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

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

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.

Study Overview

• Status: Completed
• Conditions: Multiple Myeloma
• Intervention / Treatment: Drug: JNJ-2641585 / VELCADE / 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 Patients with progressive disease (PD) or unacceptable toxicity will be withdrawn from treatment.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.

• Study Type: Interventional
• Enrollment (Actual): 18
• Phase: Phase 1

Contacts and Locations

Study Locations

• France
  • Lille Cedex, France
  • Nantes, France
  • Tours, France

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 99 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / 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.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Janssen Research & Development, LLC

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (ACTUAL): September 16, 2011
• Primary Completion (ACTUAL): November 19, 2013
• Study Completion (ACTUAL): November 19, 2013

Study Registration Dates

• First Submitted: August 30, 2011
• First Submitted That Met QC Criteria: October 31, 2011
• First Posted (ESTIMATE): November 3, 2011

Study Record Updates

• Last Update Posted (ACTUAL): January 22, 2020
• Last Update Submitted That Met QC Criteria: January 21, 2020
• Last Verified: January 1, 2020

More Information

Terms related to this study

• Keywords: Dexamethasone; Bortezomib; Relapsed Multiple Myeloma; VELCADE; Multiple myeloma that has relapsed or is progressive following prior therapy; JNJ 26481585
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Immunoproliferative Disorders; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Multiple Myeloma; Neoplasms, Plasma Cell; Physiological Effects of Drugs; Autonomic Agents; Peripheral Nervous System Agents; Anti-Inflammatory Agents; Antineoplastic Agents; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Dexamethasone; Bortezomib
• Other Study ID Numbers: CR018661; 26481585MMY1001 (OTHER: Janssen Research & Development, LLC); 2011-001001-27 (EUDRACT_NUMBER)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes