Back to resultsTrial of PXD101 (Belinostat) in Combination With Idarubicin to Treat AML Not Suitable for Standard Intensive Therapy
Primary Purpose
Acute Myeloid Leukemia
Status
Completed
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
PXD101
idarubicin
Sponsored by
About this trial
This is an interventional treatment trial for Acute Myeloid Leukemia focused on measuring Acute Myeloid Leukemia, PXD101, Belinostat, Idarubicin
Eligibility Criteria
Inclusion Criteria: (abbreviated)
- Signed consent
AML patients:
- above 60 years in first relapse or refractory.
- 18-60 years 2nd relapse or refractory to at least two intensive chemotherapy regimens.
- 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.
- Performance status (ECOG) ≤ 2
- Age ≥ 18 years
- Acceptable liver, renal and bone marrow function as defined
- Serum potassium within normal range.
- Acceptable coagulation status as defined
- Precautions for female patients with reproductive potential as defined
Exclusion Criteria:
- Treatment with investigational agents within the last 4 weeks
- Prior treatment with HDAC (Histone deacetylases) inhibitors including valproic acid
- Prior anti-leukemic therapy (except hydroxyurea) within the last 3 weeks of trial dosing
- Co-existing active infection (including HIV) or any co-existing medical condition likely to interfere with trial procedures, including significant cardiovascular disease
- Altered mental status precluding understanding of the informed consent process and/or completion of the necessary study procedures.
- Concurrent second malignancy.
- History of hypersensitivity to idarubicin
- Cumulative idarubicin dose exceeding 100 mg/m², or a (with respect cardiotoxicity) corresponding dose of other anthracyclines
- LVEF (left ventricular ejection fraction) below normal range (< 45% )
- Known Central Nervous System (CNS) leukemia
Sites / Locations
- CHU Lapeyronie
- Hôpital St. Louis
- Uniklinik Homburg
- Uni Hospital Marburg
- Universitätsklinikum Ulm
- Christie Hospital NHS Trust
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Experimental
Arm Label
Arm A
Arm B
Arm Description
PXD101 administered as a 30-minute intravenous (IV) infusion of 1000 mg/m²/d for five consecutive days every 3 weeks. Idarubicin administered on day 5 (first steps) or days 4 and 5 (later steps). Patients will be treated in a 21-day cycle for a minimum of 2 cycles and a maximum of 6 cycles (depending on cumulated idarubicin dose).
PXD101 administered by continuous intravenous infusion over 24-48 hours and idarubicin (in the later steps) added after the first 24 hours. The second cycle will start on day 15 but under observation of possible toxicity. Further cycles will be administered q 14 d for up to 6 cycles. The first dose steps will be carried out with PXD101 alone for safety reasons.
Outcomes
Primary Outcome Measures
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
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).
Secondary Outcome Measures
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)
Duration of Response (CR and PR)
Duration of Response (CR and PR) in Weeks
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.
Relapse-Free Survival
Relapse-free survival: time (weeks) from leukemia-free state to relapse or death from any cause.
Event-Free Survival
Event-free survival: time (weeks) from entry into study until treatment failure, disease relapse or death from any cause.
Remission Duration
Remission duration: time (weeks) from date of remission status to disease relapse.
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
Belinostat AUC (Area Under Curve)
Elimination t½
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT00878722
Brief Title
Trial of PXD101 (Belinostat) in Combination With Idarubicin to Treat AML Not Suitable for Standard Intensive Therapy
Official Title
A Phase I/II Clinical Trial of PXD101 in Combination With Idarubicin in Patients With AML Not Suitable for Standard Intensive Therapy
Study Type
Interventional
2. Study Status
Record Verification Date
July 2015
Overall Recruitment Status
Completed
Study Start Date
August 2007 (undefined)
Primary Completion Date
May 2009 (Actual)
Study Completion Date
April 2012 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Onxeo
4. Oversight
5. Study Description
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).
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute Myeloid Leukemia
Keywords
Acute Myeloid Leukemia, PXD101, Belinostat, Idarubicin
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
41 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Arm A
Arm Type
Experimental
Arm Description
PXD101 administered as a 30-minute intravenous (IV) infusion of 1000 mg/m²/d for five consecutive days every 3 weeks.
Idarubicin administered on day 5 (first steps) or days 4 and 5 (later steps). Patients will be treated in a 21-day cycle for a minimum of 2 cycles and a maximum of 6 cycles (depending on cumulated idarubicin dose).
Arm Title
Arm B
Arm Type
Experimental
Arm Description
PXD101 administered by continuous intravenous infusion over 24-48 hours and idarubicin (in the later steps) added after the first 24 hours. The second cycle will start on day 15 but under observation of possible toxicity. Further cycles will be administered q 14 d for up to 6 cycles. The first dose steps will be carried out with PXD101 alone for safety reasons.
Intervention Type
Drug
Intervention Name(s)
PXD101
Other Intervention Name(s)
Belinostat
Intervention Type
Drug
Intervention Name(s)
idarubicin
Other Intervention Name(s)
Zavedos
Primary Outcome Measure Information:
Title
Maximum Tolerated Dose, Dose Limiting Toxicity
Description
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
Title
Overall Response
Description
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
Secondary Outcome Measure Information:
Title
Time to Response (CR and PR)
Description
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
Title
Duration of Response (CR and PR)
Description
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
Title
Overall Survival
Description
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
Title
Relapse-Free Survival
Description
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
Title
Event-Free Survival
Description
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
Title
Remission Duration
Description
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
Title
Belinostat Cmax
Description
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
Title
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
Title
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
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: (abbreviated)
Signed consent
AML patients:
above 60 years in first relapse or refractory.
18-60 years 2nd relapse or refractory to at least two intensive chemotherapy regimens.
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.
Performance status (ECOG) ≤ 2
Age ≥ 18 years
Acceptable liver, renal and bone marrow function as defined
Serum potassium within normal range.
Acceptable coagulation status as defined
Precautions for female patients with reproductive potential as defined
Exclusion Criteria:
Treatment with investigational agents within the last 4 weeks
Prior treatment with HDAC (Histone deacetylases) inhibitors including valproic acid
Prior anti-leukemic therapy (except hydroxyurea) within the last 3 weeks of trial dosing
Co-existing active infection (including HIV) or any co-existing medical condition likely to interfere with trial procedures, including significant cardiovascular disease
Altered mental status precluding understanding of the informed consent process and/or completion of the necessary study procedures.
Concurrent second malignancy.
History of hypersensitivity to idarubicin
Cumulative idarubicin dose exceeding 100 mg/m², or a (with respect cardiotoxicity) corresponding dose of other anthracyclines
LVEF (left ventricular ejection fraction) below normal range (< 45% )
Known Central Nervous System (CNS) leukemia
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
e-mail contact via enquiries@topotarget.com
Organizational Affiliation
Onxeo
Official's Role
Study Chair
Facility Information:
Facility Name
CHU Lapeyronie
City
Montpellier
ZIP/Postal Code
34295
Country
France
Facility Name
Hôpital St. Louis
City
Paris
ZIP/Postal Code
75475
Country
France
Facility Name
Uniklinik Homburg
City
Homburg
ZIP/Postal Code
66424
Country
Germany
Facility Name
Uni Hospital Marburg
City
Marburg
ZIP/Postal Code
35043
Country
Germany
Facility Name
Universitätsklinikum Ulm
City
Ulm
ZIP/Postal Code
89081
Country
Germany
Facility Name
Christie Hospital NHS Trust
City
Manchester
ZIP/Postal Code
M20 4BX
Country
United Kingdom
12. IPD Sharing Statement
Learn more about this trial
Trial of PXD101 (Belinostat) in Combination With Idarubicin to Treat AML Not Suitable for Standard Intensive Therapy
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