Phase I Study of MK-0683 in Combination With Bortezomib in Participants With Multiple Myeloma (MK-0683-098)

• Sponsor: Merck Sharp & Dohme LLC (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00858234
• Collaborator: (none)
• Enrollment: 9
• Arm: 1
• Actual Duration (Months): 38.1

Study Details

Study Description

Brief Summary

The primary purpose of this clinical study is to determine the recommended clinical doses of vorinostat (MK-0683) and bortezomib administered in combination to participants with relapsed and/or refractory multiple myeloma (MM). It was hypothesized that administration of vorinostat in combination with bortezomib is sufficiently safe and tolerated well enough to permit further study in participants with relapsed and/or refractory MM. Study results are based on data collected up to the data cut-off date of 20-March-2011.

Condition or Disease	Intervention/Treatment	Phase
Multiple Myeloma	Drug: Vorinostat; Drug: Bortezomib	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 9 participants
• Allocation: N/A
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Multicenter, Open-Label, Phase I Study of MK-0683 in Combination With Bortezomib in Patients With Relapsed and/or Refractory Multiple Myeloma
• Actual Study Start Date: Feb 13, 2009
• Actual Primary Completion Date: Jun 11, 2010
• Actual Study Completion Date: Apr 19, 2012

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Vorinostat + Bortezomib Participants undergo up to 3 successive 21-day treatment cycles. During Cycle 1, participants receive vorinostat (400 mg once daily [QD] on Days 1 through 14) + bortezomib (1.3 mg/m^2 intravenous [IV] on Days 1, 4, 8, and 11). If that dose is not well tolerated, during Cycle 2 participants receive vorinostat (400 mg QD on Days 1 through 14) + bortezomib (1.0 mg/m^2 IV on Days 1, 4, 8, and 11). If that dose is not well tolerated, during Cycle 3 participants receive vorinostat (300 mg QD on Days 1 through 14) + bortezomib (1.0 mg/m^2 IV on Days 1, 4, 8, and 11).

Drug: Vorinostat; Vorinostat (MK-0683) three or four 100 mg capsules taken by mouth with food.; Other Names: MK-0683 ZOLINZA™ ; Drug: Bortezomib; Bortezomib (1.0 or 1.3 mg/m^2) intravenous infusion.; Other Names: VELCADE®

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Dose-Limiting Toxicity (DLT) During Cycle 1 [Up to 21 days]

   The number of participants with ≥1 DLT during Cycle 1 is reported. A DLT is defined as an event considered by the investigator to be related to study treatment, and either: 1) a Grade 3 or 4 non-hematologic event (except for manageable toxicity by supportive care or non-prohibited therapies, or a transient increase in alanine aminotransferase [ALT]/aspartate aminotransferase [AST]); or 2) a Grade 4 hematologic toxicity except neutropenia or hemoglobin decreased (neutropenia was a DLT if it was Grade 3-4 with fever ≥38.5°C; Grade 3-4 with an infection requiring antibiotic/antifungal therapy; or Grade 4 and lasting ≥5 days).

Other Outcome Measures

1. Number of Participants With an Adverse Event (AE) [Up to 346 days (up to 30 days after the final dose of study treatment)]

   The number of participants with ≥1 AE is reported. An AE is any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the study product(s), whether or not considered related to the use of the product(s).

2. Area Under the Plasma Concentration-Time Curve From 0 to 24 Hours Postdose (AUC0-24hr) of Vorinostat Administered With Bortezomib on Days 1 and 11 [Predose and 0.8, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 hours postdose on Days 1 and 11]

   The AUC0-24hr of vorinostat in plasma on Days 1 and 11 is reported in participants who also received bortezomib.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 20 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• is ≥20 years of age.

• has an established diagnosis of MM based on the myeloma diagnostic criteria

• has received at least 1 but not more than 3 prior anti-myeloma regimens and has progressive disease after the most recent treatment regimen

• has adequate organ function

Exclusion Criteria:

• has had a prior allogeneic bone marrow transplant or plans to undergo any type of bone marrow transplantation during the study

• has known hypersensitivity to any components of vorinostat or bortezomib

• has active hepatitis B or C, plasma cell leukemia, or is human immunodeficiency virus (HIV) positive

• has had prior treatment with vorinostat or histone deacetylase (HDAC) inhibitors

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Merck Sharp & Dohme LLC

Investigators

• Study Director: Medical Monitor, Merck Sharp & Dohme LLC

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Merck Sharp & Dohme LLC
• ClinicalTrials.gov Identifier: NCT00858234
• Other Study ID Numbers: 0683-098; MK-0683-098
• First Posted: Mar 9, 2009
• Last Update Posted: Apr 9, 2021
• Last Verified: Apr 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Additional relevant MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell; Bortezomib; Vorinostat

Study Results

Participant Flow

Recruitment Details	Adult male and female participants with relapsed and/or refractory multiple myeloma (MM) were enrolled at study sites in Japan.

Arm/Group Title	Vorinostat + Bortezomib
Arm/Group Description	Participants undergo ≤3 successive 21-day treatment cycles. During Cycle 1, participants receive vorinostat (400 mg QD on Days 1 through 14) + bortezomib (1.3 mg/m^2 IV on Days 1, 4, 8, and 11). If that dose is not well tolerated, during Cycle 2 participants receive vorinostat (400 mg QD on Days 1 through 14) + bortezomib (1.0 mg/m^2 IV on Days 1, 4, 8, and 11). If that dose is not well tolerated, during Cycle 3 participants receive vorinostat (300 mg QD on Days 1 through 14) + bortezomib (1.0 mg/m^2 IV on Days 1, 4, 8, and 11).
Period Title: Overall Study
STARTED	9
COMPLETED	0
NOT COMPLETED	9

Baseline Characteristics

Arm/Group Title	Vorinostat + Bortezomib
Arm/Group Description	Participants undergo ≤3 successive 21-day treatment cycles. During Cycle 1, participants receive vorinostat (400 mg QD on Days 1 through 14) + bortezomib (1.3 mg/m^2 IV on Days 1, 4, 8, and 11). If that dose is not well tolerated, during Cycle 2 participants receive vorinostat (400 mg QD on Days 1 through 14) + bortezomib (1.0 mg/m^2 IV on Days 1, 4, 8, and 11). If that dose is not well tolerated, during Cycle 3 participants receive vorinostat (300 mg QD on Days 1 through 14) + bortezomib (1.0 mg/m^2 IV on Days 1, 4, 8, and 11).
Overall Participants	9
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	63.3 (11.9)
Sex: Female, Male (Count of Participants)
Female	1 11.1%
Male	8 88.9%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	9 100%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	0 0%
More than one race	0 0%
Unknown or Not Reported	0 0%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Dose-Limiting Toxicity (DLT) During Cycle 1
Description	The number of participants with ≥1 DLT during Cycle 1 is reported. A DLT is defined as an event considered by the investigator to be related to study treatment, and either: 1) a Grade 3 or 4 non-hematologic event (except for manageable toxicity by supportive care or non-prohibited therapies, or a transient increase in alanine aminotransferase [ALT]/aspartate aminotransferase [AST]); or 2) a Grade 4 hematologic toxicity except neutropenia or hemoglobin decreased (neutropenia was a DLT if it was Grade 3-4 with fever ≥38.5°C; Grade 3-4 with an infection requiring antibiotic/antifungal therapy; or Grade 4 and lasting ≥5 days).
Time Frame	Up to 21 days

Outcome Measure Data

Analysis Population Description

All treated participants who were not refractory to bortezomib and met all inclusion criteria are included.

Arm/Group Title	Vorinostat + Bortezomib
Arm/Group Description	Participants undergo ≤3 successive 21-day treatment cycles. During Cycle 1, participants receive vorinostat (400 mg QD on Days 1 through 14) + bortezomib (1.3 mg/m^2 IV on Days 1, 4, 8, and 11). If that dose is not well tolerated, during Cycle 2 participants receive vorinostat (400 mg QD on Days 1 through 14) + bortezomib (1.0 mg/m^2 IV on Days 1, 4, 8, and 11). If that dose is not well tolerated, during Cycle 3 participants receive vorinostat (300 mg QD on Days 1 through 14) + bortezomib (1.0 mg/m^2 IV on Days 1, 4, 8, and 11).
Measure Participants	6
Count of Participants [Participants]	1 11.1%

2. Other Pre-specified Outcome

Title	Number of Participants With an Adverse Event (AE)
Description	The number of participants with ≥1 AE is reported. An AE is any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the study product(s), whether or not considered related to the use of the product(s).
Time Frame	Up to 346 days (up to 30 days after the final dose of study treatment)

Outcome Measure Data

Analysis Population Description

All treated participants are included.

Arm/Group Title	Vorinostat + Bortezomib
Arm/Group Description	Participants undergo ≤3 successive 21-day treatment cycles. During Cycle 1, participants receive vorinostat (400 mg QD on Days 1 through 14) + bortezomib (1.3 mg/m^2 IV on Days 1, 4, 8, and 11). If that dose is not well tolerated, during Cycle 2 participants receive vorinostat (400 mg QD on Days 1 through 14) + bortezomib (1.0 mg/m^2 IV on Days 1, 4, 8, and 11). If that dose is not well tolerated, during Cycle 3 participants receive vorinostat (300 mg QD on Days 1 through 14) + bortezomib (1.0 mg/m^2 IV on Days 1, 4, 8, and 11).
Measure Participants	9
Count of Participants [Participants]	9 100%

3. Other Pre-specified Outcome

Title	Area Under the Plasma Concentration-Time Curve From 0 to 24 Hours Postdose (AUC0-24hr) of Vorinostat Administered With Bortezomib on Days 1 and 11
Description	The AUC0-24hr of vorinostat in plasma on Days 1 and 11 is reported in participants who also received bortezomib.
Time Frame	Predose and 0.8, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 hours postdose on Days 1 and 11

Outcome Measure Data

Analysis Population Description

Participants with data available are included.

Arm/Group Title	Vorinostat + Bortezomib
Arm/Group Description	Participants undergo ≤3 successive 21-day treatment cycles. During Cycle 1, participants receive vorinostat (400 mg QD on Days 1 through 14) + bortezomib (1.3 mg/m^2 IV on Days 1, 4, 8, and 11). If that dose is not well tolerated, during Cycle 2 participants receive vorinostat (400 mg QD on Days 1 through 14) + bortezomib (1.0 mg/m^2 IV on Days 1, 4, 8, and 11). If that dose is not well tolerated, during Cycle 3 participants receive vorinostat (300 mg QD on Days 1 through 14) + bortezomib (1.0 mg/m^2 IV on Days 1, 4, 8, and 11).
Measure Participants	9
Day 1	5.41
Day 11	5.84

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Vorinostat + Bortezomib
	Comments
	Type of Statistical Test	Other
	Comments	Accumulation Ratio (Day 11 AUC0-24hr/Day 1 AUC0-24hr)
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Accumulation ratio
	Estimated Value	1.08
	Confidence Interval	(2-Sided) 90%; 0.80 to 1.45
	Parameter Dispersion	Type: Value:
	Estimation Comments	Back-transformed least squares mean difference and 90% confidence interval from mixed effects model performed on natural log-transformed values.

Adverse Events

Time Frame	Up to 346 days (up to 30 days after the final dose of study treatment)
Adverse Event Reporting Description	All treated participants are included.
Arm/Group Title	Vorinostat + Bortezomib
Arm/Group Description	Participants undergo ≤3 successive 21-day treatment cycles. During Cycle 1, participants receive vorinostat (400 mg QD on Days 1 through 14) + bortezomib (1.3 mg/m^2 IV on Days 1, 4, 8, and 11). If that dose is not well tolerated, during Cycle 2 participants receive vorinostat (400 mg QD on Days 1 through 14) + bortezomib (1.0 mg/m^2 IV on Days 1, 4, 8, and 11). If that dose is not well tolerated, during Cycle 3 participants receive vorinostat (300 mg QD on Days 1 through 14) + bortezomib (1.0 mg/m^2 IV on Days 1, 4, 8, and 11).
All Cause Mortality
	Vorinostat + Bortezomib
	Affected / at Risk (%)	# Events
Total	0/9 (0%)
Serious Adverse Events
	Vorinostat + Bortezomib
	Affected / at Risk (%)	# Events
Total	3/9 (33.3%)
Blood and lymphatic system disorders
Disseminated intravascular coagulation	1/9 (11.1%)	1
General disorders
Fatigue	1/9 (11.1%)	1
Infections and infestations
Pneumonia	2/9 (22.2%)	2
Pyelonephritis	1/9 (11.1%)	1
Sepsis	1/9 (11.1%)	1
Metabolism and nutrition disorders
Decreased appetite	1/9 (11.1%)	1
Other (Not Including Serious) Adverse Events
	Vorinostat + Bortezomib
	Affected / at Risk (%)	# Events
Total	9/9 (100%)
Blood and lymphatic system disorders
Anaemia	3/9 (33.3%)	8
Leukopenia	9/9 (100%)	98
Lymphopenia	6/9 (66.7%)	32
Neutropenia	9/9 (100%)	99
Thrombocytopenia	9/9 (100%)	189
Eye disorders
Conjunctivitis	1/9 (11.1%)	1
Gastrointestinal disorders
Abdominal discomfort	1/9 (11.1%)	1
Constipation	6/9 (66.7%)	16
Diarrhoea	9/9 (100%)	44
Dry mouth	1/9 (11.1%)	1
Dyspepsia	1/9 (11.1%)	1
Gingival bleeding	1/9 (11.1%)	1
Gingivitis	1/9 (11.1%)	1
Mouth haemorrhage	1/9 (11.1%)	1
Nausea	8/9 (88.9%)	31
Stomatitis	2/9 (22.2%)	3
Vomiting	7/9 (77.8%)	19
General disorders
Fatigue	5/9 (55.6%)	18
Injection site reaction	1/9 (11.1%)	1
Malaise	2/9 (22.2%)	2
Pyrexia	3/9 (33.3%)	9
Hepatobiliary disorders
Drug-induced liver injury	1/9 (11.1%)	1
Hepatic function abnormal	1/9 (11.1%)	1
Infections and infestations
Enteritis infectious	1/9 (11.1%)	1
Herpes zoster	1/9 (11.1%)	1
Hordeolum	1/9 (11.1%)	1
Nasopharyngitis	2/9 (22.2%)	3
Pneumonia	1/9 (11.1%)	1
Sinusitis	1/9 (11.1%)	2
Upper respiratory tract infection	1/9 (11.1%)	1
Investigations
Alanine aminotransferase increased	3/9 (33.3%)	8
Aspartate aminotransferase increased	4/9 (44.4%)	6
Blood albumin decreased	2/9 (22.2%)	2
Blood alkaline phosphatase increased	1/9 (11.1%)	2
Blood creatinine increased	2/9 (22.2%)	9
Blood glucose increased	1/9 (11.1%)	1
Blood phosphorus decreased	2/9 (22.2%)	2
Blood potassium increased	1/9 (11.1%)	1
Electrocardiogram QT prolonged	3/9 (33.3%)	4
Electrocardiogram ST-T segment depression	1/9 (11.1%)	1
Gamma-glutamyltransferase increased	1/9 (11.1%)	1
Lymphocyte count decreased	1/9 (11.1%)	1
Neutrophil count decreased	1/9 (11.1%)	1
Weight decreased	3/9 (33.3%)	7
Metabolism and nutrition disorders
Decreased appetite	8/9 (88.9%)	24
Dehydration	2/9 (22.2%)	4
Hypercreatininaemia	1/9 (11.1%)	3
Hyperglycaemia	2/9 (22.2%)	20
Hyperkalaemia	1/9 (11.1%)	2
Hypermagnesaemia	1/9 (11.1%)	2
Hyperuricaemia	1/9 (11.1%)	1
Hypoalbuminaemia	2/9 (22.2%)	2
Hypokalaemia	5/9 (55.6%)	24
Hypomagnesaemia	1/9 (11.1%)	1
Hyponatraemia	1/9 (11.1%)	5
Hypophosphataemia	2/9 (22.2%)	2
Tumour lysis syndrome	1/9 (11.1%)	1
Nervous system disorders
Dizziness	1/9 (11.1%)	1
Dysgeusia	1/9 (11.1%)	1
Headache	1/9 (11.1%)	2
Hypoaesthesia	2/9 (22.2%)	3
Neuropathy peripheral	1/9 (11.1%)	5
Peripheral sensory neuropathy	1/9 (11.1%)	1
Psychiatric disorders
Insomnia	1/9 (11.1%)	1
Respiratory, thoracic and mediastinal disorders
Dysphonia	1/9 (11.1%)	2
Skin and subcutaneous tissue disorders
Dry skin	1/9 (11.1%)	1
Haemorrhage subcutaneous	1/9 (11.1%)	1
Onychoclasis	1/9 (11.1%)	1
Petechiae	1/9 (11.1%)	2
Purpura	1/9 (11.1%)	1
Rash	2/9 (22.2%)	2
Vascular disorders
Flushing	1/9 (11.1%)	1
Hypertension	2/9 (22.2%)	3
Orthostatic hypotension	1/9 (11.1%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The Sponsor must have the opportunity to review all proposed abstracts, manuscripts, or presentations regarding this study 60 days prior to submission for publication/presentation.