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

Sponsor

Janssen Research & Development, LLC (Industry)

Overall Status

Completed

CT.gov ID

NCT01464112

Collaborator

(none)

Enrollment

Locations

Arm

26.1

Actual Duration (Months)

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Multiple Myeloma	Drug: JNJ-2641585 / VELCADE / Dexamethasone	Phase 1

Detailed Description

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 Patients with progressive disease (PD) or unacceptable toxicity will be withdrawn from treatment.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.

Study Design

Study Type:

Interventional

Actual Enrollment :

18 participants

Allocation:

Non-Randomized

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Sep 16, 2011

Actual Primary Completion Date :

Nov 19, 2013

Actual Study Completion Date :

Nov 19, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 001	Drug: JNJ-2641585 / VELCADE / Dexamethasone 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.

Arm

Intervention/Treatment

Experimental: 001

Drug: JNJ-2641585 / VELCADE / Dexamethasone

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.

Outcome Measures

Primary Outcome Measures

Determine the dose-limiting toxicity and set the MTD for the combination of JNJ-26481585 and VELCADE-dexamethasone [Maximum of 18 months]
Based on the safety analysis of all cohorts using the patients-treated population

Secondary Outcome Measures

Adverse events [Maximum of 18 months]
As a measure of safety
Clinical laboratory tests [Maximum of 18 months]
As a measure of safety
Overall response rate [Maximum of 18 months]
Duration of response [Maximum of 18 months]
Profile of pharmacokinetics evaluations for JNJ-26481585 [Maximum of 18 months]
Cmax, Area Under Curve, Tmax
Profile of pharmacokinetics evaluations for VELCADE [Maximum of 18 months]
Cmax, Area Under Curve, Tmax
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]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 99 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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