BI 811283 in Combination With Cytarabine in Previously Untreated AML Ineligible for Intensive Treatment

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Boehringer Ingelheim
ClinicalTrials.gov Identifier:
NCT00632749
First received: March 4, 2008
Last updated: May 7, 2015
Last verified: May 2015
  Purpose

Investigation of maximum tolerated dose, safety, efficacy and pharmcokinetics of BI 811283 in combination with cytarabine (LD-Ara-C) in previously untreated acute myeloid leukaemia (AML) patients


Condition Intervention Phase
Leukemia, Myeloid, Acute
Drug: BI 811283 (d 1 and 15)
Drug: Cytarabine
Drug: BI 811283 (d1)
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: An Open Phase I/IIa Trial to Investigate the Maximum Tolerated Dose, Safety, Efficacy and Pharmacokinetics of BI 811283 in Combination With Cytarabine in Patients With Previously Untreated Acute Myeloid Leukaemia Ineligible for Intensive Treatment

Resource links provided by NLM:


Further study details as provided by Boehringer Ingelheim:

Primary Outcome Measures:
  • The Maximum Tolerated Dose (MTD) of 2 Schedules of BI 811283 in Combination With Cytarabine. [ Time Frame: up to 28 days of treatment ] [ Designated as safety issue: No ]

    The MTD was defined as the highest dose at which 6 patients were treated and less than 2 patients who experienced a dose limiting toxicities (DLT) within the first cycle of treatment.The MTD was defined based on safety data from the first cycle only.

    It was determined using a standard "3 + 3 design with de-escalation".



Secondary Outcome Measures:
  • Response (Complete Remission [CR], Complete Remission With Incomplete Blood Count Recovery [CRi]) [ Time Frame: Data collected up to cut-off date 20Oct2011, Up to 1239 days ] [ Designated as safety issue: No ]

    Response to treatment was evaluated according to the following criteria (modified from the National Cancer Institute/Cancer and Leukemia Group B criteria:

    The best overall response was defined as the best overall response recorded during the time period from the start of the treatment until the end of the treatment period, progression or death (whichever was earlier). Possible categories for best overall response were CR, CRi, Partial remission (PR), no change (NC), Progressive disease (PD) and no assessment.

    • Complete remission (CR): morphologically leukaemia free state (i.e. bone marrow with < 5% blasts by morphologic criteria and no Auer rods, no evidence of extramedullary leukaemia) and absolute neutrophil count ≥ 1,000/μL and platelets > 100,000/μL.
    • Complete remission with incomplete blood count recovery ("incomplete" CR, CRi).All of the above criteria for CR had to be met, except that neutrophils < 1,000/μL or platelets < 100,000/μL in the blood.

  • Incidence and Intensity of AEs Graded According to CTCAE (Version 3.0) [ Time Frame: Data from first treatment administration until cut-off date of 20 October 2011; up to 1239 days ] [ Designated as safety issue: No ]

    The severity and timing of AEs indicates how well the treatment regimen was tolerated.

    Toxicities were evaluated using the common terminology criteria for adverse events (CTCAE) grading scheme.


  • Incidence of Dose Limiting Toxicity (DLT) [ Time Frame: up to 28 days of treatment ] [ Designated as safety issue: No ]
    Number of participants with DLT in the first cycle (28 days) for the determination of the maximum tolerated dose (MTD)

  • Partial Remission [ Time Frame: Data collected up to cut-off date 20 Oct 2011, Up to 1239 days ] [ Designated as safety issue: No ]

    Response to treatment was evaluated according to the following criteria (modified from the National Cancer Institute/Cancer and Leukemia Group B criteria; The best overall response was defined as the best overall response recorded during the time period from the start of the treatment until the end of the treatment period, progression or death (whichever was earlier). Possible categories for best overall response were CR, CRi, Partial remission (PR), no change (NC), Progressive disease (PD) and no assessment.

    Partial remission (PR). All of the criteria for CR had to be met, except that the bone marrow had to contain ≥ 5% but less than 25% blasts (or ≤ 50% of initial blast count), or < 5% blasts in the presence of Auer rods or abnormal morphology.


  • Event Free Survival (EFS) [ Time Frame: Data collected up to cut-off date 20 Oct 2011, Up to 1239 days ] [ Designated as safety issue: No ]
    EFS was defined as the duration of time from randomisation to time of treatment failure (i.e. PD), relapse from CR, or death from any cause, whichever came first.

  • Relapse Free Survival [ Time Frame: Data collected up to cut-off date 20 Oct 2011, Up to 1239 days ] [ Designated as safety issue: No ]

    Relapse-free survival was defined only for patients who achieved CR/CRi and was measured from the date of attaining CR/CRi until the date of recurrence or death from any cause, whichever occurred first.

    Number of patients having relapse free survival are presented.


  • Remission Duration [ Time Frame: Data collected up to cut-off date 20 Oct 2011, Up to 1239 days ] [ Designated as safety issue: No ]
    Remission duration analysis was defined only for patients who achieved CR, and was measured from the date of attaining CR until the date of disease recurrence (relapse). For patients who died without report of relapse, remission duration was censored on the date of death, regardless of the cause.

  • Overall Survival (OS) [ Time Frame: Data collected up to cut-off date 20 Oct 2011, Up to 1239 days ] [ Designated as safety issue: No ]
    OS was defined for all patients that entered the trial, and measured from the date of randomization until death from any cause.

  • Cmax (Maximum Measured Concentration of BI 811283 in Plasma) [ Time Frame: -0.05 hours before and 1:00, 4:00, 6:00, 24:00, 25:00, 26:00, 28:00, 32:00, 36:00, 48:00 hours after administration of BI 811283 ] [ Designated as safety issue: No ]
    Cmax (maximum measured concentration of BI 811283 in plasma) during Cycle 1

  • AUC(0-inf) (Area Under the Concentration-time Curve of BI 811283 in Plasma Over the Time Interval From 0 Extrapolated to Infinity) [ Time Frame: -0.05 hours before and 1:00, 4:00, 6:00, 24:00, 25:00, 26:00, 28:00, 32:00, 36:00, 48:00 hours after administration of BI 811283 ] [ Designated as safety issue: No ]
    AUC(0-inf) (area under the concentration-time curve of BI 811283 in plasma over the time interval from 0 extrapolated to infinity) during Cycle 1

  • AUC0-tz (Area Under the Concentration-time Curve of BI 811283 in Plasma Over the Time Interval From 0 to the Time of the Last Quantifiable Data Point) [ Time Frame: -0.05 hours before and 1:00, 4:00, 6:00, 24:00, 25:00, 26:00, 28:00, 32:00, 36:00, 48:00 hours after administration of BI 811283 ] [ Designated as safety issue: No ]
    AUC0-tz (area under the concentration-time curve of BI 811283 in plasma over the time interval from 0 to the time of the last quantifiable data point) during Cycle 1

  • Cmax,ss (Maximum Measured Concentration of BI 811283 in Plasma at Steady State) [ Time Frame: -0.05 hours before and 1:00, 4:00, 6:00, 24:00, 25:00, 26:00, 28:00, 32:00, 36:00, 48:00 hours after administration of BI 811283 ] [ Designated as safety issue: No ]
    Cmax (maximum measured concentration of BI 811283 in plasma at steady state) during Cycle 1

  • AUC (0-inf, ss)(Area Under the Concentration-time Curve of BI 811283 in Plasma Over the Time Interval From 0 Extrapolated to Infinity) at Steady State [ Time Frame: -0.05 hours before and 1:00, 4:00, 6:00, 24:00, 25:00, 26:00, 28:00, 32:00, 36:00, 48:00 hours after administration of BI 811283 ] [ Designated as safety issue: No ]
    AUC (0-inf, ss)(area under the concentration-time curve of BI 811283 in plasma over the time interval from 0 extrapolated to infinity) at steady state during Cycle 1

  • AUC (0-tz,ss) (Area Under the Concentration-time Curve of BI 811283 in Plasma Over the Time Interval From 0 to the Time of the Last Quantifiable Data Point) at Steady State [ Time Frame: -0.05 hours before and 1:00, 4:00, 6:00, 24:00, 25:00, 26:00, 28:00, 32:00, 36:00, 48:00 hours after administration of BI 811283 ] [ Designated as safety issue: No ]
    AUC (0-tz,ss) (area under the concentration-time curve of BI 811283 in plasma over the time interval from 0 to the time of the last quantifiable data point) at steady state during Cycle 1

  • Tmax (Time From Dosing to Maximum Measured Concentration of BI 811283 in Plasma) [ Time Frame: -0.05 hours before and 1:00, 4:00, 6:00, 24:00, 25:00, 26:00, 28:00, 32:00, 36:00, 48:00 hours after administration of BI 811283 ] [ Designated as safety issue: No ]
    tmax (time from dosing to maximum measured concentration of BI 811283 in plasma) during Cycle 1

  • Tmax,ss (Time From Dosing to Maximum Measured Concentration of BI 811283 in Plasma at Steady State) [ Time Frame: -0.05 hours before and 1:00, 4:00, 6:00, 24:00, 25:00, 26:00, 28:00, 32:00, 36:00, 48:00 hours after administration of BI 811283 ] [ Designated as safety issue: No ]
    tmax,ss (time from dosing to maximum measured concentration of BI 811283 in plasma at steady state) during Cycle 1

  • Cmax (Maximum Measured Concentration of Cytarabine in Plasma) [ Time Frame: -0.05 hours before and 0:30, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00 hours after administration of Cytarabine ] [ Designated as safety issue: No ]
    Cmax of Cytarabine after a 20 mg Subcutaneous Dose on the First Day of BI 811283

  • Tmax (Time From Dosing to Maximum Measured Concentration of Cytarabine in Plasma) [ Time Frame: -0.05 hours before and 0:30, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00 hours after administration of Cytarabine ] [ Designated as safety issue: No ]
    Tmax of Cytarabine after a 20 mg Subcutaneous Dose on the First Day of BI 811283

  • AUC (0-inf) (Area Under the Concentration-time Curve of Cytarabine in Plasma Over the Time Interval From 0 Extrapolated to Infinity) [ Time Frame: -0.05 hours before and 0:30, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00 hours after administration of Cytarabine ] [ Designated as safety issue: No ]
    AUC (0-inf) of Cytarabine after a 20 mg Subcutaneous Dose on the First Day of BI 811283

  • AUC (0-tz) (Area Under the Concentration-time Curve of Cytarabine in Plasma Over the Time Interval From 0 to the Time of the Last Quantifiable Data Point) [ Time Frame: -0.05 hours before and 0:30, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00 hours after administration of Cytarabine ] [ Designated as safety issue: No ]
    AUC (0-tz) of Cytarabine after a 20 mg Subcutaneous Dose on the First Day of BI 811283

  • Pharmacodynamic Monitoring [ Time Frame: On Day 5, i.e. 72 hours after the end of the first BI 811283 infusion, and on Day 28 in the first cycle only ] [ Designated as safety issue: No ]

    Pharmacodynamic monitoring: drug effect on leukaemia cells (e.g. polyploidy, histone H3 phosphorylation, morphologic changes).

    An evaluation of this secondary endpoint is not possible due to missing samples / samples of poor quality of the provided material.


  • Pharmacokinetics of Cytarabine After a Single Dose and at Steady State When Given Alone [ Time Frame: -0.05, 0:30, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00 hours ] [ Designated as safety issue: No ]

    The study protocol originally included a phase II part with a treatment arm in which Cytarabine was given alone, however the sponsor discontinued the clinical development of BI 811283, therefore the protocol was amended and the reference therapy arm was removed from the study protocol" -> (Protocol Amendment 5, version 19 -May-2010, approved 28-Jun-2010).

    Since there was never a treatment arm in which Cytarabine was given alone; hence pharmacokinetics are not calculated.



Enrollment: 68
Study Start Date: May 2008
Study Completion Date: March 2014
Primary Completion Date: March 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Schedule A
BI 811283 on days 1 and 15 in combination with Cytarabine 20 mg twice daily on Days 1-10
Drug: BI 811283 (d 1 and 15)
BI 811283 (24 hours i.v.c.i.) on day 1 and 15 of a 4-week treatment cycle
Drug: Cytarabine
Cytarabine 2 x 20 mg/d s.c. on days 1-10 of a 4-week treatment cycle
Experimental: Schedule B
BI 811283 on Day 1 in combination with Cytarabine 20 mg twice daily on Days 1-10
Drug: Cytarabine
Cytarabine 2 x 20 mg/d s.c. on days 1-10 of a 4-week treatment cycle
Drug: BI 811283 (d1)
BI 811283 (24 hours i.v.c.i.) on day 1 of a 4-week treatment cycle

  Eligibility

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

Inclusion criteria:

  • Male or female adult with previously untreated acute myeloid leukaemia (AML)
  • Confirmed diagnosis of AML according to the WHO definition (except for acute promyelocytic leukaemia, APL)
  • Patient is considered ineligible for intensive treatment
  • Patient is eligible for low-dose cytarabine (LD-Ara-C) treatment
  • Life expectancy > 3 months
  • Eastern co-operative oncology group (ECOG, R01-0787) performance score <=2 at screening
  • Signed written informed consent consistent with international conference on harmonisation good clinical practice (ICH-GCP) and local legislation

Exclusion criteria:

  • Patient with APL (AML subtype M3 according to the French-American-British (FAB) classification).
  • Relapsed or treatment refractory AML.
  • Hypersensitivity to one of the trial drugs or the excipients.
  • Other malignancy requiring treatment.
  • Known central nervous system involvement.
  • Aspartate amino transferase (AST) or alanine amino transferase (ALT) greater than 2.5 times the upper limit of normal (ULN).
  • INR > 1.5 x ULN for subjects not on therapeutic vitamin K antagonists (phenprocoumon, warfarin).
  • Bilirubin greater than 1.5 mg/dl.
  • Serum creatinine greater than 2.0 mg/dl.
  • LVEF (Left ventricular ejection fraction) < 50% in echocardiography or clinical congestive heart failure New York Heart Association (NYHA) grade III or IV.
  • Concomitant intercurrent illness, which would compromise the evaluation of efficacy or safety of the trial drug, e.g. active severe infection, unstable angina pectoris or cardiac arrhythmia.
  • Psychiatric illness or social situation that would limit compliance with trial requirements.
  • Concomitant therapy, which is considered relevant for the evaluation of the efficacy or safety of the trial drug (i.e. other chemo- or immunotherapy, see also section 4.2.2).
  • Contraindications for cytarabine treatment according to the summary of product characteristics (SPC).
  • Patients who are sexually active and unwilling to use a medically acceptable method of contraception during the trial (hormonal contraception, intrauterine device, condom with spermicide, etc.).
  • Pregnant or nursing female patients.
  • Patient unable to comply with the protocol.
  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: NCT00632749

Locations
Germany
1247.3.49007 Boehringer Ingelheim Investigational Site
Berlin, Germany
1247.3.49005 Boehringer Ingelheim Investigational Site
Frankfurt/Main, Germany
1247.3.49004 Boehringer Ingelheim Investigational Site
Freiburg, Germany
1247.3.49006 Boehringer Ingelheim Investigational Site
Hamburg, Germany
1247.3.49003 Boehringer Ingelheim Investigational Site
Heidelberg, Germany
1247.3.49002 Boehringer Ingelheim Investigational Site
Münster, Germany
1247.3.49001 Boehringer Ingelheim Investigational Site
Ulm, Germany
Sponsors and Collaborators
Boehringer Ingelheim
Investigators
Study Chair: Boehringer Ingelheim Boehringer Ingelheim
  More Information

Additional Information:
No publications provided

Responsible Party: Boehringer Ingelheim
ClinicalTrials.gov Identifier: NCT00632749     History of Changes
Other Study ID Numbers: 1247.3, 2007-005684-10
Study First Received: March 4, 2008
Results First Received: March 27, 2015
Last Updated: May 7, 2015
Health Authority: Germany: Bundesinstitut fuer Arzneimittel und Medizinprodukte

Additional relevant MeSH terms:
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Leukemia
Neoplasms
Neoplasms by Histologic Type
Cytarabine
Anti-Infective Agents
Antimetabolites
Antimetabolites, Antineoplastic
Antineoplastic Agents
Antiviral Agents
Immunologic Factors
Immunosuppressive Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses

ClinicalTrials.gov processed this record on July 28, 2015