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

Study Overview
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Brief Summary
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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.

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

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: vorinostat
* Drug: bortezomib


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

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

What is the study measuring?
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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 |