Suberoylanilide Hydroxamic Acid in Advanced Solid Tumors - Study Results

Study Type:	Interventional
Study Design:	Non-Randomized, Open Label, Uncontrolled, Single Group Assignment
Condition:	Advanced Cancer
Intervention:	Drug: vorinostat (Suberoylanilide Hydroxamic Acid [SAHA]) in combination with Pemetrexed and Cisplatin

Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
First Patient In = 29-Aug-05. Last Patient Last Visit = 03-Dec-07. Multicenter (4 Outpatient Clinics) in US.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Post-group assignment information: For all cohorts doses were administered in repeated 21-day cycles. Determination of the Maximum Tolerated Dose (MTD), by using dose-escalating design and measured by Dose Limiting Toxicity (DLT) is a standard procedure in the development of chemotherapeutic combinations.

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment

Post-group assignment information: For all cohorts doses were administered in repeated 21-day cycles.

Determination of the Maximum Tolerated Dose (MTD), by using dose-escalating design and measured by Dose Limiting Toxicity (DLT) is a standard procedure in the development of chemotherapeutic combinations.

Reporting Groups

	Description
Cohort A - Vorinostat BID + Pemetrexed + Cisplatin	Dose level A.1 - Vorinostat 200 mg twice daily (BID) for 14 days out of 3 weeks + Pemetrexed + Cisplatin Dose level A.2 - Vorinostat 300 mg twice daily (BID) for 3 consecutive days out of 7 days in first week, two weeks off + Pemetrexed + Cisplatin
Cohort B - Vorinostat QD + Pemetrexed + Cisplatin	Dose level B.1 - Vorinostat 300 mg once daily (QD) for 7 days + Pemetrexed + Cisplatin Dose level B.2 - Vorinostat 400 mg once daily (QD) for 7 days + Pemetrexed + Cisplatin
Cohort C - Vorinostat BID + Pemetrexed	Dose level C.1 - Vorinostat 300 mg twice daily (BID) for 3 consecutive days out of 7 days in first week, two weeks off + Pemetrexed Dose level C.2 - Vorinostat 300 mg twice daily (BID) for 3 consecutive days out of 7 days in first two weeks, one week off + Pemetrexed Dose level C.3 - Vorinostat 300 mg twice daily (BID) for 3 consecutive days out of 7 days repeated weekly + Pemetrexed
Cohort D - Vorinostat QD + Pemetrexed	Dose level D.1 - Vorinostat 300 mg once daily (QD) for 7 days + Pemetrexed Dose level D.2 - Vorinostat 400 mg once daily (QD) for 7 days + Pemetrexed

Participant Flow: Overall Study

	Cohort A - Vorinostat BID + Pemetrexed + Cisplatin	Cohort B - Vorinostat QD + Pemetrexed + Cisplatin	Cohort C - Vorinostat BID + Pemetrexed	Cohort D - Vorinostat QD + Pemetrexed
STARTED	13	9	14	16
COMPLETED	3	3	2	3
NOT COMPLETED	10	6	12	13
Adverse Event	5	4	3	3
Progressive Disease	4	1	9	10
Received radiation on new therapy	1	0	0	0
> 14 day delay in therapy start	0	1	0	0

Baseline Characteristics

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Reporting Groups

	Description
Cohort A - Vorinostat BID + Pemetrexed + Cisplatin	Dose level A.1 - Vorinostat 200 mg twice daily (BID) for 14 days out of 3 weeks + Pemetrexed + Cisplatin Dose level A.2 - Vorinostat 300 mg twice daily (BID) for 3 consecutive days out of 7 days in first week, two weeks off + Pemetrexed + Cisplatin
Cohort B - Vorinostat QD + Pemetrexed + Cisplatin	Dose level B.1 - Vorinostat 300 mg once daily (QD) for 7 days + Pemetrexed + Cisplatin Dose level B.2 - Vorinostat 400 mg once daily (QD) for 7 days + Pemetrexed + Cisplatin
Cohort C - Vorinostat BID + Pemetrexed	Dose level C.1 - Vorinostat 300 mg twice daily (BID) for 3 consecutive days out of 7 days in first week, two weeks off + Pemetrexed Dose level C.2 - Vorinostat 300 mg twice daily (BID) for 3 consecutive days out of 7 days in first two weeks, one week off + Pemetrexed Dose level C.3 - Vorinostat 300 mg twice daily (BID) for 3 consecutive days out of 7 days repeated weekly + Pemetrexed
Cohort D - Vorinostat QD + Pemetrexed	Dose level D.1 - Vorinostat 300 mg once daily (QD) for 7 days + Pemetrexed Dose level D.2 - Vorinostat 400 mg once daily (QD) for 7 days + Pemetrexed

Baseline Measures

	Cohort A - Vorinostat BID + Pemetrexed + Cisplatin	Cohort B - Vorinostat QD + Pemetrexed + Cisplatin	Cohort C - Vorinostat BID + Pemetrexed	Cohort D - Vorinostat QD + Pemetrexed	Total
Number of Participants [units: participants]	13	9	14	16	52
Age [units: years] Mean ( Full Range )	60.52 ( 35 to 81 )	58.23 ( 31 to 74 )	60.09 ( 41 to 78 )	63.63 ( 39 to 81 )	61 ( 31 to 81 )
Gender [units: participants]
Female	4	5	7	8	24
Male	9	4	7	8	28
Race/Ethnicity [units: participants]
Asian	0	0	0	1	1
Black	0	2	0	1	3
European	0	1	0	0	1
Hispanic American	1	0	0	2	3
White	12	6	14	12	44

Outcome Measures

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1. Primary:

Maximum Tolerated Dose (MTD) Status as Determined by Number of Participants With Dose Limiting Toxicity (DLT) at Each Dose Level [ Cycle 1 (21 days) ]

Measure Type	Primary
Measure Title	Maximum Tolerated Dose (MTD) Status as Determined by Number of Participants With Dose Limiting Toxicity (DLT) at Each Dose Level
Measure Description	MTD was determined by the occurrence of DLTs during the first treatment cycle. DLT describes side effects of a drug or other treatment that are serious enough to prevent an increase in dose or level of that treatment. The dose level is equal to the MTD if < 2 patients experience a DLT and is also the highest tolerated dose level in the cohort.
Time Frame	Cycle 1 (21 days)
Safety Issue	Yes

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
A total of 52 participants were enrolled in this study. Six were violations pts (1 in Cohort C Dose Level 1, 1 in Cohort C Dose Level 2, 3 in Cohort D Dose Level 1, and 1 in Cohort D Dose Level 2) and were replaced. None of the violations pts had any DLTs in the first cycle of the study.

Reporting Groups

	Description
Dose Level A.1	(Cohort A) Dose level A.1 - Vorinostat 200 mg twice daily (BID) for 14 days out of 3 weeks + Pemetrexed + Cisplatin
Dose Level A.2	(Cohort A) Dose level A.2 - Vorinostat 300 mg twice daily (BID) for 3 consecutive days out of 7 days in first week, two weeks off + Pemetrexed + Cisplatin
Dose Level B.1	(Cohort B) Dose level B.1 - Vorinostat 300 mg once daily (QD) for 7 days + Pemetrexed + Cisplatin
Dose Level B.2	(Cohort B) Dose level B.2 - Vorinostat 400 mg once daily (QD) for 7 days + Pemetrexed + Cisplatin
Dose Level C.1	(Cohort C) Dose level C.1 - Vorinostat 300 mg twice daily (BID) for 3 consecutive days out of 7 days in first week, two weeks off + Pemetrexed
Dose Level C.2	(Cohort C) Dose level C.2 - Vorinostat 300 mg twice daily (BID) for 3 consecutive days out of 7 days in first two weeks, one week off + Pemetrexed
Dose Level C.3	(Cohort C) Dose level C.3 - Vorinostat 300 mg twice daily (BID) for 3 consecutive days out of 7 days repeated weekly + Pemetrexed
Dose Level D.1	(Cohort D) Dose level D.1 - Vorinostat 300 mg once daily (QD) for 7 days + Pemetrexed
Dose Level D.2	(Cohort D) Dose level D.2 - Vorinostat 400 mg once daily (QD) for 7 days + Pemetrexed

Measured Values

	Dose Level A.1	Dose Level A.2	Dose Level B.1	Dose Level B.2	Dose Level C.1	Dose Level C.2	Dose Level C.3	Dose Level D.1	Dose Level D.2
Number of Participants Analyzed [units: participants]	6	7	3	6	7	4	3	9	7
Maximum Tolerated Dose (MTD) Status as Determined by Number of Participants With Dose Limiting Toxicity (DLT) at Each Dose Level [units: Participants]
Number (#) of DLT	1	3	0	2	1	0	0	1	2
# Participants treated at a dose level <MTD	0	0	0	0	7	4	0	0	0
# Participants treated at a dose level =MTD	6	0	3	0	0	0	3	9	0
# Participants treated at a dose level >MTD	0	7	0	6	0	0	0	0	7

No statistical analysis provided for Maximum Tolerated Dose (MTD) Status as Determined by Number of Participants With Dose Limiting Toxicity (DLT) at Each Dose Level

2. Secondary:

Safety and Tolerability as Measured by the Number of Participants With Disease Progression [ Any time during 8 cycle treatment period through 30 days after. ]

Measure Type	Secondary
Measure Title	Safety and Tolerability as Measured by the Number of Participants With Disease Progression
Measure Description	Number of participants with disease progression (protocol-mandated reason for discontinuation). Disease progression was determined by the principle investigator.
Time Frame	Any time during 8 cycle treatment period through 30 days after.
Safety Issue	Yes

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
All participants. Treated Population includes all participants who received at least one dose and had efficacy measurements at baseline and at least one post baseline treatment.

Reporting Groups

	Description
Cohort A - Vorinostat BID + Pemetrexed + Cisplatin	Dose level A.1 - Vorinostat 200 mg twice daily (BID) for 14 days out of 3 weeks + Pemetrexed + Cisplatin Dose level A.2 - Vorinostat 300 mg twice daily (BID) for 3 consecutive days out of 7 days in first week, two weeks off + Pemetrexed + Cisplatin
Cohort B - Vorinostat QD + Pemetrexed + Cisplatin	Dose level B.1 - Vorinostat 300 mg once daily (QD) for 7 days + Pemetrexed + Cisplatin Dose level B.2 - Vorinostat 400 mg once daily (QD) for 7 days + Pemetrexed + Cisplatin
Cohort C - Vorinostat BID + Pemetrexed	Dose level C.1 - Vorinostat 300 mg twice daily (BID) for 3 consecutive days out of 7 days in first week, two weeks off + Pemetrexed Dose level C.2 - Vorinostat 300 mg twice daily (BID) for 3 consecutive days out of 7 days in first two weeks, one week off + Pemetrexed Dose level C.3 - Vorinostat 300 mg twice daily (BID) for 3 consecutive days out of 7 days repeated weekly + Pemetrexed
Cohort D - Vorinostat QD + Pemetrexed	Dose level D.1 - Vorinostat 300 mg once daily (QD) for 7 days + Pemetrexed Dose level D.2 - Vorinostat 400 mg once daily (QD) for 7 days + Pemetrexed

Measured Values

	Cohort A - Vorinostat BID + Pemetrexed + Cisplatin	Cohort B - Vorinostat QD + Pemetrexed + Cisplatin	Cohort C - Vorinostat BID + Pemetrexed	Cohort D - Vorinostat QD + Pemetrexed
Number of Participants Analyzed [units: participants]	13	9	14	16
Safety and Tolerability as Measured by the Number of Participants With Disease Progression [units: Participants]	4	1	9	10

No statistical analysis provided for Safety and Tolerability as Measured by the Number of Participants With Disease Progression

Serious Adverse Events

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Other Adverse Events

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More Information

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Certain Agreements:

All Principal Investigators ARE employed by the organization sponsoring the study.

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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Results Point of Contact:

Name/Title: Senior Vice President, Clinical and Quantitative Sciences
Organization: Merck & Co., Inc.
phone: 1-800-672-6372

No publications provided

Responsible Party:	Merck & Co., Inc. ( Executive Vice President, Clinical and Quantitative Sciences )
Study ID Numbers:	2005_006, MK0683-012
Study First Received:	March 28, 2005
Results First Received:	November 25, 2008
Last Updated:	March 16, 2009
ClinicalTrials.gov Identifier:	NCT00106626 History of Changes
Health Authority:	United States: Food and Drug Administration