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

A Phase 1 Study of the Histone-deacetylase Inhibitor JNJ-26481585 in Subjects With Advanced or Refractory Leukemia or Myelodysplastic Syndrome

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).

Study Overview

• Status: Terminated
• Conditions: Myelodysplastic Syndromes; Advanced or Refractory Leukemia
• Intervention / Treatment: Drug: JNJ-26481585

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.

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States
  • Texas
    • Houston, Texas, United States

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of patients with adverse events		Upto 14 days after last dose administration of study medication
Number of patients with dose limiting toxicity [DLT]	Only toxicities that occur during Treatment Cycle 1 will be used for the purposes of defining DLT.	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
Maximum tolerated dose (MTD) of JNJ 26481585	The MTD is defined as the highest dose with an observed incidence of DLT in no more than 1 in 6 patients.	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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum plasma concentration (Cmax) of JNJ 26481585		Days 1, 2, 8, 15 and 21 of Cycle 1
Time to reach maximum plasma concentration (tmax) of JNJ-26481585		Days 1, 2, 8, 15 and 21 of Cycle 1
Area under the plasma concentration-time curve from time 0 to 24 hours (AUC0-24)		Days 1, 2, 8, 15 and 21 of Cycle 1
Elimination half-life (t1/2) of JNJ-26481585		Days 1, 2, 8, 15 and 21 of Cycle 1
Cumulative amount of drug excreted in urine over 24 hours (Ae24)		Days 1 and 21 of Cycle 1
Renal clearance (CLR) of JNJ 26395018		Days 1 and 21 of Cycle 1
Concentration of biomarker histone acetylation		Days 1 and 21 of Cycle 1; Day 21 of Cycles 2 to 20
Concentration of biomarker interleukin-6 (IL-6)		Days 1 and 21 of Cycle 1; Day 21 of Cycles 2 to 20
Concentration of biomarker heat shock protein 90 (Hsp90)		Days 1 and 21 of Cycle 1; Day 21 of Cycles 2 to 20
Complete Blood Count (CBC)	Anticancer activity of JNJ-26481585 explored by assessment of response parameters such as CBC.	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)
Assessment of Transfusion Record	Assessment of Transfusion Record is the parameter for assessment of response.	From Day 1 of Cycle 1 upto 14 days after last dose
Radiological Tumor Mass assessment	Radiological Tumor Mass assessment is the parameter for assessment of response.	Pre-treatment, Day 21 of Cycle 2 to 20 and follow up
Bone marrow aspirate/biopsy assessment	Bone marrow aspirate/biopsy assessment is the parameter for assessment of response.	Pre-treatment, Day 21 of Cycles 1 to 20

Collaborators and Investigators

• Sponsor: Johnson & Johnson Pharmaceutical Research & Development, L.L.C.

Publications and helpful links

Helpful Links

• A Phase 1 Study of the Histone-Deacetylase Inhibitor JNJ-26481585 in Subjects with Advanced or Refractory Leukemia or Myelodysplastic Syndrome

Study record dates

Study Major Dates

• Study Start: December 1, 2008
• Primary Completion (Actual): September 1, 2011
• Study Completion (Actual): September 1, 2011

Study Registration Dates

• First Submitted: May 8, 2008
• First Submitted That Met QC Criteria: May 12, 2008
• First Posted (Estimate): May 13, 2008

Study Record Updates

• Last Update Posted (Estimate): September 14, 2012
• Last Update Submitted That Met QC Criteria: September 13, 2012
• Last Verified: September 1, 2012

More Information

Terms related to this study

• Keywords: Myelodysplastic Syndromes; Advanced Leukemia; Refractory Leukemia; JNJ 26481585; Advanced or Refractory Leukemia; Histone-Deacetylase Inhibitor
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Disease; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Syndrome; Myelodysplastic Syndromes; Leukemia; Preleukemia
• Other Study ID Numbers: CR013960; 26481585CAN1003 (Other Identifier: Johnson & Johnson Pharmaceutical Research & Development, L.L.C.)