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cenersen IV infusion 0.3 mg/kg/day (0.1 mg/kg/h x 3 h x 4 days) for 6 cycles Administration of study drug will be over 4 consecutive days at the outset of each 28 day cycle for a total of 6 cycles for each patient. Dexamethasone 20 mg po weekly can be added after week 16 if stable disease but no Hematologic Improvement (HI) is observed.

cenersen IV infusion 0.6 mg/kg/day (0.2 mg/kg/h x 3 h x 4 days) for 6 cycles Administration of study drug will be over 4 consecutive days at the outset of each 28 day cycle for a total of 6 cycles for each patient. Dexamethasone 20 mg po weekly can be added after week 16 if stable disease but no HI is observed.

cenersen IV infusion 1.2 mg/kg/day (0.4 mg/kg/h x 3 h x 4 days) for 6 cycles Administration of study drug will be over 4 consecutive days at the outset of each 28 day cycle for a total of 6 cycles for each patient. Dexamethasone 20 mg po weekly can be added after week 16 if stable disease but no HI is observed.

cenersen is a phosphorothioate antisense oligonucleotide that down-regulates the production of both wild-type and mutant p53, and has a RNase H-dependent mechanism of action

cenersen

Optionally, Dexamethasone 20 mg po weekly can be added after week 16 if stable disease but no HI is observed.

Rami Komrokji, MD

The purpose of the study is to test the safety of six cycles of cenersen treatment and to begin to test the hypothesis that intermittent administration of cenersen may lead to a reduced dependence on transfusion.

The study is a nonrandomized open-label treatment with varying doses of cenersen by intravenous administration to:

Primary

\*To assess the safety profile and dose limiting toxicities (DLT) of cenersen for each of three increasing dose levels as stipulated by the protocol in patients with lower risk MDS defined as low or intermediate-1 risk by IPSS.

Secondary

* To determine the lowest pharmacologically active exposure from among three increasing dose levels as stipulated by the protocol that exhibits the desired activity on erythropoiesis after evaluation of all dose levels, and
* To determine if intermittent treatment with cenersen will reduce transfusion requirements for patients with lower risk MDS.

A Study of Aezea® (Cenersen) in Transfusion Dependent Anemia Associated With Myelodysplastic Syndrome (MDS)

A Study of Aezea® (Cenersen) in Transfusion Dependent Anemia Associated With Myelodysplastic Syndrome

Assessment of adverse events for each dosing level

Erythroid Response (HI-E) from the lowest pharmacologically active exposure after evaluation of all dose levels - Reduction in RBC transfusions by greater than or equal to 4 units/8 weeks triggered by a hemoglobin transfusion threshold lower than 9 g/dL when compared to the 8 week baseline for transfusion-dependent patients (where transfusion dependence is defined as 4 units or more RBCs in 8 weeks)

Hematologic Improvement by Hb increase by ≥ 1.5 g/dL or more for at least 8 weeks and the patient is not transfusion-dependent.

H. Lee Moffitt Cancer Center and Research Institute

Eleos, Inc.

Cytopenia

Pancytopenia

Hematinics

Micronutrients

Epoetin Alfa

Deferasirox

Iron

Chelating Agents

Iron Chelating Agents

Patients will receive erythropoietin 40,000 units/week. If after 4 weeks erythroid improvement is inadequate, dose will be escalated to 60,000 units/week. If after 12 weeks of treatment, erythroid improvement in inadequate, patients will be switched to the combination arm. At any time when erythroid response is achieved, erythropoietin treatment will be stopped until end of study.

Patients will receive deferasirox dispersible tablet (DT) 10 mg/kg/day or deferasirox film-coated tablet (FCT) 7 mg/kg/day in combination with erythropoietin 40,000 units/week. If after 4 weeks erythroid improvement is inadequate, erythropoietin dose will be escalated to 60,000 units/week. If after 12 weeks of treatment, erythroid improvement in inadequate, patients will be discontinued from the study. At any time when erythroid response is achieved, erythropoietin treatment will be stopped until end of study. Patients will continue deferasirox treatment.

provided as dispersible tablets for oral use in 125 and 250, 500 mg

Deferasirox DFX, DT

Erythropoietin alpha

provided as film-coated tablet for oral use in 90, 180, 360 mg strengths

Deferasirox DFX, FCT

Novartis Pharmaceuticals

The primary purpose of this trial was is to assess the effect of treatment with deferasirox combined with erythropoietin vs. erythropoietin alone on erythropoiesis in patients with low- and int-1-risk myelodysplastic syndrome. The addition of deferasirox to erythropoietin can lead to a potential synergism with the reduction of reactive oxygen species, through both the NF-kB pathway and the control of free toxic iron. This may create a better environment in the bone marrow for a better response with erythropoietin.

This study was designed to test in a prospective way the combination of deferasirox with erythropoietin in terms of their effect on hematopoiesis.

This study did not meet the original enrollment objective of 60 patients and was terminated without extending enrollment past original planned LPFV of 31-Oct-2016.

Combination Study of Deferasirox and Erythropoietin in Patients With Low- and Int-1-risk Myelodysplastic Syndrome.

An Open-label, Phase II, Randomized, Pilot Study to Assess the Effect in Term of Erythroid Improvement of Deferasirox Combined With Erythropoietin Compared to Erythropoietin Alone in Patients With low-and Int-1-risk Myelodysplastic Syndrome.

Difference in percentage of patients achieving an erythroid response within 12 weeks of treatment between the two arms according to modified IWG 2006 criteria increase in hemoglobin (Hb) ≥ 1.5 g/dL. Erythroid response is defined as the increase in Hb from baseline ≥ 1.5 g/dL. Patients achieving erythroid response at least once within 12 weeks were considered responders

Hematological response criteria defined as: Erythroid response: hemoglobin (Hb) increase from baseline \>= 1.5 g/dL (baseline \< 11 g/dL), neutrophil response: increase from baseline \>= 100% and increase \> 0.5 × 10\^9/L (baseline \<1 × 10\^9/L), platelet response: increase from baseline \>= 30 × 10\^9/L (baseline \<100 × 10\^9/L) according to modified IWG 2006 criteria

Percentage of participants achieving an hematologic improvement defined as: neutrophil improvement: increase from baseline \>0.5 × 10\^9/L (baseline = 1.0 × 10\^9/L ), platelet improvement: increase from baseline ≥ 30 × 10\^9/L (baseline = 100 × 10\^9/L), hemoglobin improvement: Hb increase from baseline ≥ 1 g/dL (baseline\<11 g/dL)

Absolute change in hemoglobin values for patients showing improvement: Hemoglobin improvement Hb increase from baseline ≥ 1 g/dL (baseline\<11 g/dL)

Absolute change in platelets and neutrophil levels for participants showing improvement: neutrophil improvement: increase from baseline \>0.5 × 10\^9/L (baseline = 1.0 × 10\^9/L ), platelet improvement: increase from baseline ≥ 30 × 10\^9/L (baseline = 100 × 10\^9/L)

Erythroid response: hemoglobin increase from baseline \> = 1.5 g/dL (baseline \<11 g/dL)

Erythroid response: hemoglobin increase from baseline \> = 1.5 g/dL (baseline \<11 g/dL). Percentages are based on N. Confidence intervals are calculated using Clopper-Pearson method. Hemoglobin value is at time of first response

Absolute change in serum ferritin from baseline

This analysis included patients randomized either to EPO or DFX+EPO at baseline as well as patients who did not have erythroid response at week 12 in the EPO group and switched to combination therapy.

This analysis included patients randomized either to EPO or DFX+EPO at baseline as well as patients who did not have erythroid response at week 12 in the EPO group and switched to combination therapy. The time-course of Hb and its absolute changes from baseline was summarized by descriptive statistics by visit and erythroid response. Patients randomized to EPO and not switching after 12 weeks to EPO+DFX would consist of only responders.

There was no washout period during the study before switch of treatment. Therefore effects (including AEs) from long lasting treatment like EPO can potentially still be observed after the switch, e.g. from EPO+DFX to DFX alone. Thus the resulting includes both treatments (DFX-EPO category). The same applies for staring EPO alone and switching to EPO plus DFX.

Patients receiving EPO during the first 12 weeks and no switching to EPO+DFX arm

EPO A

Patients receiving EPO+DFX from week 1 and continuing with EPO+DFX after 12 weeks or with DFX alone after 12 weeks

EPO+DFX DT

Patients receiving EPO alone and switched to EPO+DFX after 12 weeks of treatment

EPO+DFX FCT

Switched to DFX+EPO After 12 Weeks

Starting dose was erythropoietin 40,000 units/week. If after 4 weeks erythroid improvement was inadequate, dose was escalated to 60,000 units/week. If after 12 weeks of treatment, erythroid improvement was inadequate, participants were switched to the combination arm. At any time when erythroid response was achieved, erythropoietin treatment was stopped until end of study.

Erythropoietin Alpha

Starting dose was deferasirox dispersible tablet (DT) 10 mg/kg/day or deferasirox film-coated tablet FCT) 7 mg/kg/day in combination with erythropoietin 40,000 units/week. If after 4 weeks erythroid improvement was inadequate, erythropoietin dose was escalated to 60,000 units/week. If after 12 weeks of treatment, erythroid improvement was inadequate, participants were discontinued from the study. At any time when erythroid response was achieved, erythropoietin treatment was stopped study and Deferasirox treatment was continued until end of study

Deferasirox + Erythropoietin Alpha

Total

Age, Continuous

Sex: Female, Male

Caucasian

Asian

Race/Ethnicity, Customized

Study Director

Difference in Percentage of Patients Achieving Erythroid Response Within 12 Weeks, by Treatment Group (Full Analysis Set)

Absolute Change From Baseline to Post-baseline Value for Hemoglobin(g/dL)(Full Analysis Set)

Hematologic improvement

Neutropil improvement

Platelet improvement

Hemoglobin improvement

Number of patients who met criteria varied across parameters

Summary of Hematologic Improvement in Patients Randomized to EPO+DFX and EPO Alone, Within 24 Weeks of Treatment (Full Analysis Set)

Absolute Change in Hemoglobin Values up to 24 Weeks

Platelets

Neutrophils

Absolute Change in Platelets and Neutrophil Levels up to 24 Weeks

Patients randomized to EPO alone with inadequate response at 12 weeks who had been switched over to combination EPO+DFX

EPO+DFX (12 Weeks)

Summary of Erythroid Response in Participants Randomized to EPO Alone at Baseline and Switched to EPO+DFX After 12 Weeks of Treatment (Full Analysis Set)

Patients who were in EPO alone group and were not switched to EPO+DFX after 12 weeks,

EPO (24 Weeks)

Summary of Erythroid Response Within 24 Weeks in Participants Randomized to EPO at Baseline and Not Switched to EPO+DFX After 12 Weeks of Treatment (Full Analysis Set)

Responders - Week 5

Responders - Week 9

Responders - Week 13

Responders - Week 17

Responders - Week 21

Non-responders - Week 5

Non-responders - Week 9

Non-responders - Week 13

Number of patients analyzed varied by visit

Absolute Change in Serum Ferritin up to 24 Weeks for Erythropoietin Alpha Arm (Full Analysis Set)

Responders - Week 13|

Non-responders - Week 9|

Non-responders - Week 13|

Non-responders - Week 17

Non-responders - Week 21

Absolute Change in Serum Ferritin up to 24 Weeks for Deferasirox + Erythropoietin Alpha Arm (Full Analysis Set)

EPO+DFX at 12

Absolute Change in Serum Ferritin up to 24 Weeks for EPO+DFX at 12 Weeks Arm (Full Analysis Set)

Absolute Change in Hemoglobin (Hb) From Baseline for Erythropoietin Alpha Arm (Full Analysis Set)

Absolute Change in Hemoglobin (Hb) From Baseline for Deferasirox + Erythropoietin Alpha Arm (Full Analysis Set)

Responders - Week 9|

Responders - Week 17|

Non-responders - Week 17|

This analysis included patients randomized either to EPO or DFX+EPO at baseline as well as patients who did not have erythroid response at week 12 in the EPO group and switched to combination therapy. The time-course of Hb and its absolute changes from baseline was summarized by descriptive statistics by visit and erythroid response. Patients randomized to EPO and not switching after 12 weeks to EPO+DFX would consist of only responders

EPO+DFX at 12 Weeks

Absolute Change in Hemoglobin (Hb) From Baseline for EPO+DFX at 12 Weeks Arm (Full Analysis Set)

Overall Study

Adult subjects with the diagnosis of MDS based on the French-American-British classification system.

Control subjects will be selected using frequency matching on gender and age by decade. That is for each MDS patient a healthy volunteer of the same gender and decade (50-59, 60-69, 70-79, etc) will be selected

Josef T Prchal, MD

The purpose of the study is to elucidate the causative molecular events responsible for the abnormal erythropoiesis in MDS.

Myelodysplastic syndromes are a heterogeneous group of disorders characterized by clonal expansion of hematopoietic stem cells and ineffective hematopoiesis. Although all 3 cell lineages in myeloid hematopoiesis can be involved, the erythroid dysplasia and ineffective erythropoiesis of MDS are usually the most severe, and often precede the development of other bone marrow lineage defects.

In normal erythropoiesis, erythroid progenitors differentiate and proliferate in response to stimulation by erythropoietin (Epo). Epo binds to its receptor, EpoR, constitutively expressed at the surface of committed erythroid progenitors and induces homodimerization. This study is designed to evaluate the EpoR cDNA sequence and its level of expression in the clonal erythroid progenitors of MDS patients (in cells stratified for the same degree of erythroid maturation) to determine whether mutations in the EpoR may be responsible for an aberrant Epo signal transduction in MDS. As well as analyze intrinsic erythroid Epo expression to determine whether it differs between normal controls and patients with MDS and perform a microarray analysis of genes associated with Epo signal transduction to determine if MDS patients have abnormal expression of signal transduction proteins.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Study of Aezea® (Cenersen) in Transfusion Dependent Anemia Associated With Myelodysplastic Syndrome (MDS)	NCT02243124	Myelodysplastic...	cenersen Dexamethasone	18 Years - 95 Years	Eleos, Inc.
Combination Study of Deferasirox and Erythropoietin in Patients With Low- and Int-1-risk Myelodysplastic Syndrome.	NCT01868477	Low and Int 1-r...	Deferasirox DFX... Erythropoietin ... Deferasirox DFX...	18 Years -	Novartis
The Role of Erythropoietin in Myelodysplastic Syndrome	NCT00723112	Myelodysplastic...		18 Years -	University of Utah

Spots Global Cancer Trial Database for erythropoiesis