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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
TopoTarget A/S
ClinicalTrials.gov Identifier:
NCT00878722
First received: April 7, 2009
Last updated: November 12, 2014
Last verified: November 2014
  Purpose

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.


Condition Intervention Phase
Acute Myeloid Leukemia
Drug: PXD101
Drug: idarubicin
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I/II Clinical Trial of PXD101 in Combination With Idarubicin in Patients With AML Not Suitable for Standard Intensive Therapy

Resource links provided by NLM:


Further study details as provided by TopoTarget A/S:

Primary Outcome Measures:
  • Maximum Tolerated Dose, Dose Limiting Toxicity [ Time Frame: First Cycle ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: Throughout study, after each cycle for the first two cycles, then after every second cycle ] [ Designated as safety issue: No ]
    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 Frame: Throughout study, after each cycle for the first two cycles, then after every second cycle ] [ Designated as safety issue: No ]
    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) [ Time Frame: Throughout study, after each cycle for the first two cycles, then after every second cycle ] [ Designated as safety issue: No ]
    Duration of Response (CR and PR) in Weeks

  • Overall Survival [ Time Frame: Throughout study, after each cycle for the first two cycles, then after every second cycle ] [ Designated as safety issue: No ]
    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 [ Time Frame: Throughout study, after each cycle for the first two cycles, then after every second cycle ] [ Designated as safety issue: No ]
    Relapse-free survival: time (weeks) from leukemia-free state to relapse or death from any cause.

  • Event-Free Survival [ Time Frame: Throughout study, after each cycle for the first two cycles, then after every second cycle ] [ Designated as safety issue: No ]
    Event-free survival: time (weeks) from entry into study until treatment failure, disease relapse or death from any cause.

  • Remission Duration [ Time Frame: Throughout study, after each cycle for the first two cycles, then after every second cycle ] [ Designated as safety issue: No ]
    Remission duration: time (weeks) from date of remission status to disease relapse.

  • Belinostat Cmax [ 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 ] [ Designated as safety issue: No ]
    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) [ 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 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]

Enrollment: 41
Study Start Date: August 2007
Study Completion Date: April 2012
Primary Completion Date: May 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm A

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
Other Name: Belinostat
Drug: idarubicin
Other Name: Zavedos
Experimental: Arm B
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
Other Name: Belinostat
Drug: idarubicin
Other Name: Zavedos

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).

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00878722

Locations
France
CHU Lapeyronie
Montpellier, France, 34295
Hôpital St. Louis
Paris, France, 75475
Germany
Uniklinik Homburg
Homburg, Germany, 66424
Uni Hospital Marburg
Marburg, Germany, 35043
Universitätsklinikum Ulm
Ulm, Germany, 89081
United Kingdom
Christie Hospital NHS Trust
Manchester, United Kingdom, M20 4BX
Sponsors and Collaborators
TopoTarget A/S
Investigators
Study Chair: e-mail contact via enquiries@topotarget.com TopoTarget A/S
  More Information

No publications provided

Responsible Party: TopoTarget A/S
ClinicalTrials.gov Identifier: NCT00878722     History of Changes
Other Study ID Numbers: PXD101-CLN-15
Study First Received: April 7, 2009
Results First Received: June 27, 2014
Last Updated: November 12, 2014
Health Authority: France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
Germany: Federal Institute for Drugs and Medical Devices
United Kingdom: Medicines and Healthcare Products Regulatory Agency
United States: Food and Drug Administration

Keywords provided by TopoTarget A/S:
Acute Myeloid Leukemia
PXD101
Belinostat
Idarubicin

Additional relevant MeSH terms:
Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms
Neoplasms by Histologic Type
Belinostat
Idarubicin
Antibiotics, Antineoplastic
Antineoplastic Agents
Enzyme Inhibitors
Histone Deacetylase Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Therapeutic Uses
Topoisomerase II Inhibitors
Topoisomerase Inhibitors

ClinicalTrials.gov processed this record on November 24, 2014