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

Myelodysplastic Syndromes Clinical Trial

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00676728
• Other study ID #: CR013960
• Secondary ID: 26481585CAN1003
• Status: Terminated
• Phase: Phase 1
• First received: May 8, 2008
• Last updated: September 13, 2012
• Start date: December 2008
• Est. completion date: September 2011

Study information

• Verified date: September 2012
• Source: Johnson & Johnson Pharmaceutical Research & Development, L.L.C.
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

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).

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 10
• Est. completion date: September 2011
• Est. primary completion date: September 2011
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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 Design

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

Related Conditions & MeSH terms

• Advanced or Refractory Leukemia
• Leukemia
• Myelodysplastic Syndromes
• Preleukemia
• Syndrome

Intervention

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.

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Johnson & Johnson Pharmaceutical Research & Development, L.L.C.

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of patients with adverse events		Upto 14 days after last dose administration of study medication	Yes
Primary	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	Yes
Primary	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	No
Secondary	Maximum plasma concentration (Cmax) of JNJ 26481585		Days 1, 2, 8, 15 and 21 of Cycle 1	No
Secondary	Time to reach maximum plasma concentration (tmax) of JNJ-26481585		Days 1, 2, 8, 15 and 21 of Cycle 1	No
Secondary	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	No
Secondary	Elimination half-life (t1/2) of JNJ-26481585		Days 1, 2, 8, 15 and 21 of Cycle 1	No
Secondary	Cumulative amount of drug excreted in urine over 24 hours (Ae24)		Days 1 and 21 of Cycle 1	No
Secondary	Renal clearance (CLR) of JNJ 26395018		Days 1 and 21 of Cycle 1	No
Secondary	Concentration of biomarker histone acetylation		Days 1 and 21 of Cycle 1; Day 21 of Cycles 2 to 20	No
Secondary	Concentration of biomarker interleukin-6 (IL-6)		Days 1 and 21 of Cycle 1; Day 21 of Cycles 2 to 20	No
Secondary	Concentration of biomarker heat shock protein 90 (Hsp90)		Days 1 and 21 of Cycle 1; Day 21 of Cycles 2 to 20	No
Secondary	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)	No
Secondary	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	No
Secondary	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	No
Secondary	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	No

External Links

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