Phase 1 Study of Vorinostat and Bortezomib in Multiple Myeloma (MK-0683-015 EXT 1 (AM1))

Phase I Clinical Trial of Vorinostat (MK-0683) in Combination With Bortezomib in Patients With Advanced Multiple Myeloma

The purposes of this study are:

• To determine the maximum tolerated dose (MTD) for the combination of oral vorinostat and bortezomib in participants with advanced multiple myeloma
• To assess the safety and tolerability of this regimen and to document the participant's clinical status (by anti-tumor activity) for this combination, as determined per standard of care.

Study Overview

• Status: Completed
• Conditions: Multiple Myeloma
• Intervention / Treatment: Drug: vorinostat; Drug: bortezomib

• Study Type: Interventional
• Enrollment (Actual): 34
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Adults with refractory or relapsed multiple myeloma
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 (a measurement to determine participant's ability to perform daily activities)
• Adequate bone marrow reserve
• Adequate hepatic and renal function
• Ability to swallow capsules
• 3 weeks or more since prior chemotherapy and have recovered from prior toxicities

Exclusion Criteria:

• Participants who plan to have a bone marrow transplant within 4 weeks of start of treatment
• Participants with prior treatment with other investigational agents with a similar anti-tumor mechanism
• Participants with other active/uncontrolled clinically significant illness
• Pregnant or nursing female participants
• Participants who received bortezomib within 3 months of start of this trial

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: vorinostat 200 mg + bortezomib 0.7 mg/m^2; Vorinostat capsules given twice daily (b.i.d.); bortezomib injection given on Days 4, 8, 11, and 15 of each cycle.	Drug: vorinostat; Vorinostat capsules. Treatment in 21 day cycles (participants receive vorinostat for 14 days followed by a 7 day break).; Other Names: Zolinza®; MK0683; Suberoylanilide Hydroxamic Acid (SAHA); Drug: bortezomib; Bortezomib injection. Given twice weekly for 2 weeks with a 1 week break. Treatment in 21 day cycles.; Other Names: Velcade
Experimental: vorinostat 200 mg + bortezomib 0.9 mg/m^2; Vorinostat capsules given b.i.d.; bortezomib injection given on Days 4, 8, 11, and 15 of each cycle.	Drug: vorinostat; Vorinostat capsules. Treatment in 21 day cycles (participants receive vorinostat for 14 days followed by a 7 day break).; Other Names: Zolinza®; MK0683; Suberoylanilide Hydroxamic Acid (SAHA); Drug: bortezomib; Bortezomib injection. Given twice weekly for 2 weeks with a 1 week break. Treatment in 21 day cycles.; Other Names: Velcade
Experimental: vorinostat 300 mg + bortezomib 1.3 mg/m^2; Vorinostat given once daily (q.d.); bortezomib given on Days 1, 4, 8, and 11 of each cycle.	Drug: vorinostat; Vorinostat capsules. Treatment in 21 day cycles (participants receive vorinostat for 14 days followed by a 7 day break).; Other Names: Zolinza®; MK0683; Suberoylanilide Hydroxamic Acid (SAHA); Drug: bortezomib; Bortezomib injection. Given twice weekly for 2 weeks with a 1 week break. Treatment in 21 day cycles.; Other Names: Velcade
Experimental: vorinostat 400 mg + bortezomib 0.9 mg/m^2; Vorinostat given q.d.; bortezomib given on Days 1, 4, 8, and 11 of each cycle.	Drug: vorinostat; Vorinostat capsules. Treatment in 21 day cycles (participants receive vorinostat for 14 days followed by a 7 day break).; Other Names: Zolinza®; MK0683; Suberoylanilide Hydroxamic Acid (SAHA); Drug: bortezomib; Bortezomib injection. Given twice weekly for 2 weeks with a 1 week break. Treatment in 21 day cycles.; Other Names: Velcade
Experimental: vorinostat 400 mg + bortezomib 1.1 mg/m^2; Vorinostat given q.d.; bortezomib given on Days 1, 4, 8, and 11 of each cycle.	Drug: vorinostat; Vorinostat capsules. Treatment in 21 day cycles (participants receive vorinostat for 14 days followed by a 7 day break).; Other Names: Zolinza®; MK0683; Suberoylanilide Hydroxamic Acid (SAHA); Drug: bortezomib; Bortezomib injection. Given twice weekly for 2 weeks with a 1 week break. Treatment in 21 day cycles.; Other Names: Velcade
Experimental: vorinostat 400 mg + bortezomib 1.3 mg/m^2; Vorinostat given q.d.; bortezomib given on Days 1, 4, 8, and 11 of each cycle.	Drug: vorinostat; Vorinostat capsules. Treatment in 21 day cycles (participants receive vorinostat for 14 days followed by a 7 day break).; Other Names: Zolinza®; MK0683; Suberoylanilide Hydroxamic Acid (SAHA); Drug: bortezomib; Bortezomib injection. Given twice weekly for 2 weeks with a 1 week break. Treatment in 21 day cycles.; Other Names: Velcade

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Duration of Treatment With Vorinostat	Event causing discontinuation from the study was defined as (1) progressive disease OR (2) intolerable toxicity. Progressive disease was defined as: >25% increase in the level of serum monoclonal paraprotein.; 25% increase in 24-hour urinary light chain excretion.; >25% increase in plasma cells in a bone marrow aspirate or on trephine biopsy.; Development of new bone lesions or soft tissue plasmacytomas.; Development of hypercalcemia. Intolerable toxicity was based on the clinical judgment of the investigator.	Day 1 to an event causing discontinuation from the study, assessed up to 29 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Dose Modifications of Either Vorinostat or Bortezomib Due to Adverse Experiences (AEs) After Treatment With Study Drug	An adverse experience (AE) was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the sponsor's product, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which was temporally associated with the use of the sponsor's product, was also an adverse experience.	Day 1 to disease progression, toxicity, or death, assessed up to 29 months
Mean Time to First AE Resulting in a Dose Modification in Either Vorinostat or Bortezomib	An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the sponsor's product, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which was temporally associated with the use of the sponsor's product, was also an adverse experience.	Day 1 to disease progression, toxicity, or death, assessed up to 29 months
Clinical AE Summary	An AE was defined as any unfavorable/unintended change in the structure/function/chemistry of the body temporally associated with the use of study drug, or any worsening of a preexisting condition. A serious AE (SAE) was any AE that resulted in death, was life threatening, resulted in a persistent or significant disability/incapacity, resulted in or prolonged an existing inpatient hospitalization, was a congenital anomaly/birth defect, was a new cancer, or was an overdose.	Day 1 up to disease progression, toxicity, or death, assessed up to 30 days after end of treatment (up to 30 months)
Laboratory AE Summary	An AE was defined as any unfavorable/unintended change in the structure/function/chemistry of the body temporally associated with the use of study drug, or any worsening of a preexisting condition. A SAE was any AE that resulted in death, was life threatening, resulted in a persistent or significant disability/incapacity, resulted in or prolonged an existing inpatient hospitalization, was a congenital anomaly/birth defect, was a new cancer, or was an overdose. A lab (S)AE was any lab value considered clinically significant in the investigator's judgment.	Day 1 up to disease progression, toxicity, or death, assessed up to 29 months

Collaborators and Investigators

• Sponsor: Merck Sharp & Dohme LLC

Publications and helpful links

General Publications

• Weber DM, Graef T, Hussein M, Sobecks RM, Schiller GJ, Lupinacci L, Hardwick JS, Jagannath S. Phase I trial of vorinostat combined with bortezomib for the treatment of relapsing and/or refractory multiple myeloma. Clin Lymphoma Myeloma Leuk. 2012 Oct;12(5):319-24. doi: 10.1016/j.clml.2012.07.007.

Study record dates

Study Major Dates

• Study Start: September 1, 2005
• Primary Completion (Actual): December 1, 2009
• Study Completion (Actual): May 1, 2011

Study Registration Dates

• First Submitted: May 25, 2005
• First Submitted That Met QC Criteria: May 25, 2005
• First Posted (Estimate): May 26, 2005

Study Record Updates

• Last Update Posted (Estimate): May 21, 2015
• Last Update Submitted That Met QC Criteria: May 5, 2015
• Last Verified: May 1, 2015

More Information

Terms related to this study

• 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; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Histone Deacetylase Inhibitors; Bortezomib; Vorinostat
• Other Study ID Numbers: 0683-015; 2005_018