > 11 g/dL (untransfused,  patient not on erythropoietin) 
Neutrophils  > 1500/mm3 or more (not on myeloid  growth factor) 
Platelets > 100,000/mm3 or more (not on thrombopoietic  factor) 
Blasts 0% 
 
(*) Dysplastic  changes should consider the normal range of dysplastic  changes (modification). 
 
12.3 
Partial Re mission (PR) 
 
Absolute values must last at least 1 months unless  interrupted  by therapy as described above. 
All the CR criteria  (if abnormal before treatment)  except: 
Bone marrow evaluation:  Blasts decreased by 50% or more over pretreatment,  but  still more 
than 5 %.. Cellularity and morphology are not relevant 
 
12.3 
Marrow CR 
 
Bone Marrow: 5% myeloblasts  or less and decrease by 50 % or greater over pretreatment. 
Peripheral Blood: if HI responses, they will be noted in addition to marrow CR 
12.4 
Stable Dise ase 
 
Failure to achieve at least a PR, but with no evidence of progression for at least 2 months 
 
12.5 
Failure 
 
Death during treatment or disease progression characterized  by worsening of 
cytopenias, increase in the percentage of bone marrow blasts, or progression to an 
MDS FAB subtype more advanced than pretreatment. Progression to AML (30% 
or more bone marrow blasts) 


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12.6 
Re lapse afte r CR or PR 
 
One or more of the following: 
a) Return to pretreatment  bone marrow blast percentage 
b) Decrement of 50% or greater from maximum  remission / response levels  in 
granulocytes  or platelets 
c) Reduction in hemoglobin concentration by at least1.5 g/dL or new/recurrent 
transfusion dependence (in the absence of another explanation such as treatment 
effect, acute infection,  gastrointestinal  bleeding,  hemolysis  and so on) 
 
12.7 
Dise ase Progre ssion 
 
a) For patient with less than 5% blasts: a 50% or more increase in blasts to more than 
5% blasts 
b) For patients with 5% to 10% blasts: a 50% or more increase to more than 10% blasts. 
c) For patients with 10% to 20% blasts: a 50% or more increase to more than 20% blasts 
d) For patients with 20% to 30% blasts: a 50% or more increase to more than 30% 
blasts. 
e) One or more of the following: 50% or greater decrement from maximum 
remission/response  levels in granulocytes  or platelets, reduction in hemoglobin 
concentration by at least 2 g/dL, or transfusion dependence (in absence of another 
explanation such as acute infection,  G.I. bleeding,  hemolysis  etc.) 
 
12.8 
He matologic Improve me nt  (HI) 
 
Improvements must last at least 2 months in the absence of ongoing cytotoxic therapy. When 
protocol therapy requires the initiation of further treatment before the 2 month period, patients 
can be included  in the response criteria  into which they fit at the time therapy is started. 
 
Hematologic  improvement  should be described by the number of individual,  positively affected 
cell lines (eg, HI-E; HI-E + HI-N; HI-E + HI-P + HI-N). 
 
1. Erythroid  response (HI-E) 
For patients with pretreatment  hemoglobin less than 11g/dL: greater than 1.5 g/dL increase in 
hemoglobin,  relevant  reduction of units of RBC transfusions  by an absolute number of at least 4 
RBC/8wk compared with the pretreatment  transfusion number in the pervious 8 wk. (*) 
 
(*) Only RBC  transfusions  given for Hgb > 9.0 g/dL pretreatment  will count in the RBC 
transfusion response evaluation. 
 
2. Platelet response (HI-P) 


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For patients with a pretreatment platelet  count less than 100 000/mm³: an absolute increase of 30 
000/mm³ or more for patients  starting  with more than 20 000/mm3  platelets,  an increase from 
less than 20 000/mm3  to greater than 20 000/mm3, and by at least 100%. 
 
3. Neutrophil response (HI-N) 
For patients with pretreatment  neutrophil count less than 1 000/mm3: 
at least a 100% increase 
and an absolute increase of more than 500mm³. 
 
4. Progression/relapse  after HI 
One or more of the following: A 50% or greater decrement from maximum  response levels in 
granulocytes  or platelets, a reduction in hemoglobin concentration by at least 1.5 g/dL, or 
transfusion dependence (in the absence of other explanation,  such as hemolysis,  hemorrhage, 
etc). 
 
 
 
13.0 
CRITERIA FOR REMOVAL FROM STUDY 
 
13.1 
Progressive  disease and transformation to acute leukemia   (Response criteria are defined 
in section 12.0) 
13.2 
Failure to achieve at least a PR after 6 cycles of treatment 
13.3 
Unacceptable toxicity defined as grade III or IV non-hematologic  toxicity requiring 
greater than 8 weeks to return to < grade 2 (NCI CTC version 2.0). 
13.4 
Patient’s withdrawal of consent for any reason 
13.5 
Patient non-compliance  with the treatment and monitoring plan 
13.6 
Patient death 
 
 
 
14.1 
BIOSTATISTICS 
 
Phase I Compone nt:   The following design will be used to determine  the maximum  tolerated 
dose (MTD) of tretinoin in combination with decitabine.   Three dose levels of tretinoin will be 
investigated  (45 mg/m2/day,  65 mg/m2/day,  and 85 mg/m2/day).   Patients will be treated in 
cohorts of size three to six and the dosage will be escalated if the clinical  toxicity is acceptable. 
Dose-limiting toxicity (DLT) is defined as a grade 3-4 non-hematologic  toxicity observed within 
the first cycle of treatment.   The design is constructed to reduce the chance of escalating the dose 
when the probability of DLT is high, and increase the chance of escalating the dose when the 
probability of DLT is low.  The maximum tolerated dose is defined as the highest  dose level with 
an observed incidence  of DLT in no more than one out of six patients treated at a particular  dose 
level.  The dose escalation scheme is as follows: 


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1) If none of initial three patients at a given dose level experience DLT, the next dose 
level is studied in another cohort of three patients. 
 
2) If one of the initial three patients at a given dose level experience  DLT, up to three 
additional patients will be treated at that same dose level.  Escalation will continue  if 
one of the six patients experience  DLT. 
 
3) If two or three patients experience DLT in the first three patients, or two or more 
patients experience DLT in six patients at a given dose level, the MTD will be 
determined  as the preceding dose level. 
 
4) If three or fewer patients  are treated at a dose under consideration as the MTD, 
additional patients to total six will be treated at that level to confirm MTD 
 
The dose escalation scheme provides the following probabilities of escalation based on the true 
chances of DLT at a specific dose level. One can see that the probability of escalation is high if 
the toxicity risks are low. 
 
True Probability of Toxicity: 
.10 
.20 
.30 
.40 
.50 
.60 
Probability of Escalation: 
.91 
.71 
.49 
.31 
.17 
.08 
 
If 2 patients experience  DLT at the first dose level (45 mg/m2/day),  a dose de-escalation scheme 
will be employed, testing doses of 30 mg/m2/day and 15 mg/m2/day.  Cohorts of three to six 
patients will be treated at each dose level, if necessary. 
A minimum of two and a maximum of 18 patients could be treated in this portion of the trial. At 
the end of this study, the phase II component of the trial will begin at the MTD determined. The 
six patients treated at the MTD will be included  as part of the phase II component of the trial. 
 
Phase II Compone nt:   The primary objective of the phase II component of the trial is to 
determine  the response rate (defined as Complete Remission or Partial Remission)  to the 
combination of decitabine  and tretinoin (with tretinoin administered  at the MTD from the phase I 
component above) in patients with myelodysplastic  syndromes.   A Simon minimax two-stage 
design will be utilized,  in which a 10% response rate is considered not promising,  a 25% 
response rate is considered promising,  and the probabilities  of a type I error (falsely accepting a 
non-promising therapy) and type II error (falsely rejecting a promising therapy) are set at 0.10 
and 0.10, respectively. 
 
In the first stage of this design, 27 patients will be accrued.  If at least 3 patients achieve a 
complete remission or partial remission among these 27 patients, then an additional 13 patients 
will be accrued to the second stage.  If two or fewer responses are seen, the study will be 
terminated  and declared negative. At the end of the trial, the combination will be considered 


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worthy of further study if 7 or more responses are observed out of 40 patients. This design yields 
at least a 0.90 probability of a positive result if the true response rate is at least 25% and yields a 
0.90 probability of a negative  result if the true response rate is 10%. 
 
Additionally,  secondary objectives will be examined  in patients enrolled  into phase I and phase 
II components of the trial. The proportion of Hematologic  Improvements  will be recorded.  The 
frequency of transfusions,  bleeding and infections  will be summarized. Peripheral blood and 
bone marrow aspirate mononuclear  cells will be assessed for the extent of DNA methylation 
using PCR based technologies.   The expression and methylation status of specific  genes will be 
analyzed,  focusing on, but not necessarily restricted to the following genes: p57, p 21, p73, 
p15INK4b, TGFβRII, RARβ, and JunB. In this study we willl      examine  whether methylation of 
these genes (yes/no) as well as flow cytometric  indicators  of differentiation and apoptosis, 
correlate with response to treatment.  Associations  will be examined  using a Fishers exact test. 
These analyses are exploratory and hypothesis- generating. 
 
In addition,  bone marrow and blood mononuclear  cells will be analyzed  using gene profiling 
(Affymetrix).   In order to attempt to identify  genes that are most affected by treatment,  a paired 
sample t-test will be used to rank the genes.  Samples pre and post chemotherapy will be paired 
together and a fold change will be computed for each pair. The log of the fold change will then 
be used and genes will be scored by how large and consistent  the fold change is among the 
patients. To deal with issues of non-normality of the signal levels p-values will be computed 
using a permutation algorithm which shuffles  the sample labels and recomputes the t-score. To 
correct for multiple  testing the False Discovery Rate (FDR) method will be used to compute rate 
of false positives.  Due to the two-stage design, and uncertainty regarding the rate of disease 
response, the exact number of samples that will be included  in the microarray analysis  is 
unknown. 
 
Frequencies of toxicities  based on the NCI Common Toxicity Criteria version 2.0 will be 
tabulated. 
 
A minimum  of 27 patients (including 6 patients from the phase I component) and a maximum  of 
40 patients will be accrued to the phase II component of this trial.  Approximately 3-4 patients 
will be accrued per month, and hence, the trial will be completed in approximately 2 years. 
 
 
 
15.1 
PATIENT REGISTRATION AND RANDOMIZATION PROCEDURES 
 
15.2 
Patie nt Re gistration 
 
Confirm eligibility as defined in the section entitled  Criteria for Patient/Subject 
Eligibility. 


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Obtain informed  consent, by following procedures defined  in section entitled  Informed 
Consent Procedures. 
 
During the registration process registering individuals  will be required to complete a 
protocol specific  Eligibility Checklist. 
All participants  must be registered through the Protocol Participant  Registration (PPR) 
Office at Memorial Sloan-Kettering Cancer Center. PPR is available  Monday through 
Friday from 8:30am – 5:30pm at 646-735-8000. The PPR fax numbers are (646) 735- 
0008 and (646) 735-0003. Registrations  can be phoned in or faxed. The completed 
signature  page of the written consent/verbal script and a completed Eligibility Checklist 
must be faxed to PPR. 
 
 
 
16.1 
DATA  MANAGEMENT ISSUES 
 
A Research Study Assistant (RSA) will be assigned to the study.  The responsibilities  of the RSA 
include  project compliance,  data collection,  abstraction and entry, data reporting,  regulatory 
monitoring,  problem resolution and prioritization,  and coordinate the activities  of the protocol 
study team. 
 
The data collected for this study will be entered into a secure database Clinical  Research 
Database (CRDB).  Source documentation will be available  to support the computerized  patient 
record. 
 
16.2 
Quality Assurance 
 
Weekly registration reports will be generated to monitor  patient accruals and completeness  of 
registration data.  Routine data quality reports will be generated to assess missing data and 
inconsistencies.   Accrual rates and accuracy of evaluations  and follow-up  will be monitored 
periodically throughout  the study period and potential problems will be brought to the attention 
of the study team for discussion and action. 
 
Random-sample  data quality and protocol compliance  audits will be conducted by the study 
team, at a minimum of two times per year, more frequently if indicated. 
 
16.3 
Data and Safe ty M onitoring 
 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan-Kettering Cancer Center were 
approved by the National Cancer Institute  in September 2001. The plans address the new 


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policies  set forth by the NCI in the document entitled  “Policy of the National Cancer Institute  for 
Data and Safety Monitoring of Clinical Trials” which can be found at: 
 
http://cancertria ls. nc i. nih. go v/resea rc hers/dsm/inde x. html. 
The DSM Plans at MSKCC were 
established  and are monitored  by the Office of Clinical Research.  The MSKCC Data and Safety 
Monitoring Plans can be found on the MSKCC Intranet at: 
http://msk web2.msk cc.org/irb/index .htm 
 
There are several different  mechanisms  by which clinical  trials are monitored  for data, safety and 
quality.   There are institutional  processes in place for quality assurance (e.g., protocol 
monitoring,  compliance  and data verification audits, therapeutic  response, and staff education on 
clinical research QA) and departmental procedures for quality control,  plus there are two 
institutional committees  that are responsible  for monitoring the activities  of our clinical  trials 
programs.  The committees:  Data and Safety Monitoring Committee (DSMC) for Phase I and II 
clinical trials, and the Data and Safety Monitoring Board (DSMB) for Phase III clinical trials, 
report to the Center’s Research Council and Institutional Review Board. 
 
During the protocol development  and review process, each protocol willl      be assessed for it’s level 
of risk and degree of monitoring required.  Every type of protocol (e.g., NIH sponsored, in-house 
sponsored, industrial sponsored, NCI cooperative group, etc.) Will be addressed and the 
monitoring procedures will be established  at the time of protocol activation. 
 
 
 
 
17.1 
PROTECTION  OF HUMAN SUBJECTS 
 
Pote ntial Risks: Based on prior clinical trials (for decitabine,  tretinoin)  and post-marketing 
surveillance  (tretinoin),  the following adverse events can be expected: 
 
Decitabine: 
Common – Myelosuppression,  nausea, vomiting. 
Uncommon  – Diarrhea, mucositis,  abdominal pain, anorexia, seizures,  alopecia, fever. 
Rare – Death. 
 
Tretinoin: 
Common – Headache; dryness, scaling or flaking of skin; dry mouth and mucous membranes; 
cracking of lips; hyperlipidemia. 
Uncommon  – Increase in hepatic transaminases;  hypercalcemia;  nausea and vomiting; 
Rare – Pancreatitis 


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Be ne fits:  Decitabine  has been administered  to patients with myelodysplastic  syndromes (MDS) 
in phase II studies where the overall response rate was ~ 50%. A phase III study was performed 
that compared decitabine  on a three day schedule compared to best supportive  care. That trial 
showed a 15% response rate (compared to a 0% response rate for the supportive  care arm) with 
an 8% complete response rate. Responders had a prolonged survival  and reduced risk of AML 
transformation,  and this was significant  in the IPSS high-risk  cohort. A recent small phase II 
study showed that a 5-day regimen of 20 mg/m2/day every 28 days produced 40% complete 
responses, which is the schedule that will be used in this study. The rationale  for the current  
study is that the addition of tretinoin to decitabine  may improve the response rate and increase  
the CR rate in patients with MDS over treatment with decitabine alone. 
 
Alte rnative s:  The standard treatment for patients with MDS who are not candidates for an 
allogeneic  stem cell transplant  is Supportive Care or 5-azacytidine.  Other alternatives  include 
treatment with other agents in other clinical trials. 
 
Ince ntive s:  Participation in this trial is voluntary.  No incentive,  financial or otherwise,  will be 
offered in exchange for participation in this study. 
 
Financial Conside rations:  All standard tests, physician visits,  and hospitalization for treatment 
and management  of treatment/disease  complications  will be billed  to the patient and their 
insurance  company. Both tretinoin and decitabine will be billed  to the patient and their insurance 
company. . 
 
17.2 
Privacy 
 
MSKCC’s Privacy Office may a lllow the use and disclosure of protected health information 
pursuant to a completed and signed Research Authorization form.  The use and disclosure  of 
protected health information will be limited  to the individuals  described in the Research 
Authorization form.  A Research Authorization form must be completed by the Principal 
Investigator  and approved by the IRB and Privacy Board. 
 
 
 
17.3 
Serious Adverse Event (SAE) Reporting 
A 
Any SAE must be reported to the IRB/PB as soon as possible but no later than 5 calendar days. 
The IRB/PB requires a Clinical Research Database (CRDB) SAE report be submitted 
electronically to the SAE Office at sae@mskcc.org containing the following information: 
 
 
Fields populated from the CRDB: 


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• Subject’s name 
• Medical record number 
• Disease/histology  (if applicable) 
• Protocol number 
Data needing to be entered: 
• The date the adverse event occurred 
• The adverse event 
• Relationship  of the adverse event to the treatment  (drug, device, or intervention) 
• If the AE was expected 
• The severity of the AE 
• The intervention 
• Detailed text that includes  the following information: 
o A explanation of how the AE was handled 
o A description of the subject's condition 
o Indication if the subject remains on the study 
o If an amendment  will need to be made to the protocol and/or consent form 
The PI’s signature  and the date it was signed are required on the completed report. 
 
 
18.1 
INFORMED CONSENT PROCEDURES 
 
Before protocol-specified  procedures are carried out, consenting professionals  will 
explain full details of the protocol and study procedures as well as the risks involved  to 
participants  prior to their inclusion in the study. Participants  will also be informed  that 
they are free to withdraw  from the study at any time. All participants  must sign an 
IRB/PB-approved consent form indicating their consent to participate.  This consent form 
meets the requirements  of the Code of Federal Regulations  and the Institutional Review 
Board/Privacy Board of this Center. The consent form will include  the following: 
1. The nature and objectives, potential risks and benefits of the intended study. 
2. The length of study and the likely  follow-up required. 
3. Alternatives to the proposed study. (This will include  available standard and 
investigational  therapies. In addition,  patients will be offered an option of supportive care 
for therapeutic studies.) 
4. The name of the investigator(s) responsible for the protocol. 
5. The right of the participant to accept or refuse study interventions/interactions  and to 
withdraw from participation  at any time. 
Before any protocol-specific  procedures can be carried out, the consenting professional 
will fully explain the aspects of patient privacy concerning research specific  information. 


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In addition to signing the IRB Informed Consent, all patients must agree to the Research 
Authorization component of the informed  consent form. 
Each participant  and consenting professional will sign the consent form. The participant 
must receive a copy of the signed informed  consent form. 


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19.0 
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20.1 
APPENDICES 
 
Appendix I:  The International Prognostic Scoring System (2) 
 
BM Blast % 
<5% 
0.0 
5-10% 
0.5 
11-20% 
1.5 
21-30% 
2.0 
Cytogenetic s 
Good Risk [-Y, del(5q),del(20q), normal] 
0.0 
Intermediate  Risk [8+, other] 
0.5 
Poor Risk [Ch 7 abn., > 3 abnormalities] 
1.0 
 
Cytopenias   
0-1 cytopenia 
0.0 
2-3 cytopenias 
0.5 


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Cytopenias: ANC < 1.5, HGB < 10.0, PLT < 100,000 
 
 
 
 
 
Calculating the IPSS Score and determining the IPSS risk category: 
 
Using the table above, total the scores obtained for the three individual categories (i.e., 
cytopenias, cytogenetics  and bone marrow blast count). 
 
Depending on the total score, the patient is determined  to have IPSS Low, Intermediate-1, 
Intermediate-2, or High risk MDS. 
 
Total IPSS score of 0 = Low Risk 
Total IPSS score of 0.5-1.0 = Intermediate-1 Risk 
Total IPSS score of 1.5-2.0 = Intermediate-2 Risk 
Total IPSS score of > 2.5 =  High Risk 
 
 
 
 
Appendix II: French-American-British (FAB) Criteria for MDS 
 
Five subtypes of MDS are recognized in the FAB classification system. These 
subtypes are distinguished by the percentage of myeloblasts, presence or absence 
of ringed sideroblasts, or a monocytosis as summarized in the following table: 
 
FAB Category 
Myeloblast  % 
% Ringed  Sideroblasts 
Bone Marrow 
Monocytes>1x 109/L 
Peripheral Blood 
Bone 
Marrow 
Peripheral 
Blood 
Refractory Anemia 
(RA) 
<5 
<1 
<15 
- 
RA with ringed 
sideroblasts 
(RARS) 
<5 
<1 
>15 
- 
RA with excess 
blasts (RAEB) 
5-20 
<5 
Variable 
- 


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Chronic 
Myelomonocytic 
leukemia (CMML) 
<20 
<5 
Variable 
- 
RAEB in 
transformation 
(RAEB-t) 
21-30 or 
Auer 
rods 
present 
Auer rods 
present 
Variable 
+/- 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix III: Tretinoin Med Log 


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TRETINOIN MEDLOG 
# OF 
PILLS 
TIME 
TAKEN 
# OF 
PILLS 
TIME 
TAKEN 
INT 
1 
MON 
2 
TUES 
3 
WED 
4 
THUR 
5 
FRI 
6 
SAT 
7 
SUN 
8 
MON 
9 
TUES 
10 WED 
AM 
PM 
AM 
PM 
11 THUR 
AM 
PM 
AM 
PM 
12 FRI 
AM 
PM 
AM 
PM 
13 SAT 
AM 
PM 
AM 
PM 
14 SUN 
AM 
PM 
AM 
PM 
15 MON 
AM 
PM 
AM 
PM 
16 TUES 
AM 
PM 
AM 
PM 
17 WED 
AM 
PM 
AM 
PM 
18 THUR 
AM 
PM 
AM 
PM 
19 FRI 
AM 
PM 
AM 
PM 
20 
SAT 
21 
SUN 
22 
MON 
23 
TUES 
24 
WED 


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25 
THUR 
26 
FRI 
27 
SAT 
28 
SUN 
Please complete this diary on a daily basis.  Write in the number of capsules of Tretinoin you took 
and the time you took them in the appropriate date box. On the days that you do not take any 
capsules, please write “0.”  If you forget to take your daily dose, please write “0”, but remember to 
take your prescribed dose at the next regularly scheduled time 
Tretinoin Dose Level: ____ mg (  __ 10mg pills 
+ __  5mg pill ) 
PROTOCOL 06-054: CYCLE 1 
HEALTH PROBLEMS/MEDICAL COMPLAINTS: 
Please record ALL Health Problems/Medical Complaints  you experience below 
 
Please describe what you experienced 
Start Date 
Stop Date 
1. 
2. 
3. 
4. 
5. 
6. 
7. 
8. 
9. 
 
OTHER MEDICATIONS: 
Please record ALL medication other than tretinoin 
Including:  prescription,  over-the-counter, herbal, and vitamins 
 
Medication 
Why did you take this medication? 
Start Date 
Stop Date 
1. 
2. 
3. 
4. 


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5. 
6. 
7. 
8. 
9. 
* If you have any questions, please call Dr. Rampal’s office at 646-608-3746. 


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Appendix IV: Schema 
 
 
Pre- 
treatment 
Cycle 1 (Subsequent Odd Cycles) 
Cycle 2 (Subsequent Eve n Cycles) 
Within 
30days 
Within 
7days 
Week1 
Day 1-7 
Week2 
Day 8-14 
Week3 
Day15-21 
Week4 
Day22-28 
Week1 
Day 1-7 
Week2 
Day 8-14 
Week3 
Day15-21 
Week4 
Day21-28 
Decitabine 
Day1-5 
Day1-5 
Tretinoin 
Day 10 – Day 19 
Day 10 – Day 19 
Informed  Consent 
X 
Inclusion/Exclusion   Criteria 
X 
Physical Exam 
X 
X 
X 
Medical  History 
X 
KPS 
X 
X 
X 
IPSS 
X3 
Fab  Classification 
X 
EKG 
X 
Comp 
X 
X 
X 
CBC - differential  & smear 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Reticulocyte  Count 
X 
B HCG  (if applicable) 
X 
X 
X 
Basic Metabolic  Panel 
X 
X 
Height/Weight/BSA 
X 
Vital Signs 
X 
Prior Medications 
X 
X 
X 
Transfusion  Requirements 
X 
PT/PTT 
X 
DNA  Methylation/Array/ Flow 
on Blood (30 cc in heparin) 
X 
Day101
 
Day191
 
Day101
 
Day191
 
X 
DNA  Methylation/Array/ Flow 
on BM (10 cc in heparin) 
X 
Day102 
Day192 
X 
Routine  Disease Assessment: 
BMbx,  BMA,  Cytogenetics, 
X 
X 
Pill Count 
X 
X 
Diary Card Check 
X 
X 
Adverse  Events 
X 
X 
 
1 Day 10 & Day 19 Research Blood Sample collected only in Cycle 1 & Cycle 2. 
- Day 10 Blood Sample: after completing decitabine, but prior to first dose of tretinoin 
- Day 19 Blood Sample: after completion of tretinoin. 
2 Day 10 & Day 19 Research Bone Marrow Aspirate Sample collected only in Cycle 1 
- Day 10 Bone Marrow Aspirate Sample: after completing decitabine, but prior to first dose of tretinoin 
- Day 19 Bone Marrow Aspirate Sample: after completion of tretinoin 
3Baseline IPSSscore needs to be determined to be >0.5 within 30 days of the initiation of decitabineand tretinoin. Bone marrow 
cytogenetic results do not need to be resulted at thetime of registration if the IPSSscore is >0.5 by other criteria.