Phase IIa Vorinostat (MK0683, Suberoylanilide Hydroxamic Acid (SAHA)) Study in Lower Risk Myelodysplastic Syndromes (0683-064)

• Sponsor: Merck Sharp & Dohme LLC (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT00486720
• Collaborator: (none)
• Enrollment: 22
• Arms: 2
• Duration (Months): 25

Study Details

Study Description

Brief Summary

This study is to evaluate the efficacy, safety and tolerability of vorinostat in patients with lower risk Myelodysplastic Syndrome (MDS).

Condition or Disease	Intervention/Treatment	Phase
Myelodysplastic Syndromes; Blood Disease; Bone Marrow Disease	Drug: vorinostat; Drug: vorinostat	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 22 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized Phase IIa Study of Vorinostat in Patients With Low or Intermediate-1 Risk Myelodysplastic Syndrome
• Study Start Date: Jun 1, 2007
• Actual Primary Completion Date: Jul 1, 2009
• Actual Study Completion Date: Jul 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1 vorinostat 400 mg	Drug: vorinostat; vorinostat 400 mg by mouth (P.O.) capsules once daily (q.d.). Treatment in 21 day cycles for up to 8 cycles.; Other Names: suberoylanilide hydroxamic acid (SAHA) ZOLINZA®
Experimental: 2 vorinostat 200 mg	Drug: vorinostat; vorinostat 200 mg by mouth (P.O.) capsules three times daily (t.i.d.). Treatment in 21 day cycles for up to 8 cycles.; Other Names: suberoylanilide hydroxamic acid (SAHA) ZOLINZA®

Outcome Measures

Primary Outcome Measures

1. Number of Responders and Number of Non-responders Defined by International Working Group Response Criteria [2 Years]

   Number of responders is defined as the number of patients in the analysis population who have complete response (CR), partial response (PR), or hematologic improvement (HI) per International Working Group Response Criteria during the course of the study. Confirmation of CR or PR will require a second assessment performed 4 weeks or more after the initial assessment. Confirmation of HI will require a second assessment performed 8 weeks or more after the initial assessment. Number of non-responders is defined as the number of patients who did not achieve CR, PR or HI in the study.

2. Safety and Tolerability as Assessed by the Number of Participants With Adverse Events. [Every 21 days while on therapy and at 30 days after the last dose of study therapy]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

Patient is a male or female, at least 18 years of age with low or intermediate-1 risk Myelodysplastic Syndrome (MDS) defined by the International Prognostic Scoring System

• Patient has previously untreated disease, or has received up to one prior treatment regimen for lower-risk Myelodysplastic Syndrome

• Patient has a performance status of equal to or less than 2 on the Eastern Cooperative Oncology Group Performance Scale

• Patient must have adequate organ function

Exclusion Criteria:

• Patient has clinical evidence of Central Nervous System (CNS) leukemia

• Patient is pregnant or breastfeeding, or expecting to conceive within the projected duration of the study

• Patient had prior treatment with a histone deacetylase inhibitor

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: NCT00486720
• Other Study ID Numbers: 0683-064; MK0683-064; 2007_536
• First Posted: Jun 15, 2007
• Last Update Posted: Jul 3, 2015
• Last Verified: Jun 1, 2015

• Additional relevant MeSH terms: Preleukemia; Myelodysplastic Syndromes; Hematologic Diseases; Bone Marrow Diseases; Syndrome; Vorinostat

Study Results

Participant Flow

Recruitment Details	Date of first patient in was 26-Jun-2007. The date of last patient last visit for the study was 16-Jul-2009.
Pre-assignment Detail	Vorinostat was studied in patients who were first stratified by their International Prognostic Scoring System for myelodysplastic syndrome (low versus intermediate-1) and than randomized into one of two dose schedules.

Arm/Group Title	Vorinostat Once Daily Dose Schedule	Vorinostat Thrice Daily Dose Schedule
Arm/Group Description	Vorinostat 400 mg once daily for 14 consecutive days in a 21 day cycle.	Vorinostat 200 mg three times daily for 14 consecutive days in a 21 day cycle.
Period Title: Overall Study
STARTED	10	12
COMPLETED	0	0
NOT COMPLETED	10	12

Baseline Characteristics

Arm/Group Title	Vorinostat Once Daily Dose Schedule	Vorinostat Thrice Daily Dose Schedule	Total
Arm/Group Description	Vorinostat 400 mg once daily for 14 consecutive days in a 21 day cycle.	Vorinostat 200 mg three times daily for 14 consecutive days in a 21 day cycle.	Total of all reporting groups
Overall Participants	9	12	21
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	69.0 (18.5)	64.0 (10.5)	66.0 (14.1)
Sex: Female, Male (Count of Participants)
Female	1 11.1%	5 41.7%	6 28.6%
Male	8 88.9%	7 58.3%	15 71.4%
Race/Ethnicity, Customized (participants) [Number]
White	9 100%	10 83.3%	19 90.5%
Black	0 0%	1 8.3%	1 4.8%
Asian	0 0%	1 8.3%	1 4.8%
Eastern Cooperative Oncology Group (ECOG) Performance Scale Status (participants) [Number]
0 = Normal Activity	4 44.4%	10 83.3%	14 66.7%
1 = Symptoms, but ambulatory	4 44.4%	1 8.3%	5 23.8%
2 = In bed < 50% of the time	1 11.1%	1 8.3%	2 9.5%
International Prognostic Scoring System Risk (IPSS) (Number) [Number]
Low	3 33.3%	4 33.3%	7 33.3%
Intermediate-1	6 66.7%	8 66.7%	14 66.7%
Prior Myelodysplastic Syndromes Therapy (Number) [Number]
Yes	6 66.7%	3 25%	9 42.9%
No	3 33.3%	9 75%	12 57.1%

Outcome Measures

1. Primary Outcome

Title	Number of Responders and Number of Non-responders Defined by International Working Group Response Criteria
Description	Number of responders is defined as the number of patients in the analysis population who have complete response (CR), partial response (PR), or hematologic improvement (HI) per International Working Group Response Criteria during the course of the study. Confirmation of CR or PR will require a second assessment performed 4 weeks or more after the initial assessment. Confirmation of HI will require a second assessment performed 8 weeks or more after the initial assessment. Number of non-responders is defined as the number of patients who did not achieve CR, PR or HI in the study.
Time Frame	2 Years

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) population is the analysis population. This population consists of all randomized patients who have received at least one dose of study medication.

Arm/Group Title	Vorinostat Once Daily Dose Schedule	Vorinostat Thrice Daily Dose Schedule
Arm/Group Description	Vorinostat 400 mg once daily for 14 consecutive days in a 21 day cycle.	Vorinostat 200 mg three times daily for 14 consecutive days in a 21 day cycle.
Measure Participants	9	12
Responder	0 0%	0 0%
Non-responder	9 100%	12 100%

2. Primary Outcome

Title	Safety and Tolerability as Assessed by the Number of Participants With Adverse Events.
Time Frame	Every 21 days while on therapy and at 30 days after the last dose of study therapy

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Vorinostat Once Daily Dose Schedule	Vorinostat Thrice Daily Dose Schedule
Arm/Group Description	Vorinostat 400 mg once daily for 14 consecutive days in a 21 day cycle.	Vorinostat 200 mg three times daily for 14 consecutive days in a 21 day cycle.
Measure Participants	9	12
With one or more adverse events	9 100%	12 100%
With no adverse events	0 0%	0 0%
With drug-related adverse events	4 44.4%	11 91.7%
With serious adverse events	2 22.2%	5 41.7%
With serious drug-related adverse events	0 0%	2 16.7%

Adverse Events

Time Frame	Serious and non-serious adverse experiences occurring from the time of consent up through 30 days after the last dose of study drug were reported.
Adverse Event Reporting Description	One patient was randomized to the Once Daily Dose Schedule, but discontinued before receiving study medication due to a protocol violation and is not included in the safety assessment.
Arm/Group Title	Vorinostat Once Daily Dose Schedule		Vorinostat Thrice Daily Dose Schedule
Arm/Group Description	Vorinostat 400 mg once daily for 14 consecutive days in a 21 day cycle.		Vorinostat 200 mg three times daily for 14 consecutive days in a 21 day cycle.
All Cause Mortality
	Vorinostat Once Daily Dose Schedule		Vorinostat Thrice Daily Dose Schedule
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Vorinostat Once Daily Dose Schedule		Vorinostat Thrice Daily Dose Schedule
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/9 (22.2%)		5/12 (41.7%)
Blood and lymphatic system disorders
Anaemia	0/9 (0%)		1/12 (8.3%)
Neutropenia	0/9 (0%)		1/12 (8.3%)
Splenic haemorrhage	0/9 (0%)		1/12 (8.3%)
Cardiac disorders
Pericardial effusion	0/9 (0%)		1/12 (8.3%)
General disorders
Disease progression	1/9 (11.1%)		0/12 (0%)
Infections and infestations
Eye infection	0/9 (0%)		1/12 (8.3%)
Lung infection	1/9 (11.1%)		0/12 (0%)
Pharyngitis	0/9 (0%)		1/12 (8.3%)
Pneumonia	1/9 (11.1%)		0/12 (0%)
Urinary tract infection	1/9 (11.1%)		0/12 (0%)
Nervous system disorders
Neuropathy peripheral	0/9 (0%)		1/12 (8.3%)
Psychiatric disorders
Confusional state	1/9 (11.1%)		0/12 (0%)
Renal and urinary disorders
Urinary retention	1/9 (11.1%)		0/12 (0%)
Respiratory, thoracic and mediastinal disorders
Pleural effusion	0/9 (0%)		1/12 (8.3%)
Other (Not Including Serious) Adverse Events
	Vorinostat Once Daily Dose Schedule		Vorinostat Thrice Daily Dose Schedule
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/9 (100%)		12/12 (100%)
Blood and lymphatic system disorders
Anaemia	1/9 (11.1%)		7/12 (58.3%)
Leukopenia	0/9 (0%)		2/12 (16.7%)
Neutropenia	2/9 (22.2%)		4/12 (33.3%)
Thrombocytopenia	1/9 (11.1%)		2/12 (16.7%)
Cardiac disorders
Left ventricular dysfunction	1/9 (11.1%)		0/12 (0%)
Left ventricular hypertrophy	1/9 (11.1%)		0/12 (0%)
Palpitations	1/9 (11.1%)		0/12 (0%)
Supraventricular tachycardia	1/9 (11.1%)		0/12 (0%)
Ear and labyrinth disorders
Ear pain	1/9 (11.1%)		0/12 (0%)
Eye disorders
Eye irritation	0/9 (0%)		1/12 (8.3%)
Eye pruritus	0/9 (0%)		1/12 (8.3%)
Gastrointestinal disorders
Abdominal pain	1/9 (11.1%)		0/12 (0%)
Abdominal pain upper	1/9 (11.1%)		1/12 (8.3%)
Constipation	0/9 (0%)		2/12 (16.7%)
Diarrhoea	5/9 (55.6%)		11/12 (91.7%)
Dry mouth	0/9 (0%)		2/12 (16.7%)
Dyspepsia	1/9 (11.1%)		0/12 (0%)
Eructation	0/9 (0%)		1/12 (8.3%)
Flatulence	0/9 (0%)		1/12 (8.3%)
Gastrointestinal pain	0/9 (0%)		1/12 (8.3%)
Gastrooesophageal reflux disease	0/9 (0%)		1/12 (8.3%)
Haemorrhoids	0/9 (0%)		1/12 (8.3%)
Nausea	5/9 (55.6%)		9/12 (75%)
Oesophagitis	0/9 (0%)		1/12 (8.3%)
Retching	1/9 (11.1%)		0/12 (0%)
Stomatitis	0/9 (0%)		1/12 (8.3%)
Tongue discolouration	0/9 (0%)		1/12 (8.3%)
Vomiting	4/9 (44.4%)		5/12 (41.7%)
General disorders
Chest pain	0/9 (0%)		1/12 (8.3%)
Chills	1/9 (11.1%)		0/12 (0%)
Fatigue	4/9 (44.4%)		7/12 (58.3%)
Pain	0/9 (0%)		2/12 (16.7%)
Pyrexia	1/9 (11.1%)		0/12 (0%)
Hepatobiliary disorders
Hyperbilirubinaemia	2/9 (22.2%)		0/12 (0%)
Infections and infestations
Cellulitis	1/9 (11.1%)		0/12 (0%)
Cystitis	1/9 (11.1%)		1/12 (8.3%)
Hordeolum	0/9 (0%)		1/12 (8.3%)
Paronychia	1/9 (11.1%)		0/12 (0%)
Pneumonia	1/9 (11.1%)		0/12 (0%)
Rhinitis	0/9 (0%)		1/12 (8.3%)
Skin bacterial infection	0/9 (0%)		1/12 (8.3%)
Injury, poisoning and procedural complications
Thermal burn	0/9 (0%)		1/12 (8.3%)
Investigations
Alanine aminotransferase increased	0/9 (0%)		1/12 (8.3%)
Aspartate aminotransferase increased	0/9 (0%)		1/12 (8.3%)
Blood alkaline phosphatase increased	0/9 (0%)		1/12 (8.3%)
Blood creatinine increased	2/9 (22.2%)		0/12 (0%)
Haematocrit decreased	0/9 (0%)		1/12 (8.3%)
Red blood cell count decreased	0/9 (0%)		1/12 (8.3%)
Metabolism and nutrition disorders
Anorexia	1/9 (11.1%)		5/12 (41.7%)
Decreased appetite	0/9 (0%)		2/12 (16.7%)
Dehydration	0/9 (0%)		1/12 (8.3%)
Hyperglycaemia	2/9 (22.2%)		0/12 (0%)
Hyperuricaemia	1/9 (11.1%)		1/12 (8.3%)
Hypokalaemia	0/9 (0%)		4/12 (33.3%)
Hypomagnesaemia	1/9 (11.1%)		0/12 (0%)
Hyponatraemia	0/9 (0%)		1/12 (8.3%)
Increased appetite	0/9 (0%)		1/12 (8.3%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/9 (11.1%)		0/12 (0%)
Arthritis	1/9 (11.1%)		0/12 (0%)
Back pain	1/9 (11.1%)		0/12 (0%)
Groin pain	1/9 (11.1%)		0/12 (0%)
Joint swelling	1/9 (11.1%)		0/12 (0%)
Muscle spasms	3/9 (33.3%)		0/12 (0%)
Muscular weakness	1/9 (11.1%)		2/12 (16.7%)
Nervous system disorders
Balance disorder	0/9 (0%)		1/12 (8.3%)
Cognitive disorder	0/9 (0%)		1/12 (8.3%)
Dizziness	2/9 (22.2%)		3/12 (25%)
Dysgeusia	0/9 (0%)		2/12 (16.7%)
Somnolence	0/9 (0%)		1/12 (8.3%)
Syncope	1/9 (11.1%)		0/12 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	0/9 (0%)		1/12 (8.3%)
Dyspnoea	2/9 (22.2%)		2/12 (16.7%)
Dyspnoea exertional	0/9 (0%)		1/12 (8.3%)
Epistaxis	2/9 (22.2%)		1/12 (8.3%)
Oropharyngeal pain	0/9 (0%)		1/12 (8.3%)
Productive cough	0/9 (0%)		1/12 (8.3%)
Respiratory tract congestion	0/9 (0%)		1/12 (8.3%)
Rash	2/9 (22.2%)		2/12 (16.7%)
Skin and subcutaneous tissue disorders
Alopecia	0/9 (0%)		2/12 (16.7%)
Petechiae	0/9 (0%)		1/12 (8.3%)
Pruritus	1/9 (11.1%)		0/12 (0%)
Skin lesion	1/9 (11.1%)		0/12 (0%)
Skin ulcer	0/9 (0%)		1/12 (8.3%)
Vascular disorders
Flushing	0/9 (0%)		1/12 (8.3%)
Hot flush	1/9 (11.1%)		0/12 (0%)
Hypotension	0/9 (0%)		1/12 (8.3%)
Orthostatic hypotension	1/9 (11.1%)		0/12 (0%)

Limitations/Caveats

This trial was terminated because the pre-specified futility criterion was met.

More Information

Certain Agreements

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

Merck agreements may vary with individual investigators, but will not prohibit any investigator from publishing. Merck supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.