Acute Myelogenous Leukemia, Refractory Leukemia
Conditions
Keywords
Acute myeloid leukemia, AML, relapsed acute myeloid leukemia, refractory AML, refractory de novo AML, refractory secondary AML, secondary AML, AML following myelodysplastic syndrome (MDS), AML following antecedent hematological disorder (AHD), AML resistant to therapy
Brief summary
This study was to evaluate the efficacy and safety of single agent oral panobinostat in patients who have refractory de novo or refractory secondary AML.
Interventions
DRUGPanobinostat/LBH589
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* Written informed consent prior to study-specific screening procedures * Life expectancy of ≥ 60 days * Eastern Cooperative Group (ECOG) performance status ≤ 2 * Refractory AML with confirmed initial diagnosis of de novo AML (excluding APL) - OR- Refractory AML with confirmed initial diagnosis of AML (excluding APL) secondary to AHD or MDS with either condition precedent to AML (MDS/AHD) * Negative serum pregnancy test (within 7 days of first dose) * Negative urine pregnancy test immediately prior to first dose
Exclusion criteria
* Known HIV * Psychiatric disorder that interfered with ability to understand the study and give informed consent, and/or would impact study participation or follow-up * Concurrent use of medications that might prolong the QT interval or of inducing Torsade de Pointes * Female patients who were pregnant or breast-feeding or patients of childbearing potential who were not willing to use a double barrier method of contraception during the study and for 3 months following the last dose of study drug. * Male patients whose sexual partner(s) were women of childbearing potential who were not willing to use a double method of contraception, one of which included a condom, during the study and for 3 months after the end of treatment * Patient unable to swallow capsules * Patients with impaired gastrointestinal systems which might cause interference with digesting and absorbing panobinostat Other Protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Best Response as Per Investigator Assessment by Stratum (FAS) | 6 cycles of treatment with a 28-day treatment cycle (Day 168) | Response to treatment was defined as complete remission rate (CRR). CRR is complete remission (CR) and morphologic CR with incomplete blood count recovery (residual neutropenia or thrombocytopenia) (CRi). To stop or to proceed with Stage 2 of a given stratum of the Simon's optimal 2-stage design was based on the number of patients with CR/CRi and a safety evaluation of the patients from Stage 1 in that stratum. If early results clearly indicated that the drug was not active or worthy of further investigation, enrollment of that particular stratum would be terminated. CR and CRi were assessed by the Investigator according to IWG response Criteria for AML (Cheson et al 2003). As per protocol we would continue to stage II if ≥ 4 patients out of 26 patients enrolled to stage I had a CR or a CRi. As per response observed there was only 1 patient with CR/CRi in stratum A and 2 patients with CR/CRi in Stratum B. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Partial Response Measured in Stratum A and B | 6 treatment cycles (28-day/treatment cycle) | As predefined in the study's protocol, stage II was not pursued due to lack of activity (at end of stage I less than 4 patients in each stratum with CR/CRi) |
| Time to Remission Measured in Stratum A and B | 6 treatment cycles (28-day/treatment cycle) | — |
| Duration of Remission Measured in Stratum A and B | 6 treatment cycles (28-day/treatment cycle) | — |
| Event-free Survival Measured in Stratum A and B | 6 treatment cycles (28-day/treatment cycle) | — |
| Overall Survival Measured in Stratum A and B | 6 treatment cycles (28-day/treatment cycle) | — |
Countries
Australia, Belgium, France, Germany, Italy, Peru, South Korea, Spain, Switzerland, Turkey (Türkiye), United Kingdom, United States
Participant flow
Recruitment details
Participant flow is based on the full analysis set (FAS) which is the same as the safety set and includes one dose of the study drug.
Pre-assignment details
Although this study did not complete stage 2, it is considered as a completed study because it follows Simon's optimal two-stage design in each stratum (predefined in the protocol), the study can stop due to futility at the end of Stage 1 and not be considered as a terminated study.
Participants by arm
| Arm | Count |
|---|---|
| Stratum A patients with refractory acute myelogenous leukemia (AML) initially diagnosed as de novo AML received 60 mg of panobinostat per day on three discontinuous days per week. | 32 |
| Stratum B patients with refractory AML initially diagnosed as AML secondary to myelodysplastic syndrome (MDS)/antecedent hematologic disorder (AHD) received 60 mg of panobinostat per day on three discontinuous days per week. | 27 |
| Total | 59 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 10 | 9 |
| Overall Study | Death | 4 | 2 |
| Overall Study | Disease Progression | 13 | 11 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | New Cancer Therapy | 1 | 0 |
| Overall Study | Protocol Violation | 1 | 0 |
| Overall Study | Withdrawal by Subject | 3 | 4 |
Baseline characteristics
| Characteristic | Stratum A | Stratum B | Total |
|---|---|---|---|
| Age, Continuous | 63 years STANDARD_DEVIATION 12.13 | 68.5 years STANDARD_DEVIATION 7.75 | 65.5 years STANDARD_DEVIATION 10.65 |
| Gender Female | 20 Participants | 8 Participants | 28 Participants |
| Gender Male | 12 Participants | 19 Participants | 31 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 32 / 32 | 26 / 27 |
| serious Total, serious adverse events | 29 / 32 | 23 / 27 |
Outcome results
Primary
Best Response as Per Investigator Assessment by Stratum (FAS)
Response to treatment was defined as complete remission rate (CRR). CRR is complete remission (CR) and morphologic CR with incomplete blood count recovery (residual neutropenia or thrombocytopenia) (CRi). To stop or to proceed with Stage 2 of a given stratum of the Simon's optimal 2-stage design was based on the number of patients with CR/CRi and a safety evaluation of the patients from Stage 1 in that stratum. If early results clearly indicated that the drug was not active or worthy of further investigation, enrollment of that particular stratum would be terminated. CR and CRi were assessed by the Investigator according to IWG response Criteria for AML (Cheson et al 2003). As per protocol we would continue to stage II if ≥ 4 patients out of 26 patients enrolled to stage I had a CR or a CRi. As per response observed there was only 1 patient with CR/CRi in stratum A and 2 patients with CR/CRi in Stratum B.
Time frame: 6 cycles of treatment with a 28-day treatment cycle (Day 168)
Population: Full analysis set (FAS) is the same as the Safety set and includes all patients who received at least one dose of study drug. The FAS was used for final efficacy analyses.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Stratum A | Best Response as Per Investigator Assessment by Stratum (FAS) | Unknown | 56.3 Percentage of Participants |
| Stratum A | Best Response as Per Investigator Assessment by Stratum (FAS) | Partial remission (PR) | 0 Percentage of Participants |
| Stratum A | Best Response as Per Investigator Assessment by Stratum (FAS) | Treatment failure | 40.6 Percentage of Participants |
| Stratum A | Best Response as Per Investigator Assessment by Stratum (FAS) | Complete remission (CR) | 0 Percentage of Participants |
| Stratum A | Best Response as Per Investigator Assessment by Stratum (FAS) | CR with incomplete blood count recovery (CRi) | 3.1 Percentage of Participants |
| Stratum A | Best Response as Per Investigator Assessment by Stratum (FAS) | Complete remission rate (CR/CRi) | 3.1 Percentage of Participants |
| Stratum B | Best Response as Per Investigator Assessment by Stratum (FAS) | Unknown | 51.9 Percentage of Participants |
| Stratum B | Best Response as Per Investigator Assessment by Stratum (FAS) | Complete remission rate (CR/CRi) | 7.4 Percentage of Participants |
| Stratum B | Best Response as Per Investigator Assessment by Stratum (FAS) | Complete remission (CR) | 3.7 Percentage of Participants |
| Stratum B | Best Response as Per Investigator Assessment by Stratum (FAS) | CR with incomplete blood count recovery (CRi) | 3.7 Percentage of Participants |
| Stratum B | Best Response as Per Investigator Assessment by Stratum (FAS) | Treatment failure | 40.7 Percentage of Participants |
| Stratum B | Best Response as Per Investigator Assessment by Stratum (FAS) | Partial remission (PR) | 0 Percentage of Participants |
Secondary
Duration of Remission Measured in Stratum A and B
Time frame: 6 treatment cycles (28-day/treatment cycle)
Population: No secondary analyses were performed since study enrollment was stopped early at stage 1 for lack of evidence of activity.
Secondary
Event-free Survival Measured in Stratum A and B
Time frame: 6 treatment cycles (28-day/treatment cycle)
Population: No secondary analyses were performed since study enrollment was stopped early at stage 1 for lack of evidence of activity.
Secondary
Overall Survival Measured in Stratum A and B
Time frame: 6 treatment cycles (28-day/treatment cycle)
Population: No secondary analyses were performed since study enrollment was stopped early at stage 1 for lack of evidence of activity.
Secondary
Partial Response Measured in Stratum A and B
As predefined in the study's protocol, stage II was not pursued due to lack of activity (at end of stage I less than 4 patients in each stratum with CR/CRi)
Time frame: 6 treatment cycles (28-day/treatment cycle)
Population: No secondary analyses were performed since study enrollment was stopped early at stage 1 for lack of evidence of activity.
Secondary
Time to Remission Measured in Stratum A and B
Time frame: 6 treatment cycles (28-day/treatment cycle)
Population: No secondary analyses were performed since study enrollment was stopped early at stage 1 for lack of evidence of activity.