A Study of the Histone-deacetylase Inhibitor JNJ-26481585 in Patients With Advanced or Refractory Leukemia or Myelodysplastic Syndrome

This study has been terminated.
(Sponsor Decision)
Sponsor:
Information provided by (Responsible Party):
Johnson & Johnson Pharmaceutical Research & Development, L.L.C.
ClinicalTrials.gov Identifier:
NCT00676728
First received: May 8, 2008
Last updated: September 13, 2012
Last verified: September 2012
  Purpose

The purpose of this study is to explore the safety, pharmacokinetic (what the body does to the medication), pharmacodynamic (what the medication does to the body), and activity of JNJ-26481585 in patients with advanced or refractory leukemia and myelodysplastic syndrome (MDS).


Condition Intervention Phase
Advanced or Refractory Leukemia
Myelodysplastic Syndromes
Drug: JNJ-26481585
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase 1 Study of the Histone-deacetylase Inhibitor JNJ-26481585 in Subjects With Advanced or Refractory Leukemia or Myelodysplastic Syndrome

Resource links provided by NLM:


Further study details as provided by Johnson & Johnson Pharmaceutical Research & Development, L.L.C.:

Primary Outcome Measures:
  • Number of patients with adverse events [ Time Frame: Upto 14 days after last dose administration of study medication ] [ Designated as safety issue: Yes ]
  • Number of patients with dose limiting toxicity [DLT] [ Time Frame: From the date of dosing upto 3 months after the date the last patient enrolled in Part I of the study, received the first dose of study medication ] [ Designated as safety issue: Yes ]
    Only toxicities that occur during Treatment Cycle 1 will be used for the purposes of defining DLT.

  • Maximum tolerated dose (MTD) of JNJ 26481585 [ Time Frame: From the date of dosing upto 3 months after the date the last patient enrolled in Part I of the study, received the first dose of study medication ] [ Designated as safety issue: No ]
    The MTD is defined as the highest dose with an observed incidence of DLT in no more than 1 in 6 patients.


Secondary Outcome Measures:
  • Maximum plasma concentration (Cmax) of JNJ 26481585 [ Time Frame: Days 1, 2, 8, 15 and 21 of Cycle 1 ] [ Designated as safety issue: No ]
  • Time to reach maximum plasma concentration (tmax) of JNJ-26481585 [ Time Frame: Days 1, 2, 8, 15 and 21 of Cycle 1 ] [ Designated as safety issue: No ]
  • Area under the plasma concentration-time curve from time 0 to 24 hours (AUC0-24) [ Time Frame: Days 1, 2, 8, 15 and 21 of Cycle 1 ] [ Designated as safety issue: No ]
  • Elimination half-life (t1/2) of JNJ-26481585 [ Time Frame: Days 1, 2, 8, 15 and 21 of Cycle 1 ] [ Designated as safety issue: No ]
  • Cumulative amount of drug excreted in urine over 24 hours (Ae24) [ Time Frame: Days 1 and 21 of Cycle 1 ] [ Designated as safety issue: No ]
  • Renal clearance (CLR) of JNJ 26395018 [ Time Frame: Days 1 and 21 of Cycle 1 ] [ Designated as safety issue: No ]
  • Concentration of biomarker histone acetylation [ Time Frame: Days 1 and 21 of Cycle 1; Day 21 of Cycles 2 to 20 ] [ Designated as safety issue: No ]
  • Concentration of biomarker interleukin-6 (IL-6) [ Time Frame: Days 1 and 21 of Cycle 1; Day 21 of Cycles 2 to 20 ] [ Designated as safety issue: No ]
  • Concentration of biomarker heat shock protein 90 (Hsp90) [ Time Frame: Days 1 and 21 of Cycle 1; Day 21 of Cycles 2 to 20 ] [ Designated as safety issue: No ]
  • Complete Blood Count (CBC) [ Time Frame: Pre-treatment (within 4 weeks prior to first dose of JNJ-26481585); Days 1, 3, 8, 15 and 21 of Cycle 1; Days 8, 15 and 21 of Cycle 2; Day 21 of Cycle 3 to 20; follow up (within 14 days after last dose of JNJ-26481585) ] [ Designated as safety issue: No ]
    Anticancer activity of JNJ-26481585 explored by assessment of response parameters such as CBC.

  • Assessment of Transfusion Record [ Time Frame: From Day 1 of Cycle 1 upto 14 days after last dose ] [ Designated as safety issue: No ]
    Assessment of Transfusion Record is the parameter for assessment of response.

  • Radiological Tumor Mass assessment [ Time Frame: Pre-treatment, Day 21 of Cycle 2 to 20 and follow up ] [ Designated as safety issue: No ]
    Radiological Tumor Mass assessment is the parameter for assessment of response.

  • Bone marrow aspirate/biopsy assessment [ Time Frame: Pre-treatment, Day 21 of Cycles 1 to 20 ] [ Designated as safety issue: No ]
    Bone marrow aspirate/biopsy assessment is the parameter for assessment of response.


Enrollment: 10
Study Start Date: December 2008
Study Completion Date: September 2011
Primary Completion Date: September 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: JNJ-26481585 Drug: JNJ-26481585
In Part 1, Initial dose of JNJ-26481585 4 mg oral capsule is administered once daily on each day of a 21-day cycle. Dose will be escalated or de-escalated until Maximum tolerated dose (MTD) of JNJ-26481585 is determined in Part 1. MTD of JNJ-26481585 will be the initial dose in Part 2.

Detailed Description:

This is an open-label (all people know the identity of the intervention), Phase 1 dose escalation, 2-part study (Part I and Part II). In Part I of the study, the Maximum Tolerated Dose (MTD) defined as the highest dose with an observed incidence of dose limiting toxicity (DLT) in no more than 1 in 6 patients, will be determined using rapid escalation (Stage 1) followed by conventional escalation (Stage 2). In Stage 1, at least 2 patients will be enrolled at each dose level; dose increments of 100% will be applied. In Stage 2, at least 3 patients will be enrolled at each dose level and dose increments of 20-50% will be implemented. Decisions on dose escalation or de-escalation, changes in the timing of pharmacokinetic/pharmacodynamic sampling, and the exploration of an alternative schedule were to be made by the Study Evaluation Team (SET), which consisted of all principal investigators, the medical monitor, and 1 of the sponsor's clinical pharmacologists. Part II of the study will be the expansion phase, which will begin after the MTD had been determined in Part I and an additional cohort of patients with MDS will be enrolled to further explore the safety and activity of JNJ 26481585 in patients with MDS. The starting dose for patients enrolled in Part II of the study was to be the MTD established in Part I. Depending on the outcome, the SET may decide to continue at the MTD dose, or dose-de-escalate to the next lower level (25 50% decrement from MTD). The cohort for MDS will be expanded to consist of 16 evaluable patients. Safety will be evaluated throughout the study and will include evaluations of adverse events clinical laboratory tests, electrocardiogram (ECG), vital signs, 24 hours Holter ECG, physical examination, Eastern Cooperative Oncology Group performance status and Multiple Gated Acquisition scan or echocardiography.

  Eligibility

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

Inclusion Criteria:

  • Histologically or cytologically confirmed advanced or refractory acute myeloid leukemia, acute lymphocytic leukemia, chronic myeloid leukemia in blast phase, refractory chronic lymphocytic leukemia, myelodysplastic syndrome, or chronic myelomonocytic leukemia
  • For Part II, patients with myelodysplastic syndrome
  • Eastern Cooperative Oncology Group Performance Status Score 0, 1 or 2
  • Left Ventricular Ejection Fraction greater than or equal to 50%
  • Negative hepatitis B, C and human immunodeficiency virus (HIV) test within last 3 months
  • Adequate liver and kidney function

Exclusion Criteria:

  • Known or suspected involvement of the central nervous system
  • Chemotherapy (nitrosoureas and mitomycin C within 6 weeks), radiotherapy, immunotherapy or treatment with investigative agent within 3 weeks before study drug administration (except hydroxyurea which should be stopped at least 24 hours prior to first dose)
  • Unstable angina or myocardial infarction within the preceding 12 months; congestive heart failure
  • Poorly controlled hypertension or diabetes, ongoing active infection and psychiatric illness
  • Receiving medications known to have a risk of causing QTc prolongation
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00676728

Locations
United States, Maryland
Baltimore, Maryland, United States
United States, Texas
Houston, Texas, United States
Sponsors and Collaborators
Johnson & Johnson Pharmaceutical Research & Development, L.L.C.
Investigators
Study Director: Johnson & Johnson Pharmaceutical Research & Development, L.L. C. Clinical Trial Johnson & Johnson Pharmaceutical Research & Development, L.L.C.
  More Information

Additional Information:
No publications provided

Responsible Party: Johnson & Johnson Pharmaceutical Research & Development, L.L.C.
ClinicalTrials.gov Identifier: NCT00676728     History of Changes
Other Study ID Numbers: CR013960, 26481585CAN1003
Study First Received: May 8, 2008
Last Updated: September 13, 2012
Health Authority: United States: Food and Drug Administration

Keywords provided by Johnson & Johnson Pharmaceutical Research & Development, L.L.C.:
Advanced or Refractory Leukemia
Myelodysplastic Syndromes
JNJ 26481585
Histone-Deacetylase Inhibitor
Advanced Leukemia
Refractory Leukemia

Additional relevant MeSH terms:
Leukemia
Myelodysplastic Syndromes
Preleukemia
Neoplasms by Histologic Type
Neoplasms
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Histone Deacetylase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions

ClinicalTrials.gov processed this record on April 17, 2014