Clinical trial NCT01464112: 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
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Multiple Myeloma
Keywords: Multiple myeloma that has relapsed or is progressive following prior therapy
Relapsed Multiple Myeloma
JNJ 26481585
VELCADE
Bortezomib
Dexamethasone
Lead sponsor: Janssen Research & Development, LLC
Sponsor class: INDUSTRY
First posted: 2011-11-03
Enrollment: 18
Sex: ALL
Minimum age (years): 18
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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 Patients with progressive disease (PD) or unacceptable toxicity will be withdrawn from treatment.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

Eligibility criteria: 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

Primary outcomes:
measure: Determine the dose-limiting toxicity and set the MTD for the combination of JNJ-26481585 and VELCADE-dexamethasone
timeFrame: Maximum of 18 months
Secondary outcomes:
measure: Adverse events
timeFrame: Maximum of 18 months
measure: Clinical laboratory tests
timeFrame: Maximum of 18 months
measure: Overall response rate
timeFrame: Maximum of 18 months
measure: Duration of response
timeFrame: Maximum of 18 months
measure: Profile of pharmacokinetics evaluations for JNJ-26481585
timeFrame: Maximum of 18 months
measure: Profile of pharmacokinetics evaluations for VELCADE
timeFrame: Maximum of 18 months
measure: Bone cell morphology
timeFrame: Maximum of 18 months
measure: Pulse
timeFrame: Maximum of 18 months
measure: Heart rate
timeFrame: Maximum of 18 months
measure: Blood pressure
timeFrame: Maximum of 18 months
measure: Body temperature
timeFrame: Maximum of 18 months
measure: Height
timeFrame: Maximum of 18 months
measure: Weight
timeFrame: Maximum of 18 months
measure: Body surface area
timeFrame: Maximum of 18 months
Other outcomes:
Locations:
city: Lille Cedex
country: France
city: Nantes
country: France
city: Tours
country: France
Study officials:
affiliation: Janssen Research & Development, LLC
name: Janssen Research & Development, LLC & Development, L.L.C. Clinical Trial
role: STUDY_DIRECTOR
References:
citation: Moreau P, Facon T, Touzeau C, Benboubker L, Delain M, Badamo-Dotzis J, Phelps C, Doty C, Smit H, Fourneau N, Forslund A, Hellemans P, Leleu X. Quisinostat, bortezomib, and dexamethasone combination therapy for relapsed multiple myeloma. Leuk Lymphoma. 2016 Jul;57(7):1546-59. doi: 10.3109/10428194.2015.1117611. Epub 2016 Jan 12.