A Dose Escalation Study of the Histone Deacetylase Inhibitor (HDACi) JNJ 26481585 in Combination With VELCADE (Bortezomib) and Dexamethasone for Patients With Relapsed Multiple Myeloma

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety and tolerability and to establish the maximum tolerated dose of JNJ-26481585 combined with VELCADE and dexamethasone.

Detailed Description
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This is an open-label (patient and study personnel will know what treatment is being administered), multicenter, dose escalation study. Increasing doses of JNJ-26481585 will be explored in combination with the standard VELCADE/dexamethasone dose. After the maximum tolerated dose (MTD) is determined, up to 24 patients will be entered in a treatment group to receive the MTD (and if deemed necessary a lower dose level) to further assess the safety and activity of this combination. There will be 3 phases in the study: a Screening Phase (from signing of informed consent until immediately before dosing), an open-label Treatment Phase (from the first dose of JNJ-26481585 and VELCADE-dexamethasone until the End of Treatment Visit), and a Posttreatment/Follow-up Phase. Patients who achieve a positive response to treatment at the end of Cycle 1 will continue to receive JNJ-26481585 and VELCADE-dexamethasone for a maximum of 11 cycles (eight 3-week treatment cycles, followed by three 5-week treatment cycles). Patients with progressive disease (PD) or unacceptable toxicity will be withdrawn from treatment. In the Follow-Up Phase, patients whose disease has not progressed or who discontinued treatment for reasons other than PD will be assessed approximately every 6 weeks until PD is recorded or until the start of subsequent therapy. The study will end when all patients have been assessed with PD, or 12 months after the last patient is enrolled, whichever is earlier. Patient safety will be monitored. Drug A, JNJ-26481585, will be taken orally on Days 1, 3, and 5 of each week at doses starting at 6 mg and escalating to 12 mg. Drug B, VELCADE, will be given by subcutaneous injection (under the skin) at a dose of 1.3 mg/m2 on Days 1, 4, 8, and 11 of each 21-day cycle (Cycles 1 to 8) and on Days 1, 8, 15, and 22 of each 35-day cycle (Cycles 9-11). Drug C, dexamethasone, will be taken orally on the day of and after VELCADE at a dose of 20 mg. Dosing may be adjusted, based on tolerability.

Official Title
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A Phase 1b Dose Escalation Study of the Histone Deacetylase Inhibitor (HDACi) JNJ-26481585 in Combination With VELCADE (Bortezomib) and Dexamethasone for Subjects With Relapsed Multiple Myeloma

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: JNJ-2641585 / VELCADE / Dexamethasone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Eastern Cooperative Oncology Group (ECOG) Performance status score 0-2 Measurable or secretory multiple myeloma Relapse or progression of myeloma following prior systemic antineoplastic therapy Pretreatment clinical laboratory values meeting protocol-specified criteria Left ventricular ejection fraction rate within normal limits Exclusion Criteria: Peripheral neuropathy or neuralgia >=2, according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.0 Diagnosis of primary amyloidosis, plasma cell leukemia, or other similar conditions Diagnosis of Waldenstrom macroglobulinemia with protocol-specified immunoglobulin levels Prior histone-deacetylase inhibitor therapy - More than 3 prior lines of therapy Cardiac risk factors: unstable angina or myocardial infarction within the preceding 12 months, congestive heart failure (New York Heart Association Class II-IV), known presence of dilated, hypertrophic, or restrictive cardiomyopathy Any other cardiac abnormality that, in the opinion of the investigator, medical monitor, or consultant cardiologist, may place the patient at an unacceptably increased risk with study drug History of any of the following: sustained ventricular tachycardia, ventricular fibrillation, Torsades de Pointes, atrial fibrillation, cardiac arrest, Mobitz II second degree heart block, or third degree heart block - QTc at Screening > 450 ms in males / > 470 ms in females Family history of short QT syndrome, long QT syndrome Obligate use of a cardiac pacemaker - Use of medications that may cause Torsades de Pointes

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 001<br> | Drug: JNJ-2641585 / VELCADE / Dexamethasone<br>* JNJ-26481585: type=range, unit=mg, number=6 to 12, form=capsules, route=oral use, on Days 1, 3, and 5 of each week. VELCADE: type=exact, unit=mg/m2, number=1.3, form=powder for solution for injection, route=subcutaneous use, on Days 1, 4, 8, and 11 of each 21-day cycle (Cycles 1 to 8) and on Days 1, 8, 15, and 22 of each 35-day cycle (Cycles 9-11). Dexamethasone: type=exact, unit=mg, number=20, form=tablets, route=oral use, on the day of and after VELCADE.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine the dose-limiting toxicity and set the MTD for the combination of JNJ-26481585 and VELCADE-dexamethasone | Based on the safety analysis of all cohorts using the patients-treated population | Maximum of 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse events | As a measure of safety | Maximum of 18 months | 
| Clinical laboratory tests | As a measure of safety | Maximum of 18 months | 
| Overall response rate |  | Maximum of 18 months | 
| Duration of response |  | Maximum of 18 months | 
| Profile of pharmacokinetics evaluations for JNJ-26481585 | Cmax, Area Under Curve, Tmax | Maximum of 18 months | 
| Profile of pharmacokinetics evaluations for VELCADE | Cmax, Area Under Curve, Tmax | Maximum of 18 months | 
| Bone cell morphology |  | Maximum of 18 months | 
| Pulse |  | Maximum of 18 months | 
| Heart rate |  | Maximum of 18 months | 
| Blood pressure |  | Maximum of 18 months | 
| Body temperature |  | Maximum of 18 months | 
| Height |  | Maximum of 18 months | 
| Weight |  | Maximum of 18 months | 
| Body surface area |  | Maximum of 18 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Multiple myeloma that has relapsed or is progressive following prior therapy, Relapsed Multiple Myeloma, JNJ 26481585, VELCADE, Bortezomib, Dexamethasone