A Study of JNJ-30979754 (Decitabine) in Patients With Myelodysplastic Syndrome

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to to determine the recommended dose level of JNJ-30979754 (decitabine) as well as to assess the safety and effectiveness in patients with Myelodysplastic Syndrome (MDS).

Detailed Description
-----------------
This is an open-label (both physician and patient know the name and dosage of drug), multi-center study. This study consists of two parts, Phase I and Phase II. In Phase I, approximately 9 participants will be enrolled ie, 3 participants for dose level 1 (15 mg/m2 of JNJ-30979754) and 6 participants for dose level 2 (20 mg/m2 of JNJ-30979754). Once the tolerability of 20 mg/m2 is confirmed additional 30 participants will be included to receive 20 mg/m2 and approximate total participants in Phase II will be 36. This study will include screening period (within 14 days prior to the day of initial administration of Cycle 1) and dosing period (1 cycle consists of administration of study medication for first 5 consecutive days + rested for 23 days; ie, total 28 days). Cycles will be reapeated in participants in whom decitabine was expected to be effective. Safety evaluations will include assessment of adverse events, vital signs, body weight, clinical laboratory tests: hematology, blood biochemistry and urinalysis, cardiopulmonary function tests: ECG, chest X ray and oximeter analysis.

Official Title
-----------------
A Phase I/II Clinical Study of JNJ-30979754 (Decitabine) in Patients With Myelodysplastic Syndrome

Conditions
-----------------
Myelodysplastic Syndrome

Intervention / Treatment
-----------------
* Drug: JNJ-30979754 15 mg/m2
* Drug: JNJ-30979754 20 mg/m2


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Myelodysplastic syndrome (de novo or secondary) fitting any of the recognized French-American-British classifications: refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, chronic myelomonocytic leukemia with white blood cells less than 13,000 /mm3 International Prognostic Scoring System (IPSS) greater than or equal to 0.5 (Intermediate-1, Intermediate-2 or high risk) by bone marrow assessment and bone marrow cytogenetics within 28 days before study registration 20 years or older Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 Normal renal and hepatic function Exclusion Criteria: Acute Myeloid Leukemia (AML) with bone marrow blasts greater than or equal to 30% Participants with a history of high-dose cytarabine (Ara-C) therapy (greater than 1,000 mg/m2/day) Participants administered adrenal cortex hormones or anabolic hormones within 7 days of study initiation Participants who have received a colony stimulating factor (CSF) formulation within 7 days of study initiation Active double cancer Uncontrolled cardiac disease or cognitive heart failure Uncontrolled restrictive or obstructive pulmonary disease Uncontrolled diabetes mellitus Active viral or bacterial infection Known positive serology for Human immunodeficiency virus

Ages Eligible for Study
-----------------
Minimum Age: 20 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase I: JNJ-30979754 15 mg/m2<br>JNJ-30979754 (decitabine) 15 mg/m2 will be administered once daily by 1-hour intravenous infusion from Day 1 to 5 of 4-Week (28-day) Cycle 1 | Drug: JNJ-30979754 15 mg/m2<br>* JNJ-30979754 (decitabine) 15 mg/m2 will be administered once daily by 1-hour intravenous infusion from Day 1 to 5 of 4-Week (28-day) Cycle 1.<br>* Other names: decitabine;|
| Experimental: Phase I: JNJ-30979754 20 mg/m2<br>JNJ-30979754 (decitabine) 20 mg/m2 will be administered once daily by 1-hour intravenous infusion from Day 1 to 5 of 4-Week (28-day) Cycle 1 | Drug: JNJ-30979754 20 mg/m2<br>* Phase I: JNJ-30979754 (decitabine) 20 mg/m2 will be administered once daily by 1-hour intravenous infusion from Day 1 to 5 of 4-Week (28-day) Cycle 1. Phase II: JNJ-30979754 (decitabine) 20 mg/m2 will be administered once daily by 1-hour intravenous infusion from Day 1 to 5 of 4-Week (28-day) cycles until the decitabine was expected to be effective in participants.<br>* Other names: decitabine;|
| Experimental: Phase II: JNJ-30979754 20 mg/m2<br>JNJ-30979754 (decitabine) 20 mg/m2 will be administered once daily by 1-hour intravenous infusion from Day 1 to 5 of 4-Week (28-day) cycles | Drug: JNJ-30979754 20 mg/m2<br>* Phase I: JNJ-30979754 (decitabine) 20 mg/m2 will be administered once daily by 1-hour intravenous infusion from Day 1 to 5 of 4-Week (28-day) Cycle 1. Phase II: JNJ-30979754 (decitabine) 20 mg/m2 will be administered once daily by 1-hour intravenous infusion from Day 1 to 5 of 4-Week (28-day) cycles until the decitabine was expected to be effective in participants.<br>* Other names: decitabine;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase II: Overall Remission Rate (ORR): Number of Participants Who Achieved Complete Remission (CR)+Partial Remission (PR) - as Per International Working Group (IWG) Response Criteria (2000) | IWG response criteria (2000) - CR: bone marrow evaluations show < 5% blasts; no dysplasia; normal maturation of all cell lines and peripheral blood shows hemoglobin ≥ 11 g/dL; neutrophils ≥ 1,500/mL; platelets ≥ 100,000/mL; 0% blasts; no dysplasia and PR: same as CR, except blasts decrease by ≥ 50% or lower French-American-British (FAB) classification of Myelodysplastic Syndromes. | Up to 1 years after the last participant enrolled | 
| Phase I and II: Number of Participants Who Experienced Adverse Events |  | Up to 1.5 years after the last participant enrolled | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase I: Maximum Observed Plasma Concentration of Decitabine (Cmax) |  | Before dosing (Pre-dose), 30 min, 60 min (end of infusion), 65 min, 75 min, 90 min, 120 min, 180 min, 240 min after the start of decitabine infusion on Day 1 and Day 5 of 28-Days Cycle 1 | 
| Phase I: Area Under the Plasma Concentration-time Curve (AUC) | Area under the curve from time zero to extrapolated infinite time (AUC Infinity) and area under the curve from time zero to last quantifiable concentration (AUC Last). | Before dosing (Pre-dose), 30 min, 60 min (end of infusion), 65 min, 75 min, 90 min, 120 min, 180 min, 240 min after the start of decitabine infusion on Day 1 and Day 5 of 28-Days Cycle 1 | 
| Phase I: Number of Participants Who Achieved Complete Remission (CR)+Partial Remission (PR)+Hematological Improvement (HI) - as Per International Working Group (IWG) Response Criteria (2000) | IWG response criteria (2000) - CR: bone marrow evaluations (mCR) show < 5% blasts; no dysplasia; normal maturation of all cell lines and peripheral blood shows hemoglobin ≥ 11 g/dL; neutrophils ≥ 1,500/mL; platelets ≥ 100,000/mL; 0% blasts; no dysplasia; PR: same as CR, except blasts decrease by ≥ 50% or lower French-American-British (FAB) classification of Myelodysplastic Syndromes; HI: hemoglobin < 11 g/dL (erythroid); platelet < 100,000/mL; neutrophils < 1,000/mL. | Up to 28 Days of treatment Cycle 1 | 
| Phase II: Median Time to Remission | Median time required for the participants to achieve remission (complete remission+partial remission). | Up to 1.5 years after the last participant enrolled | 
| Phase II: Median Time to Improvement | Median time required for the participants to achieve overall improvement (complete remission+partial remission+hematologic improvement) | Up to 1.5 years after the last participant enrolled | 
| Phase II: Median Duration of Remission | Median time duration for which participants achieved remission (complete remission+partial remission). | Up to 1.5 years after the last participant enrolled | 
| Phase II: Median Duration of Overall Improvement | Median time duration for which participants achieved overall improvement (complete remission+partial remission+hematologic improvement). | Up to 1.5 years after the last participant enrolled | 
| Phase II: Overall Improvement Rate: Number of Participants Who Achieved Complete Response (CR)+Partial Response (PR)+Hematological Improvement (HI) - as Per International Working Group (IWG) Response Criteria (2000) | IWG response criteria (2000) - CR: bone marrow evaluations (mCR) show < 5% blasts; no dysplasia; normal maturation of all cell lines and peripheral blood shows hemoglobin ≥ 11 g/dL; neutrophils ≥ 1,500/mL; platelets ≥ 100,000/mL; 0% blasts; no dysplasia and PR: same as CR, except blasts decrease by ≥ 50% or lower French-American-British (FAB) classification of Myelodysplastic Syndromes. HI: hemoglobin < 11 g/dL (erythroid); platelet < 100,000/mL; neutrophils < 1,000/mL. | Up to 1.5 years after the last participant enrolled | 
| Phase II: Number of Participants With Cytogenic Response - as Per International Working Group (IWG) Response Criteria 2000 (Major/Minor) and IWG 2006 (Complete/Partial) | IWG 2000 - Major: disappearance of cytogenetic abnormality; Minor: 50% or more reduction in abnormal metaphases. IWG 2006 - Complete: disappearance of the chromosomal abnormality without appearance of new ones; Partial: At least 50% reduction of the chromosomal abnormality. | Up to 1.5 years after the last participant enrolled | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
MDS, Myelodysplastic syndrome, Decitabine, JNJ-30979754