Myelodysplastic Syndrome
Conditions
Keywords
Myelodysplastic syndrome, MDS, Decitabine, JNJ-30979754
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.
Interventions
DRUGJNJ-30979754 15 mg/m2
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.
DRUGJNJ-30979754 20 mg/m2
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.
Sponsors
Janssen Pharmaceutical K.K.
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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) | Up to 1 years after the last participant enrolled | 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. |
| Phase I and II: Number of Participants Who Experienced Adverse Events | Up to 1.5 years after the last participant enrolled | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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) | Up to 28 Days of treatment Cycle 1 | 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. |
| Phase II: Median Time to Remission | Up to 1.5 years after the last participant enrolled | Median time required for the participants to achieve remission (complete remission+partial remission). |
| Phase II: Median Time to Improvement | Up to 1.5 years after the last participant enrolled | Median time required for the participants to achieve overall improvement (complete remission+partial remission+hematologic improvement) |
| 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 II: Median Duration of Overall Improvement | Up to 1.5 years after the last participant enrolled | Median time duration for which participants achieved overall improvement (complete remission+partial remission+hematologic improvement). |
| 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) | Up to 1.5 years after the last participant enrolled | 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. |
| Phase II: Number of Participants With Cytogenic Response - as Per International Working Group (IWG) Response Criteria 2000 (Major/Minor) and IWG 2006 (Complete/Partial) | Up to 1.5 years after the last participant enrolled | 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. |
| Phase II: Median Duration of Remission | Up to 1.5 years after the last participant enrolled | Median time duration for which participants achieved remission (complete remission+partial remission). |
| Phase I: Area Under the Plasma Concentration-time Curve (AUC) | 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 | 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). |
Countries
Japan
Participant flow
Recruitment details
39 participants were enrolled at multiple sites in Japan.
Pre-assignment details
9 participants were enrolled and treated in Phase 1. 36 participants (including 6 participants from Phase I) were enrolled in Phase II. 34 participants were treated and 2 participants were untreated in Phase II.
Participants by arm
| Arm | Count |
|---|---|
| Phase I: 15 mg/m2 15 mg/m2 of JNJ-30979754 (decitabine) administered once daily by 1-hour intravenous infusion from Day 1 to 5 of a 4-Week (28-day) Cycle 1 | 3 |
| Phase I and II: 20 mg/m2 Phase I: 20 mg/m2 of JNJ-30979754 (decitabine) administered once daily by 1-hour intravenous infusion from Day 1 to 5 of a 4-Week (28-day) Cycle 1. Phase II: 20 mg/m2 of JNJ-30979754 (decitabine) administered once daily by 1-hour intravenous infusion from Day 1 to 5 of 4-Week (28-day) other cycles (except Cycle I) | 34 |
| Total | 37 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 7 |
| Overall Study | Disease Progression | 2 | 13 |
| Overall Study | Other | 0 | 1 |
| Overall Study | Participants Not treated | 0 | 2 |
| Overall Study | Physician Decision | 0 | 4 |
| Overall Study | Specified organ function not met | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Phase I: 15 mg/m2 | Phase I and II: 20 mg/m2 | Total |
|---|---|---|---|
| Age Continuous | 68.7 Years STANDARD_DEVIATION 2.08 | 68.5 Years STANDARD_DEVIATION 7.09 | 68.5 Years STANDARD_DEVIATION 6.81 |
| Age, Customized >= 65 and <= 74 years | 3 Participants | 17 Participants | 20 Participants |
| Age, Customized <65 years | 0 Participants | 10 Participants | 10 Participants |
| Age, Customized >=75 years | 0 Participants | 7 Participants | 7 Participants |
| Sex: Female, Male Female | 0 Participants | 8 Participants | 8 Participants |
| Sex: Female, Male Male | 3 Participants | 26 Participants | 29 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 3 | 6 / 6 | 34 / 34 |
| serious Total, serious adverse events | 1 / 3 | 1 / 6 | 11 / 34 |
Outcome results
Primary
Phase I and II: Number of Participants Who Experienced Adverse Events
Time frame: Up to 1.5 years after the last participant enrolled
Population: Safety Population: 9 participants in Phase I and 34 participants in Phase II were evaluated for safety
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase II: 20 mg/m2 | Phase I and II: Number of Participants Who Experienced Adverse Events | 3 Participants |
| Phase I: 20 mg/m2 | Phase I and II: Number of Participants Who Experienced Adverse Events | 6 Participants |
| Phase II: 20 mg/m2 | Phase I and II: Number of Participants Who Experienced Adverse Events | 34 Participants |
Primary
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.
Time frame: Up to 1 years after the last participant enrolled
Population: Full Analysis Set (FAS): 34 participants were included in this analysis set for Phase II
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase II: 20 mg/m2 | 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) | CR | 7 Participants |
| Phase II: 20 mg/m2 | 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) | PR | 2 Participants |
Comparison: Null Hypothesis: Overall Remission Rate = 5%p-value: <0.000190% CI: [14.6, 41.6]Binomial test
Secondary
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).
Time frame: 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
Population: Pharmacokinetic Population: 8 participants were evaluated for pharmacokinetic analysis
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase II: 20 mg/m2 | Phase I: Area Under the Plasma Concentration-time Curve (AUC) | AUC Last - Day 1 | 149.0 ng*h/mL | Standard Deviation 41.102 |
| Phase II: 20 mg/m2 | Phase I: Area Under the Plasma Concentration-time Curve (AUC) | AUC Infinity - Day 1 | 150.0 ng*h/mL | Standard Deviation 40.777 |
| Phase II: 20 mg/m2 | Phase I: Area Under the Plasma Concentration-time Curve (AUC) | AUC Last - Day 5 | 136.0 ng*h/mL | Standard Deviation 37.855 |
| Phase II: 20 mg/m2 | Phase I: Area Under the Plasma Concentration-time Curve (AUC) | AUC Infinity - Day 5 | 136.9 ng*h/mL | Standard Deviation 37.897 |
| Phase I: 20 mg/m2 | Phase I: Area Under the Plasma Concentration-time Curve (AUC) | AUC Last - Day 5 | 152.0 ng*h/mL | Standard Deviation 15.712 |
| Phase I: 20 mg/m2 | Phase I: Area Under the Plasma Concentration-time Curve (AUC) | AUC Last - Day 1 | 155.2 ng*h/mL | Standard Deviation 15.754 |
| Phase I: 20 mg/m2 | Phase I: Area Under the Plasma Concentration-time Curve (AUC) | AUC Infinity - Day 5 | 151.2 ng*h/mL | Standard Deviation 17.617 |
| Phase I: 20 mg/m2 | Phase I: Area Under the Plasma Concentration-time Curve (AUC) | AUC Infinity - Day 1 | 156.1 ng*h/mL | Standard Deviation 15.497 |
Secondary
Phase II: Median Duration of Overall Improvement
Median time duration for which participants achieved overall improvement (complete remission+partial remission+hematologic improvement).
Time frame: Up to 1.5 years after the last participant enrolled
Population: 14 participants who achieved overall improvement were evaluated.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase II: 20 mg/m2 | Phase II: Median Duration of Overall Improvement | 532 Days |
Secondary
Phase II: Median Duration of Remission
Median time duration for which participants achieved remission (complete remission+partial remission).
Time frame: Up to 1.5 years after the last participant enrolled
Population: 9 participants who achieved remission were evaluated.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase II: 20 mg/m2 | Phase II: Median Duration of Remission | 489 Days |
Secondary
Phase II: Median Time to Improvement
Median time required for the participants to achieve overall improvement (complete remission+partial remission+hematologic improvement)
Time frame: Up to 1.5 years after the last participant enrolled
Population: 14 participants who achieved overall improvement were evaluated.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase II: 20 mg/m2 | Phase II: Median Time to Improvement | 26.5 Days |
Secondary
Phase II: Median Time to Remission
Median time required for the participants to achieve remission (complete remission+partial remission).
Time frame: Up to 1.5 years after the last participant enrolled
Population: 9 participants who achieved remission were evaluated.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase II: 20 mg/m2 | Phase II: Median Time to Remission | 130.0 Days |
Secondary
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.
Time frame: Up to 1.5 years after the last participant enrolled
Population: 20 participants who had chromosomal abnormality were evaluated in Phase II for cytogenetic response. The IWG criteria requires 20 analyzable metaphases using conventional cytogenetic techniques.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase II: 20 mg/m2 | Phase II: Number of Participants With Cytogenic Response - as Per International Working Group (IWG) Response Criteria 2000 (Major/Minor) and IWG 2006 (Complete/Partial) | Major/Complete | 6 Participants |
| Phase II: 20 mg/m2 | Phase II: Number of Participants With Cytogenic Response - as Per International Working Group (IWG) Response Criteria 2000 (Major/Minor) and IWG 2006 (Complete/Partial) | Minor/Partial | 1 Participants |
| Phase II: 20 mg/m2 | Phase II: Number of Participants With Cytogenic Response - as Per International Working Group (IWG) Response Criteria 2000 (Major/Minor) and IWG 2006 (Complete/Partial) | No response | 10 Participants |
| Phase II: 20 mg/m2 | Phase II: Number of Participants With Cytogenic Response - as Per International Working Group (IWG) Response Criteria 2000 (Major/Minor) and IWG 2006 (Complete/Partial) | Not estimable | 3 Participants |
Secondary
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.
Time frame: Up to 1.5 years after the last participant enrolled
Population: Full Analysis Set (FAS): 34 participants were included in this set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase II: 20 mg/m2 | 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) | CR | 7 Participants |
| Phase II: 20 mg/m2 | 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) | PR | 2 Participants |
| Phase II: 20 mg/m2 | 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) | HI | 5 Participants |
Secondary
Phase I: Maximum Observed Plasma Concentration of Decitabine (Cmax)
Time frame: 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
Population: Pharmacokinetic Population: 8 participants were evaluated for pharmacokinetic analysis
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase II: 20 mg/m2 | Phase I: Maximum Observed Plasma Concentration of Decitabine (Cmax) | Day 1 | 151.7 ng/mL | Standard Deviation 28.729 |
| Phase II: 20 mg/m2 | Phase I: Maximum Observed Plasma Concentration of Decitabine (Cmax) | Day 5 | 142.0 ng/mL | Standard Deviation 40.635 |
| Phase I: 20 mg/m2 | Phase I: Maximum Observed Plasma Concentration of Decitabine (Cmax) | Day 1 | 166.4 ng/mL | Standard Deviation 17.17 |
| Phase I: 20 mg/m2 | Phase I: Maximum Observed Plasma Concentration of Decitabine (Cmax) | Day 5 | 190.6 ng/mL | Standard Deviation 54.679 |
Secondary
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.
Time frame: Up to 28 Days of treatment Cycle 1
Population: Full Analysis Set (FAS): 9 participants were included in this set for Phase I
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase II: 20 mg/m2 | 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) | PR | 1 Participants |
| Phase II: 20 mg/m2 | 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) | HI | 1 Participants |
| Phase I: 20 mg/m2 | 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) | PR | 1 Participants |
| Phase I: 20 mg/m2 | 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) | HI | 2 Participants |