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

Acute Myeloid Leukemia Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00878722
• Other study ID #: PXD101-CLN-15
• Status: Completed
• Phase: Phase 1/Phase 2
• First received: April 7, 2009
• Last updated: July 6, 2015
• Start date: August 2007
• Est. completion date: April 2012

Study information

• Verified date: July 2015
• Source: Onxeo
• Contact: n/a
• Is FDA regulated: No
• Health authority: France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)Germany: Federal Institute for Drugs and Medical DevicesUnited Kingdom: Medicines and Healthcare Products Regulatory AgencyUnited States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 41
• Est. completion date: April 2012
• Est. primary completion date: May 2009
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Acute Myeloid Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute

Intervention

Drug:
• PXD101

• idarubicin

Locations

Country	Name	City	State
France	CHU Lapeyronie	Montpellier
France	Hôpital St. Louis	Paris
Germany	Uniklinik Homburg	Homburg
Germany	Uni Hospital Marburg	Marburg
Germany	Universitätsklinikum Ulm	Ulm
United Kingdom	Christie Hospital NHS Trust	Manchester

Sponsors (1)

Lead Sponsor	Collaborator
Onxeo

Countries where clinical trial is conducted

France,  Germany,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
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	First Cycle	Yes
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).	Throughout study, after each cycle for the first two cycles, then after every second cycle	No
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)	Throughout study, after each cycle for the first two cycles, then after every second cycle	No
Secondary	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	No
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.	Throughout study, after each cycle for the first two cycles, then after every second cycle	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
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	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	No
Secondary	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	No
Secondary	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	No