Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, Acute Myeloid Leukemia
Conditions
Keywords
Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, Acute Myeloid Leukemia, hypomethylating therapy, deacetylase inhibitor, MDS, CMML, AML
Brief summary
The purpose of this randomized, two-arm, open-label expansion phase study was to collect preliminary efficacy data of panobinostat at the recommended phase II dose (RPIID) level in combination with azacytidine (5-Aza) versus an active control arm 5-Aza alone. This randomized phase II part also allowed collecting safety data of panobinostat in combination with 5-Aza in comparison to single-agent 5-aza.
Detailed description
The primary objective of the phase lb portion of this study was to determine the maximum tolerated dose (MTD )and/or recommended phase ll dose (RPIID) of oral panobinostat in combination with a fixed dose of 5-Aza in adult patients with International Prognostic Scoring System intermediate-2 (IPSS INT-2) or high risk myelodysplastic syndrome (MDS), Chronic myelomonocytic leukemia (CMML), or Acute myelogenous leukemia (AML). The primary objective of the phase llb portion of this study was to assess preliminary efficacy of treatment with the panobinostat and 5-Aza combination at the RPIID relative to treatment with single agent 5-Aza through the assessment of composite CR (complete response (CR) or CRi or bone marrow CR). In the phase lb phase of the study, the patients received escalating oral doses of panobinostat commencing in Cycle 1. The starting dose for panobinostat was 20 mg/day administered orally commencing on Day 3. Each treatment cycle consisted of 28 days (4 weeks). In each cycle, panobinostat was administered twice in Week 1 (Day 3, Day 5), thrice in Week 2 (Day 8, Day 10, and Day 12) and once in Week 3 (Day 15), with no dosing in Week 4. Successive cohorts of patients received escalating doses of panobinostat until the MTD/RPIID was determined. The dose of 5-Aza was fixed at 75 mg/m2/day for 7 days in Week 1 of each cycle. After the MTD/RPIID was determined, enrollment in the Phase Ib part was closed and the Phase IIb part of the study commenced. Ongoing patients from the Phase Ib part continued their treatment at the assigned dose level according to the regimen and schedule for the Phase Ib part. Once the RPIID was defined in Phase Ib, additional 80 patients were to be enrolled into the Phase IIb part of the study and randomly assigned in a 1:1 ratio receiving the RPIID of panobinostat plus 5-Aza (investigational arm) or single agent 5-Aza (active control arm). The treatment schedule for the investigational arm was the same as that for the Phase Ib. Single agent 5-Aza (active control arm) was administered according to the locally approved label (75mg/m2 daily for 7 days). Patients continued treatment until disease progression, unacceptable toxicity or consent withdrawal, whichever came first.
Interventions
Panobinostat was supplied by Novartis as immediate-release hard gelatin capsules in strengths of 5 mg, 10 mg, and 20 mg packaged in high density polyethylene bottles.
DRUG5-Azacytidine
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Masking description
Treatment was assigned sequentially for the initial dose escalation part (phase Ib): If a dose was safe, the next cohort started with the next dose level. Randomization applies only for the phase IIb part.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Phase l: * Patients with cytopathologically confirmed diagnosis of AML according to WHO criteria, excluding acute promyelocytic leukemia who are eligible for Vidaza treatment * ECOG performance status greater less than or equal to 2 Phase ll: * Adult patients (age ≥ 18 years) who were candidates for treatment with 5-Aza and present with one of the following: * intermediate-2 or high-risk myelodysplastic syndromes according to the International Prognostic Scoring System (IPSS). OR * AML with multilineage dysplasia and maximum of 30% blasts (former RAEB-T according to FAB) OR * chronic myelomonocytic leukemia (CMML) * Patients must have had the following laboratory values unless elevations are considered due to MDS or leukemia: AST/SGOT and/or ALT/SGPT ≤ 2.5 x ULN; serum creatinine ≤ 1.5 x ULN; serum bilirubin (total and direct) ≤ 2 x ULN; electrolyte panel within normal ranges (WNL) for the institution.
Exclusion criteria
Phase l: * Prior treatment with deacetylase inhibitors * Concurrent therapy with any other investigational agent Phase ll: * Planned hematopoietic stem-cell transplantation (HSCT) * Patients with therapy-related MDS * Patients with therapy-related AML and/or relapsed/refractory AML * Patients with impaired cardiac function including any of the following: * Complete left bundle branch block or use of a permanent cardiac pacemaker, congenital long QT syndrome, history or presence of ventricular tachyarrhythmia, clinically significant resting bradycardia (\<50 beats per minute), QTcF \> 460 ms on screening ECG, or right bundle branch block + left anterior hemiblock (bifascicular block) * Presence of unstable atrial fibrillation (ventricular response rate \>100 bpm). Patients with stable atrial fibrillation are eligible provided they do not meet the other cardiac
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Dose Limiting Toxicity (DLT) (Phase lb) | within the first 28 days (cycle 1) | Dose limiting toxicity (DLT) was defined as a toxicity requiring treatment withdrawal and included the following: Non-hematologic toxicity qualifying for DLT and Hematologic toxicity qualifying for DLT |
| Number of Dose Limiting Toxicity (DLT) (Phase lb) | within the first 28 days (cycle 1) | Dose limiting toxicity (DLT) was defined as a toxicity requiring treatment withdrawal and included the following: Non-hematologic toxicity qualifying for DLT and Hematologic toxicity qualifying for DLT |
| Composite Complete Response (Phase Llb) | 48 months | Composite complete response is defined as complete response (CR), Complete response with incomplete blood count recovery (CRi) or bone marrow complete response (BM-CR) as defined by the International Working Group (IWG) response criteria. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) Assessed by Best Overall Response: Participants With AML Per Investigator (Phase Llb) | 48 months | Best overall response as measured by complete remission (CR) or complete response with incomplete blood count recovery (CRi) or partial remission (PR). Overall response patients achieved other than the composite CR by individual response category: CR, CRi or PR. |
| Hematologic Improvement (HI) for Myeloid Dysplastic Syndromes(MDS)/Chronic Myelomonocytic Leukemia (CMML) Patients Per Investigator (Phase Llb) | 48 months | Hematologic response consists of Erythroid response (HI-E), Platelet response (HI-P) and Neutrophil response (HI-N). HI-E: Hgb increase by ≥ 1.5 g/dL over pretreatment & relevant reduction of units of RBC transfusions by an absolute number of at least 4 units of PRBCs/8 weeks compared with the pretreatment transfusion number in the previous 8 weeks. Only RBC transfusions given for a Hgb of ≤ 9.0 g/dL pretreatment will count in the RBC transfusion response evaluation. HI-P: Absolute increase of ≥ 30 x 109/L over pretreatment or patients starting with ≥ 20 x 109/L platelets OR increase from \<20 x 109/L at pretreatment to \> 20 x 109/L and by at least 100%. HI-N: At least 100% increase and an absolute increase \> 0.5 x 109/L over pretreatment value. |
| Clinical Response Other Than Composite Clinical Response for Myeloid Dysplastic Syndromes(MDS)/Chronic Myelomonocytic Leukemia (CMML) Patients Per Investigator (Phase Llb) | 48 months | This is the best overall response as measured by Clinical response. Clinical response is defined as having complete remission (CR), bone marrow complete remission (BM-CR), partial remission or hematologic improvement (HI) as defined by the International Working Group (IWG) response criteria. |
| Time to Progression (TTP) (Phase Llb) | 48 months | Time to progression (TTP) was defined as the time from the date of randomization to the date of the first documented PD per investigator's assessment or death due to study indication. Time to progression was analyzed by the Kaplan Meier method. Based on the Guidelines for Implementation of international working group (IWG) response criteria in AML, MDS and CMML according to Cheson 2003 and 2006. |
| 1-year Survival Rate (Phase Llb) | 12 months | Overall survival was defined as the time from date of randomization to date of death due to any cause. If a patient was not known to have died, survival was censored at the date of last contact. Patients not known to have died were censored for 'Lost to follow-up' if the time between their last contact date and the analysis cut-off date was longer than 3 months and 2 weeks (104 days) during the first year after study evaluation completion, and longer than 6 months and 2 weeks (194 days), thereafter. The 1-year survival rate was obtained from the Kaplan-Meier analysis of overall survival, and its variance was estimated by Greenwood's formula. |
| Clinical Response Other Than Composite Clinical Response for Acute Myelogenous Leukemia (AML) Patients Per Investigator (Phase Llb) | 48 months | This is the best overall response as measured by Clinical response. Clinical response is defined as having complete remission (CR), complete remission with incomplete blood count recovery (CRi) or partial remission as defined by the International Working Group (IWG) response criteria. |
| Overall Response Rate (ORR) Assessed by Best Overall Response: Participants With MDS/CMML Per Investigator (Phase Llb) | 48 months | Best overall response as measured by complete remission (CR) or bone marrow CR (BM-CR) or partial remission (PR) or hematologic improvement (HI). Overall response patients achieved other than the composite CR by individual response category: CR, CRi, mCR or PR as defined by the International Working Group (IWG) response criteria. |
Countries
Austria, Belgium, Canada, France, Germany, Hungary, Italy, South Korea, Spain, Sweden, Switzerland, Thailand, United Kingdom, United States
Participant flow
Recruitment details
In phase l a total of 31 patients were treated with escalating dose of PAN, 20 mg 30 mg & 40 mg. In phase ll a total of 82 patients were actually randomized with 40 patients assigned to PAN+5-Aza and 42 patients assigned to 5-Aza.
Pre-assignment details
For phase I, approximately 26 patients were planned to be enrolled in cohorts of at least three MTD evaluable patients per dose level. For phase ll, approximately 80 patients were planned to be enrolled, 40 patients per arm.
Participants by arm
| Arm | Count |
|---|---|
| PAN + 5-Aza 20 mg In this escalating phase, participants took panobinostat of 20 mg delivered orally at Day 3, Day 5, Day 8, Day 10, Day 12, Day 15 and a fixed dose of 5-Azacytidine (5-Aza) at 75 mg/m2/day for 7 days in Week 1 of each cycle. | 6 |
| PAN + 5-Aza 30 mg In this escalating phase, participants took panobinostat of 30 mg delivered orally at Day 3, Day 5, Day 8, Day 10, Day 12, Day 15 and a fixed dose of 5-Azacytidine (5-Aza) at 75 mg/m2/day for 7 days in Week 1 of each cycle. | 18 |
| PAN + 5-Aza 40 mg In this escalating phase, participants took panobinostat of 40 mg delivered orally at Day 3, Day 5, Day 8, Day 10, Day 12, Day 15 and a fixed dose of 5-Azacytidine (5-Aza) at 75 mg/m2/day for 7 days in Week 1 of each cycle. | 7 |
| Panobinostat + 5-Azacytidine In phase II: Panobinostat : Rapid Phase II doses at 30 mg delivered orally at Day 3, Day 5, Day 8, Day 10, Day 12, Day 15.
In both phases, dose of 5-Azacytidine was 75 mg/m\^2, subcutaneously Daily for Day 1 to Day 7. | 40 |
| 5-Azacytidine The dose of 5-Aza was fixed at 75 mg/m2/day for 7 days in Week 1 of each cycle. 5-Aza was sourced locally, except in 4 countries (Hungary, Switzerland, UK, and Spain, for which a central purchase was used by Novartis.
Dose of 5-Azacytidine : 75 mg/m\^2 subcutaneously daily from Day 1 to Day 7. | 42 |
| Total | 113 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Phase 1 Part | Abnormal values | 0 | 2 | 0 | 0 | 0 |
| Phase 1 Part | Adverse Event | 2 | 5 | 3 | 0 | 0 |
| Phase 1 Part | Disease progression | 3 | 6 | 1 | 0 | 0 |
| Phase 1 Part | Reason missing | 0 | 1 | 0 | 0 | 0 |
| Phase 1 Part | Withdrawal by Subject | 1 | 4 | 3 | 0 | 0 |
| Phase ll Part | Administrative problems | 0 | 0 | 0 | 3 | 8 |
| Phase ll Part | Adverse Event | 0 | 0 | 0 | 10 | 6 |
| Phase ll Part | Death | 0 | 0 | 0 | 7 | 4 |
| Phase ll Part | Disease progression | 0 | 0 | 0 | 6 | 14 |
| Phase ll Part | Protocol Violation | 0 | 0 | 0 | 4 | 2 |
| Phase ll Part | Subj cond no longer required study drug | 0 | 0 | 0 | 2 | 0 |
| Phase ll Part | Untreated | 0 | 0 | 0 | 0 | 2 |
| Phase ll Part | Withdrawal by Subject | 0 | 0 | 0 | 8 | 6 |
Baseline characteristics
| Characteristic | PAN + 5-Aza 20 mg | PAN + 5-Aza 30 mg | PAN + 5-Aza 40 mg | Panobinostat + 5-Azacytidine | 5-Azacytidine | Total |
|---|---|---|---|---|---|---|
| Age, Customized < 65 | 1 participants | 5 participants | 1 participants | 14 participants | 8 participants | 29 participants |
| Age, Customized >= 65 | 5 participants | 13 participants | 6 participants | 26 participants | 34 participants | 84 participants |
| Race/Ethnicity, Customized Asian | 0 participants | 0 participants | 0 participants | 7 participants | 2 participants | 9 participants |
| Race/Ethnicity, Customized Black | 0 participants | 0 participants | 1 participants | 1 participants | 0 participants | 2 participants |
| Race/Ethnicity, Customized Caucasian | 5 participants | 15 participants | 6 participants | 29 participants | 36 participants | 91 participants |
| Race/Ethnicity, Customized Other | 1 participants | 3 participants | 0 participants | 3 participants | 4 participants | 11 participants |
| Sex: Female, Male Female | 2 Participants | 10 Participants | 4 Participants | 11 Participants | 17 Participants | 44 Participants |
| Sex: Female, Male Male | 4 Participants | 8 Participants | 3 Participants | 29 Participants | 25 Participants | 69 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 1 / 18 | 2 / 7 | 6 / 38 | 3 / 42 | 12 / 111 |
| other Total, other adverse events | 6 / 6 | 18 / 18 | 7 / 7 | 38 / 38 | 38 / 42 | 107 / 111 |
| serious Total, serious adverse events | 5 / 6 | 15 / 18 | 6 / 7 | 28 / 38 | 28 / 42 | 82 / 111 |
Outcome results
Primary
Composite Complete Response (Phase Llb)
Composite complete response is defined as complete response (CR), Complete response with incomplete blood count recovery (CRi) or bone marrow complete response (BM-CR) as defined by the International Working Group (IWG) response criteria.
Time frame: 48 months
Population: Full analysis set: Consisted of all patients who were randomized to one of the two treatment arms
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PAN + 5-Aza 20 mg | Composite Complete Response (Phase Llb) | 27.5 Percentage of participants |
| PAN + 5-Aza 30 mg | Composite Complete Response (Phase Llb) | 14.3 Percentage of participants |
Primary
Number of Dose Limiting Toxicity (DLT) (Phase lb)
Dose limiting toxicity (DLT) was defined as a toxicity requiring treatment withdrawal and included the following: Non-hematologic toxicity qualifying for DLT and Hematologic toxicity qualifying for DLT
Time frame: within the first 28 days (cycle 1)
Population: Maximum Tolerated Dose (MTD) determining set: Consisted of all patients of the safety set who either received sufficient study treatment as defined in the minimum exposure criteria in Cycle 1 (patients had to have 100% of the planned dose of each compound), and had sufficient safety evaluations or discontinued due to DLT in Cycle 1.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PAN + 5-Aza 20 mg | Number of Dose Limiting Toxicity (DLT) (Phase lb) | 2 DLTs |
| PAN + 5-Aza 30 mg | Number of Dose Limiting Toxicity (DLT) (Phase lb) | 6 DLTs |
| PAN + 5-Aza 40 mg | Number of Dose Limiting Toxicity (DLT) (Phase lb) | 4 DLTs |
Primary
Number of Participants With Dose Limiting Toxicity (DLT) (Phase lb)
Dose limiting toxicity (DLT) was defined as a toxicity requiring treatment withdrawal and included the following: Non-hematologic toxicity qualifying for DLT and Hematologic toxicity qualifying for DLT
Time frame: within the first 28 days (cycle 1)
Population: Maximum Tolerated Dose (MTD) determining set: Consisted of all patients of the safety set who either received sufficient study treatment as defined in the minimum exposure criteria in Cycle 1 (patients had to have 100% of the planned dose of each compound), and had sufficient safety evaluations or discontinued due to DLT in Cycle 1.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PAN + 5-Aza 20 mg | Number of Participants With Dose Limiting Toxicity (DLT) (Phase lb) | 1 Participants |
| PAN + 5-Aza 30 mg | Number of Participants With Dose Limiting Toxicity (DLT) (Phase lb) | 3 Participants |
| PAN + 5-Aza 40 mg | Number of Participants With Dose Limiting Toxicity (DLT) (Phase lb) | 2 Participants |
Secondary
1-year Survival Rate (Phase Llb)
Overall survival was defined as the time from date of randomization to date of death due to any cause. If a patient was not known to have died, survival was censored at the date of last contact. Patients not known to have died were censored for 'Lost to follow-up' if the time between their last contact date and the analysis cut-off date was longer than 3 months and 2 weeks (104 days) during the first year after study evaluation completion, and longer than 6 months and 2 weeks (194 days), thereafter. The 1-year survival rate was obtained from the Kaplan-Meier analysis of overall survival, and its variance was estimated by Greenwood's formula.
Time frame: 12 months
Population: Full analysis set: Consisted of all patients who were randomized to one of the two treatment arms
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| PAN + 5-Aza 20 mg | 1-year Survival Rate (Phase Llb) | 14.9 months |
| PAN + 5-Aza 30 mg | 1-year Survival Rate (Phase Llb) | 15.6 months |
Secondary
Clinical Response Other Than Composite Clinical Response for Acute Myelogenous Leukemia (AML) Patients Per Investigator (Phase Llb)
This is the best overall response as measured by Clinical response. Clinical response is defined as having complete remission (CR), complete remission with incomplete blood count recovery (CRi) or partial remission as defined by the International Working Group (IWG) response criteria.
Time frame: 48 months
Population: Full analysis set: Consisted of all patients who were randomized to one of the two treatment arms
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PAN + 5-Aza 20 mg | Clinical Response Other Than Composite Clinical Response for Acute Myelogenous Leukemia (AML) Patients Per Investigator (Phase Llb) | 22.2 Percentage of participants |
| PAN + 5-Aza 30 mg | Clinical Response Other Than Composite Clinical Response for Acute Myelogenous Leukemia (AML) Patients Per Investigator (Phase Llb) | 30.8 Percentage of participants |
Secondary
Clinical Response Other Than Composite Clinical Response for Myeloid Dysplastic Syndromes(MDS)/Chronic Myelomonocytic Leukemia (CMML) Patients Per Investigator (Phase Llb)
This is the best overall response as measured by Clinical response. Clinical response is defined as having complete remission (CR), bone marrow complete remission (BM-CR), partial remission or hematologic improvement (HI) as defined by the International Working Group (IWG) response criteria.
Time frame: 48 months
Population: Full analysis set: Consisted of all patients who were randomized to one of the two treatment arms
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PAN + 5-Aza 20 mg | Clinical Response Other Than Composite Clinical Response for Myeloid Dysplastic Syndromes(MDS)/Chronic Myelomonocytic Leukemia (CMML) Patients Per Investigator (Phase Llb) | 41.9 Percentage of participants |
| PAN + 5-Aza 30 mg | Clinical Response Other Than Composite Clinical Response for Myeloid Dysplastic Syndromes(MDS)/Chronic Myelomonocytic Leukemia (CMML) Patients Per Investigator (Phase Llb) | 41.4 Percentage of participants |
Secondary
Hematologic Improvement (HI) for Myeloid Dysplastic Syndromes(MDS)/Chronic Myelomonocytic Leukemia (CMML) Patients Per Investigator (Phase Llb)
Hematologic response consists of Erythroid response (HI-E), Platelet response (HI-P) and Neutrophil response (HI-N). HI-E: Hgb increase by ≥ 1.5 g/dL over pretreatment & relevant reduction of units of RBC transfusions by an absolute number of at least 4 units of PRBCs/8 weeks compared with the pretreatment transfusion number in the previous 8 weeks. Only RBC transfusions given for a Hgb of ≤ 9.0 g/dL pretreatment will count in the RBC transfusion response evaluation. HI-P: Absolute increase of ≥ 30 x 109/L over pretreatment or patients starting with ≥ 20 x 109/L platelets OR increase from \<20 x 109/L at pretreatment to \> 20 x 109/L and by at least 100%. HI-N: At least 100% increase and an absolute increase \> 0.5 x 109/L over pretreatment value.
Time frame: 48 months
Population: Full analysis set: Consisted of all patients who were randomized to one of the two treatment arms
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| PAN + 5-Aza 20 mg | Hematologic Improvement (HI) for Myeloid Dysplastic Syndromes(MDS)/Chronic Myelomonocytic Leukemia (CMML) Patients Per Investigator (Phase Llb) | Erythroid response (HI-E) | 25.8 Percentage of participants |
| PAN + 5-Aza 20 mg | Hematologic Improvement (HI) for Myeloid Dysplastic Syndromes(MDS)/Chronic Myelomonocytic Leukemia (CMML) Patients Per Investigator (Phase Llb) | Platelet response (HI-P) | 35.5 Percentage of participants |
| PAN + 5-Aza 20 mg | Hematologic Improvement (HI) for Myeloid Dysplastic Syndromes(MDS)/Chronic Myelomonocytic Leukemia (CMML) Patients Per Investigator (Phase Llb) | Neutrophil response (HI-N) | 19.4 Percentage of participants |
| PAN + 5-Aza 30 mg | Hematologic Improvement (HI) for Myeloid Dysplastic Syndromes(MDS)/Chronic Myelomonocytic Leukemia (CMML) Patients Per Investigator (Phase Llb) | Platelet response (HI-P) | 24.1 Percentage of participants |
| PAN + 5-Aza 30 mg | Hematologic Improvement (HI) for Myeloid Dysplastic Syndromes(MDS)/Chronic Myelomonocytic Leukemia (CMML) Patients Per Investigator (Phase Llb) | Erythroid response (HI-E) | 31.0 Percentage of participants |
| PAN + 5-Aza 30 mg | Hematologic Improvement (HI) for Myeloid Dysplastic Syndromes(MDS)/Chronic Myelomonocytic Leukemia (CMML) Patients Per Investigator (Phase Llb) | Neutrophil response (HI-N) | 13.8 Percentage of participants |
Secondary
Overall Response Rate (ORR) Assessed by Best Overall Response: Participants With AML Per Investigator (Phase Llb)
Best overall response as measured by complete remission (CR) or complete response with incomplete blood count recovery (CRi) or partial remission (PR). Overall response patients achieved other than the composite CR by individual response category: CR, CRi or PR.
Time frame: 48 months
Population: Full analysis set (FAS): Consisted of all patients who were randomized to one of the two treatment arms.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| PAN + 5-Aza 20 mg | Overall Response Rate (ORR) Assessed by Best Overall Response: Participants With AML Per Investigator (Phase Llb) | Clinical response (CR, CRi, PR) | 22.2 Percentage of participants |
| PAN + 5-Aza 20 mg | Overall Response Rate (ORR) Assessed by Best Overall Response: Participants With AML Per Investigator (Phase Llb) | Complete remission (CR) | 11.1 Percentage of participants |
| PAN + 5-Aza 20 mg | Overall Response Rate (ORR) Assessed by Best Overall Response: Participants With AML Per Investigator (Phase Llb) | Compl remiss. with incompl blood cnt recovery(CRi) | 11.1 Percentage of participants |
| PAN + 5-Aza 20 mg | Overall Response Rate (ORR) Assessed by Best Overall Response: Participants With AML Per Investigator (Phase Llb) | Partial remission (PR) | 0.0 Percentage of participants |
| PAN + 5-Aza 30 mg | Overall Response Rate (ORR) Assessed by Best Overall Response: Participants With AML Per Investigator (Phase Llb) | Partial remission (PR) | 7.7 Percentage of participants |
| PAN + 5-Aza 30 mg | Overall Response Rate (ORR) Assessed by Best Overall Response: Participants With AML Per Investigator (Phase Llb) | Clinical response (CR, CRi, PR) | 30.8 Percentage of participants |
| PAN + 5-Aza 30 mg | Overall Response Rate (ORR) Assessed by Best Overall Response: Participants With AML Per Investigator (Phase Llb) | Compl remiss. with incompl blood cnt recovery(CRi) | 7.7 Percentage of participants |
| PAN + 5-Aza 30 mg | Overall Response Rate (ORR) Assessed by Best Overall Response: Participants With AML Per Investigator (Phase Llb) | Complete remission (CR) | 15.4 Percentage of participants |
Secondary
Overall Response Rate (ORR) Assessed by Best Overall Response: Participants With MDS/CMML Per Investigator (Phase Llb)
Best overall response as measured by complete remission (CR) or bone marrow CR (BM-CR) or partial remission (PR) or hematologic improvement (HI). Overall response patients achieved other than the composite CR by individual response category: CR, CRi, mCR or PR as defined by the International Working Group (IWG) response criteria.
Time frame: 48 months
Population: Full analysis set (FAS): Consisted of all patients who were randomized to one of the two treatment arms.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| PAN + 5-Aza 20 mg | Overall Response Rate (ORR) Assessed by Best Overall Response: Participants With MDS/CMML Per Investigator (Phase Llb) | Clinical response (CR, BM-CR, PR, HI) | 41.9 Percentage of participants |
| PAN + 5-Aza 20 mg | Overall Response Rate (ORR) Assessed by Best Overall Response: Participants With MDS/CMML Per Investigator (Phase Llb) | Complete remission (CR) | 16.1 Percentage of participants |
| PAN + 5-Aza 20 mg | Overall Response Rate (ORR) Assessed by Best Overall Response: Participants With MDS/CMML Per Investigator (Phase Llb) | Bone marrow CR (BM-CR) | 12.9 Percentage of participants |
| PAN + 5-Aza 20 mg | Overall Response Rate (ORR) Assessed by Best Overall Response: Participants With MDS/CMML Per Investigator (Phase Llb) | Partial remission (PR) | 0.0 Percentage of participants |
| PAN + 5-Aza 30 mg | Overall Response Rate (ORR) Assessed by Best Overall Response: Participants With MDS/CMML Per Investigator (Phase Llb) | Partial remission (PR) | 6.9 Percentage of participants |
| PAN + 5-Aza 30 mg | Overall Response Rate (ORR) Assessed by Best Overall Response: Participants With MDS/CMML Per Investigator (Phase Llb) | Clinical response (CR, BM-CR, PR, HI) | 41.4 Percentage of participants |
| PAN + 5-Aza 30 mg | Overall Response Rate (ORR) Assessed by Best Overall Response: Participants With MDS/CMML Per Investigator (Phase Llb) | Bone marrow CR (BM-CR) | 3.4 Percentage of participants |
| PAN + 5-Aza 30 mg | Overall Response Rate (ORR) Assessed by Best Overall Response: Participants With MDS/CMML Per Investigator (Phase Llb) | Complete remission (CR) | 6.9 Percentage of participants |
Secondary
Time to Progression (TTP) (Phase Llb)
Time to progression (TTP) was defined as the time from the date of randomization to the date of the first documented PD per investigator's assessment or death due to study indication. Time to progression was analyzed by the Kaplan Meier method. Based on the Guidelines for Implementation of international working group (IWG) response criteria in AML, MDS and CMML according to Cheson 2003 and 2006.
Time frame: 48 months
Population: Full analysis set: Consisted of all patients who were randomized to one of the two treatment arms
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| PAN + 5-Aza 20 mg | Time to Progression (TTP) (Phase Llb) | NA months |
| PAN + 5-Aza 30 mg | Time to Progression (TTP) (Phase Llb) | 15.2 months |