Acute Myeloid Leukemia
Conditions
Keywords
Acute Myeloid Leukemia, PXD101, Belinostat, Idarubicin
Brief summary
An open-label, non-randomized, multi-centre, Phase I/II trial to assess the efficacy and safety of 2 schedules of PXD101 in combination with idarubicin in patients with AML not suitable for standard intensive therapy.
Detailed description
This trial is an open-label, multi-centre, dose-escalation Phase I/II study to evaluate safety, explore efficacy, pharmacodynamics, and pharmacokinetics of the combination of PXD101 with idarubicin administered in two different schedules in patients with AML. The PXD101 plus idarubicin treatment will be repeated at suitable intervals (target is every 3 weeks for schedule A and every 2 weeks for schedule B) depending upon toxicities or disease progression. Safety and efficacy assessments will be performed at every cycle. Schedule A uses PXD101 by 30 min infusion daily for 5 days every 3 weeks with escalating doses of idarubicin. Schedule B uses escalating doses of continuous infusion (48h) of PXD101 alone or in combination with idarubicin. In both regimens the trial may be expanded at the Maximum Tolerated Dose (MTD).
Interventions
DRUGPXD101
DRUGidarubicin
Sponsors
Valerio Therapeutics
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
(abbreviated) 1. Signed consent 2. AML patients: 1. above 60 years in first relapse or refractory. 2. 18-60 years 2nd relapse or refractory to at least two intensive chemotherapy regimens. 3. above 60 years with high risk features (cytogenetics, secondary or treatment related AML) d) above 60 years with myelodysplastic syndrome with \>10% blasts in bone marrow (WHO RAEB-2 (Refractory anemia with excess blasts-2)). For patients below 60 years potential curative treatments should have been exhausted. 3. Performance status (ECOG) ≤ 2 4. Age ≥ 18 years 5. Acceptable liver, renal and bone marrow function as defined 6. Serum potassium within normal range. 7. Acceptable coagulation status as defined 8. Precautions for female patients with reproductive potential as defined
Exclusion criteria
1. Treatment with investigational agents within the last 4 weeks 2. Prior treatment with HDAC (Histone deacetylases) inhibitors including valproic acid 3. Prior anti-leukemic therapy (except hydroxyurea) within the last 3 weeks of trial dosing 4. Co-existing active infection (including HIV) or any co-existing medical condition likely to interfere with trial procedures, including significant cardiovascular disease 5. Altered mental status precluding understanding of the informed consent process and/or completion of the necessary study procedures. 6. Concurrent second malignancy. 7. History of hypersensitivity to idarubicin 8. Cumulative idarubicin dose exceeding 100 mg/m², or a (with respect cardiotoxicity) corresponding dose of other anthracyclines 9. LVEF (left ventricular ejection fraction) below normal range (\< 45% ) 10. Known Central Nervous System (CNS) leukemia
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose, Dose Limiting Toxicity | First Cycle | DLT (dose limiting toxicities): patients with any of the toxicities: 1.Haematological toxicity is not included in the definition due to bone marrow involvement by the disease except for following grade 4 ANC (absolute neutrophil count) and PLT (platelet count) for 6 weeks with less than 5% blasts in bone marrow. 2.Drug related non hematological Grade 3 or 4 toxicity except alopecia, brief nausea and vomiting, diarrhea, rash, arthralgias and myalgias. Treatment interventions should palliate toxicity symptoms prior to concluding a DLT has occurred (e.g if nausea and vomiting to Grade 3 have been associated with the drug). If despite standard treatment Grade 3 nausea and or vomiting persisted then a DLT was considered to have occurred. Grade 4 diarrhea in spite of standard therapeutic measures was included in DLT definition. 3.Inability to tolerate full dosing cycle due to toxicity or any drug-related adverse event resulting in more than 14 day treatment delay in the next treatment cycle |
| Overall Response | Throughout study, after each cycle for the first two cycles, then after every second cycle | Efficacy measured as Response rate (complete response (\[CR\] and Complete remission with incomplete recovery of platelets \[CRi\]) and partial response (\[PR\])) using the response criteria of the International Working Group (Cheson et al 2003). CR includes CRi, CRc (Cytogenetic complete remission), and CRm (Molecular complete remission). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | Throughout study, after each cycle for the first two cycles, then after every second cycle | Overall survival: time in weeks from entry into study until death from any cause. All patients without this endpoint at the time of discontinuation or the end of trial have been censored. |
| Relapse-Free Survival | Throughout study, after each cycle for the first two cycles, then after every second cycle | Relapse-free survival: time (weeks) from leukemia-free state to relapse or death from any cause. |
| Event-Free Survival | Throughout study, after each cycle for the first two cycles, then after every second cycle | Event-free survival: time (weeks) from entry into study until treatment failure, disease relapse or death from any cause. |
| Time to Response (CR and PR) | Throughout study, after each cycle for the first two cycles, then after every second cycle | Time to response: time in weeks from first treatment to obtainment of the particular response status (CR and PR) |
| Belinostat Cmax | Samples taken in Cycle 1 only, prior to initial dose on days 4 and 5 and at end of infusion, 5, 15, and 30 min, and 1, 2, 3, 4, and 6 hours post infusion | Cmax: Arm A: at Cycle 1 Day 4, Cycle 1 Day 5 Arm B: Cycle 1 Day 1 and Cycle 1 Day 2 |
| Belinostat AUC (Area Under Curve) | Cycle 1, prior to initial dose on days 4 and 5 and at end of infusion, 5, 15, and 30 min, and 1, 2, 3, 4, and 6 hours post infusion | — |
| Elimination t½ | Cycle 1, Samples taken in Cycle 1 only, prior to initial dose on days 4 and 5 and at end of infusion, 5, 15, and 30 min, and 1, 2, 3, 4, and 6 hours post infusion | — |
| Remission Duration | Throughout study, after each cycle for the first two cycles, then after every second cycle | Remission duration: time (weeks) from date of remission status to disease relapse. |
| Duration of Response (CR and PR) | Throughout study, after each cycle for the first two cycles, then after every second cycle | Duration of Response (CR and PR) in Weeks |
Countries
France, Germany, United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm A, Step 1 PXD101 1000 mg/m²/d for 5 consecutive days every 3 weeks. On day 5, Idarubicin 5 mg/m² | 3 |
| Arm A, Step 2 PXD101 1000 mg/m²/d for 5 consecutive days every 3 weeks. On day 5, Idarubicin 10 mg/m² | 3 |
| Arm A, Step 3 PXD101 1000 mg/m²/d for 5 consecutive days every 3 weeks. On days 4 and 5, Idarubicin 7.5 mg/m²/d | 3 |
| Arm A, Step 4 PXD101 1000 mg/m²/d for 5 consecutive days every 3 weeks. On days 4 and 5, Idarubicin 10 mg/m²/d | 9 |
| Arm B, Steps 1-6 PXD101 administered by continuous intravenous infusion over 24-48 hours, doses 25 mg/m²/24 hours to 800 mg/m²/24 hours for 48 hours | 7 |
| Arm B, Step 7 PXD101 administered by continuous intravenous infusion over 48 hours, dose 1000 mg/m²/48 hours
Idarubicin added at 5 mg/m² after 48 hours. Further cycles will be administered q 14 d for up to 6 cycles | 3 |
| Arm B, Step 8 PXD101 administered by continuous intravenous infusion over 48 hours, dose 1000 mg/m²/48 hours
Idarubicin added at 5 mg/m² after 24 and 48 hours. Further cycles will be administered q 14 d for up to 6 cycles | 6 |
| Arm B, Step 9 PXD101 administered by continuous intravenous infusion over 48 hours, dose 1000 mg/m²/48 hours
Idarubicin added at 7.5 mg/m² after 24 and 48 hours. Further cycles will be administered q 14 d for up to 6 cycles | 7 |
| Total | 41 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 |
|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 0 |
| Overall Study | Death | 0 | 0 | 0 | 1 | 0 | 1 | 0 | 2 |
| Overall Study | Progressive disease | 3 | 3 | 3 | 7 | 7 | 1 | 4 | 3 |
| Overall Study | Relapse | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 |
Baseline characteristics
| Characteristic | Arm A, Step 1 | Arm A, Step 2 | Arm A, Step 3 | Arm A, Step 4 | Arm B, Steps 1-6 | Arm B, Step 7 | Arm B, Step 8 | Arm B, Step 9 | Total |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 2 Participants | 2 Participants | 6 Participants | 3 Participants | 3 Participants | 3 Participants | 4 Participants | 25 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants | 1 Participants | 1 Participants | 3 Participants | 4 Participants | 0 Participants | 3 Participants | 3 Participants | 16 Participants |
| Sex: Female, Male Female | 0 Participants | 3 Participants | 0 Participants | 1 Participants | 4 Participants | 1 Participants | 5 Participants | 2 Participants | 16 Participants |
| Sex: Female, Male Male | 3 Participants | 0 Participants | 3 Participants | 8 Participants | 3 Participants | 2 Participants | 1 Participants | 5 Participants | 25 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 | EG006 affected / at risk | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 3 | 3 / 3 | 3 / 3 | 9 / 9 | 6 / 7 | 3 / 3 | 6 / 6 | 7 / 7 |
| serious Total, serious adverse events | 2 / 3 | 2 / 3 | 2 / 3 | 7 / 9 | 2 / 7 | 2 / 3 | 6 / 6 | 6 / 7 |
Outcome results
Primary
Maximum Tolerated Dose, Dose Limiting Toxicity
DLT (dose limiting toxicities): patients with any of the toxicities: 1.Haematological toxicity is not included in the definition due to bone marrow involvement by the disease except for following grade 4 ANC (absolute neutrophil count) and PLT (platelet count) for 6 weeks with less than 5% blasts in bone marrow. 2.Drug related non hematological Grade 3 or 4 toxicity except alopecia, brief nausea and vomiting, diarrhea, rash, arthralgias and myalgias. Treatment interventions should palliate toxicity symptoms prior to concluding a DLT has occurred (e.g if nausea and vomiting to Grade 3 have been associated with the drug). If despite standard treatment Grade 3 nausea and or vomiting persisted then a DLT was considered to have occurred. Grade 4 diarrhea in spite of standard therapeutic measures was included in DLT definition. 3.Inability to tolerate full dosing cycle due to toxicity or any drug-related adverse event resulting in more than 14 day treatment delay in the next treatment cycle
Time frame: First Cycle
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A, Step 1 | Maximum Tolerated Dose, Dose Limiting Toxicity | 0 participants |
| Arm A, Step 2 | Maximum Tolerated Dose, Dose Limiting Toxicity | 0 participants |
| Arm A, Step 3 | Maximum Tolerated Dose, Dose Limiting Toxicity | 0 participants |
| Arm A, Step 4 | Maximum Tolerated Dose, Dose Limiting Toxicity | 0 participants |
| Arm B, Steps 1-6 | Maximum Tolerated Dose, Dose Limiting Toxicity | 0 participants |
| Arm B, Step 7 | Maximum Tolerated Dose, Dose Limiting Toxicity | 0 participants |
| Arm B, Step 8 | Maximum Tolerated Dose, Dose Limiting Toxicity | 0 participants |
| Arm B, Step 9 | Maximum Tolerated Dose, Dose Limiting Toxicity | 0 participants |
Primary
Overall Response
Efficacy measured as Response rate (complete response (\[CR\] and Complete remission with incomplete recovery of platelets \[CRi\]) and partial response (\[PR\])) using the response criteria of the International Working Group (Cheson et al 2003). CR includes CRi, CRc (Cytogenetic complete remission), and CRm (Molecular complete remission).
Time frame: Throughout study, after each cycle for the first two cycles, then after every second cycle
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A, Step 1 | Overall Response | 0 participants |
| Arm A, Step 2 | Overall Response | 1 participants |
| Arm A, Step 3 | Overall Response | 1 participants |
| Arm A, Step 4 | Overall Response | 1 participants |
| Arm B, Steps 1-6 | Overall Response | 1 participants |
| Arm B, Step 7 | Overall Response | 1 participants |
| Arm B, Step 8 | Overall Response | 1 participants |
| Arm B, Step 9 | Overall Response | 3 participants |
Secondary
Belinostat AUC (Area Under Curve)
Time frame: Cycle 1, prior to initial dose on days 4 and 5 and at end of infusion, 5, 15, and 30 min, and 1, 2, 3, 4, and 6 hours post infusion
Population: Results shown for dose level 1000 mg/m2/d
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm A, Step 1 | Belinostat AUC (Area Under Curve) | 21850 ng*hrs/mL | Standard Deviation 10327 |
| Arm A, Step 2 | Belinostat AUC (Area Under Curve) | 21322 ng*hrs/mL | Standard Deviation 7516 |
| Arm A, Step 3 | Belinostat AUC (Area Under Curve) | 172823 ng*hrs/mL | Standard Deviation 280715 |
Secondary
Belinostat Cmax
Cmax: Arm A: at Cycle 1 Day 4, Cycle 1 Day 5 Arm B: Cycle 1 Day 1 and Cycle 1 Day 2
Time frame: Samples taken in Cycle 1 only, prior to initial dose on days 4 and 5 and at end of infusion, 5, 15, and 30 min, and 1, 2, 3, 4, and 6 hours post infusion
Population: Results shown for dose level 1000 mg/m2/d
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm A, Step 1 | Belinostat Cmax | 38744 ng/mL | Standard Deviation 22653 |
| Arm A, Step 2 | Belinostat Cmax | 31952 ng/mL | Standard Deviation 16319 |
| Arm A, Step 3 | Belinostat Cmax | 9657 ng/mL | Standard Deviation 18859 |
Secondary
Duration of Response (CR and PR)
Duration of Response (CR and PR) in Weeks
Time frame: Throughout study, after each cycle for the first two cycles, then after every second cycle
Population: All patients who received at least one dose of belinostat and/or idarubicin were included in the full analysis set (FAS). Duration of response was reported among participants who reported response
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Arm A, Step 2 | Duration of Response (CR and PR) | 26.3 weeks |
| Arm A, Step 3 | Duration of Response (CR and PR) | 20.6 weeks |
| Arm A, Step 4 | Duration of Response (CR and PR) | 28.1 weeks |
| Arm B, Steps 1-6 | Duration of Response (CR and PR) | 5.4 weeks |
| Arm B, Step 7 | Duration of Response (CR and PR) | 30.3 weeks |
| Arm B, Step 8 | Duration of Response (CR and PR) | 19.6 weeks |
| Arm B, Step 9 | Duration of Response (CR and PR) | 4.3 weeks |
Secondary
Elimination t½
Time frame: Cycle 1, Samples taken in Cycle 1 only, prior to initial dose on days 4 and 5 and at end of infusion, 5, 15, and 30 min, and 1, 2, 3, 4, and 6 hours post infusion
Population: Results shown for dose level 1000 mg/m2/d
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm A, Step 1 | Elimination t½ | 12.7 Hours | Standard Deviation 12.2 |
| Arm A, Step 2 | Elimination t½ | 13.1 Hours | Standard Deviation 10.2 |
| Arm A, Step 3 | Elimination t½ | 4.21 Hours | Standard Deviation 2.66 |
Secondary
Event-Free Survival
Event-free survival: time (weeks) from entry into study until treatment failure, disease relapse or death from any cause.
Time frame: Throughout study, after each cycle for the first two cycles, then after every second cycle
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A, Step 1 | Event-Free Survival | 5.1 Weeks |
| Arm A, Step 2 | Event-Free Survival | 3.1 Weeks |
| Arm A, Step 3 | Event-Free Survival | 8.0 Weeks |
| Arm A, Step 4 | Event-Free Survival | 6.5 Weeks |
| Arm B, Steps 1-6 | Event-Free Survival | 2.0 Weeks |
| Arm B, Step 7 | Event-Free Survival | 5.4 Weeks |
| Arm B, Step 8 | Event-Free Survival | 5.4 Weeks |
| Arm B, Step 9 | Event-Free Survival | 6.4 Weeks |
Secondary
Overall Survival
Overall survival: time in weeks from entry into study until death from any cause. All patients without this endpoint at the time of discontinuation or the end of trial have been censored.
Time frame: Throughout study, after each cycle for the first two cycles, then after every second cycle
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A, Step 4 | Overall Survival | 10 Weeks |
| Arm B, Steps 1-6 | Overall Survival | 4.9 Weeks |
| Arm B, Step 7 | Overall Survival | 3.7 Weeks |
| Arm B, Step 9 | Overall Survival | 3.9 Weeks |
Secondary
Relapse-Free Survival
Relapse-free survival: time (weeks) from leukemia-free state to relapse or death from any cause.
Time frame: Throughout study, after each cycle for the first two cycles, then after every second cycle
Population: Relapse free survival was reported among participants who reported response
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A, Step 2 | Relapse-Free Survival | 26.3 Weeks |
| Arm A, Step 3 | Relapse-Free Survival | 20.6 Weeks |
| Arm A, Step 4 | Relapse-Free Survival | 28.1 Weeks |
| Arm B, Step 7 | Relapse-Free Survival | 30.3 Weeks |
| Arm B, Step 9 | Relapse-Free Survival | 6.1 Weeks |
Secondary
Remission Duration
Remission duration: time (weeks) from date of remission status to disease relapse.
Time frame: Throughout study, after each cycle for the first two cycles, then after every second cycle
Population: Remission duration was reported among participants who reported response
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Arm A, Step 2 | Remission Duration | 26.3 Weeks |
| Arm A, Step 3 | Remission Duration | 20.6 Weeks |
| Arm B, Steps 1-6 | Remission Duration | 5.4 Weeks |
| Arm B, Step 7 | Remission Duration | 30.3 Weeks |
| Arm B, Step 8 | Remission Duration | 19.6 Weeks |
| Arm B, Step 9 | Remission Duration | 3.0 Weeks |
Secondary
Time to Response (CR and PR)
Time to response: time in weeks from first treatment to obtainment of the particular response status (CR and PR)
Time frame: Throughout study, after each cycle for the first two cycles, then after every second cycle
Population: Time to response was reported among participants who reported response
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A, Step 2 | Time to Response (CR and PR) | 2.6 Weeks |
| Arm A, Step 3 | Time to Response (CR and PR) | 7.9 Weeks |
| Arm A, Step 4 | Time to Response (CR and PR) | 6.0 Weeks |
| Arm B, Steps 1-6 | Time to Response (CR and PR) | 4.0 Weeks |
| Arm B, Step 7 | Time to Response (CR and PR) | 1.9 Weeks |
| Arm B, Step 8 | Time to Response (CR and PR) | 4.0 Weeks |
| Arm B, Step 9 | Time to Response (CR and PR) | 1.0 Weeks |