Trial of PXD101 (Belinostat) in Combination With Idarubicin to Treat AML Not Suitable for Standard Intensive Therapy

Study Overview
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Brief Summary
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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
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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).

Official Title
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A Phase I/II Clinical Trial of PXD101 in Combination With Idarubicin in Patients With AML Not Suitable for Standard Intensive Therapy

Conditions
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Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: PXD101
* Drug: idarubicin


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A<br>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). | Drug: PXD101<br> <br> * Other names: Belinostat;Drug: idarubicin<br> <br> * Other names: Zavedos;|
| Experimental: Arm B<br>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. | Drug: PXD101<br> <br> * Other names: Belinostat;Drug: idarubicin<br> <br> * Other names: Zavedos;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | First 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). | Throughout study, after each cycle for the first two cycles, then after every second cycle | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | Throughout study, after each cycle for the first two cycles, then after every second cycle | 
| Duration of Response (CR and PR) | Duration of Response (CR and PR) in Weeks | Throughout study, after each cycle for the first two cycles, then after every second cycle | 
| 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. | Throughout study, after each cycle for the first two cycles, then after every second cycle | 
| Relapse-Free Survival | Relapse-free survival: time (weeks) from leukemia-free state to relapse or death from any cause. | Throughout study, after each cycle for the first two cycles, then after every second cycle | 
| Event-Free Survival | Event-free survival: time (weeks) from entry into study until treatment failure, disease relapse or death from any cause. | Throughout study, after each cycle for the first two cycles, then after every second cycle | 
| Remission Duration | Remission duration: time (weeks) from date of remission status to disease relapse. | Throughout study, after each cycle for the first two cycles, then after every second cycle | 
| 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 | 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 | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acute Myeloid Leukemia, PXD101, Belinostat, Idarubicin