A Phase 3 interventional study of Vorinostat and Placebo in Mesothelioma and Lung Cancer, sponsored by Merck Sharp & Dohme LLC. Completed. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2020-10-26.
Sponsored by Merck Sharp & Dohme LLC · Phase 3, Interventional, and Treatment
The goal of this study is to assess the efficacy and safety of an oral investigational drug suberoylanilide hydroxamic acid (vorinostat, MK-0683) compared to placebo, in the treatment of participants with advanced malignant pleural mesothelioma who have failed at least one prior chemotherapy regimen. The primary hypotheses are the following: (1) vorinostat improves overall survival (OS) compared to placebo (2) vorinostat is generally safe and well tolerated.
Treatment Extension Phase: Participants in this study will be eligible to enroll in an open-label treatment extension phase if they: a) were originally randomized to the vorinostat arm and have not experienced disease progression; b) were randomized to the placebo arm and meet the "Extension Phase Inclusion Criteria for Participants in the Placebo Arm" below; or c) were originally randomized to the vorinostat arm and discontinued study therapy for reasons other than progression and the investigator believes that it is in the participant's best interest to resume vorinostat treatment.
As specified by the protocol, based on planned extension phase inclusion criteria and pre-specified primary outcome analyses requirements, the extension phase of this study was not conducted.
470 studies on the registry are indexed under Mesothelioma; 75 are open to participants now.
This study's enrollment of 661 is above the median of 40 across 371 interventional studies indexed under Mesothelioma.
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Extension Phase Inclusion Criteria:
Exclusion Criteria:
Vorinostat three 100 mg capsules twice daily for 3 consecutive days of treatment followed by 4 days of rest repeated weekly, in 21-day cycles. Treatment will continue until disease progression or unacceptable toxicity.
Drug: Vorinostat
Placebo capsules twice daily for 3 consecutive days of treatment followed by 4 days of rest repeated weekly, in 21-day cycles. Treatment will continue until disease progression or unacceptable toxicity.
Drug: Placebo
Vorinostat 100 mg oral capsules
Also known as: MK-0683, Zolinza
Vorinostat-matching placebo oral capsules
Overall Survival (OS)
OS was defined as the time from randomization to death due to any cause. Participants without documented death at the time of final analysis were censored at the date of the last follow up. The final analysis for OS was planned and performed at the time of the protocol pre-specified final statistical analysis with a data cut-off of 15-July-2011. OS analysis is reported here for all randomized participants.
Time frame: Up to ~72 months (through pre-specified final statistical analysis cut-off date of 15-July-2011)
Number of Participants Who Experienced Adverse Events (AEs) Characterized as Grade 3 or Grade 4 According to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE)
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 of a pre-existing condition which is temporally associated with the use of the Sponsor's product is also an AE. Reporting of AEs per NCI CTCAE is based on 5 grades of severity; Grade 1 (mild; no treatment needed), Grade 2 (moderate; minimal treatment needed), Grade 3 (severe, not life threatening; hospitalization needed), Grade 4 (life threatening; urgent treatment needed) and Grade 5 (death).The final analysis for Grade 3 or 4 AEs was planned and performed at the time of the protocol pre-specified final statistical analysis with a data cut-off of 15-July-2011. Per protocol number of participants who experienced Grade 3/4 AEs per NCI CTCAE is reported here for all randomized participants who received ≥1 dose of study treatment.
Time frame: Up to ~72 months (through pre-specified final statistical analysis cut-off date of 15-July-2011)
Number of Participants Who Experienced an AE
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 of a pre-existing condition which is temporally associated with the use of the Sponsor's product is also an AE. The final analysis for participants who experienced an AE was planned and performed at the time of the protocol pre-specified final statistical analysis with a data cut-off of 15-July-2011. Per protocol number of participants who experienced an AE is reported here for all randomized participants who received ≥1 dose of study treatment.
Time frame: Up to ~72 months (through pre-specified final statistical analysis cut-off date of 15-July-2011)
Number of Participants Who Discontinued Study Treatment Due to an AE
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 of a pre-existing condition which is temporally associated with the use of the Sponsor's product is also an AE. The final analysis for participants who discontinued study treatment due to an AE was planned and performed at the time of the protocol pre-specified final statistical analysis with a data cut-off of 15-July-2011. Per protocol number of participants who discontinued study treatment due to an AE is reported here for all randomized participants who received ≥1 dose of study treatment. As specified by the protocol, participants who discontinued study treatment due to an AE remained on study until investigator notification to discontinue.
Time frame: Up to ~72 months (through pre-specified final statistical analysis cut-off date of 15-July-2011)
Progression Free Survival (PFS)
PFS was defined as the time from randomization to the first documented progressive disease (PD) per meso-modified-Response Evaluation Criteria in Solid Tumors (Meso-modified RECIST) based on independent radiology review or death due to any cause, whichever occurred first. Meso-modified RECIST was created and validated for disease measurement in pleural mesothelioma. Per meso-modified RECIST, PD was defined as ≥20% increase in the total tumor measurement over the nadir measurement or the appearance of ≥1 new lesions. The final analysis for PFS per Meso-modified RECIST by independent radiology review was planned and performed at the time of the protocol pre-specified final statistical analysis with a data cut-off of 15-July-2011. PFS analysis per Meso-modified RECIST by independent radiology review is reported here for all randomized participants.
Time frame: Up to ~72 months (through pre-specified final statistical analysis cut-off date of 15-July-2011)
Objective Response Rate (ORR)
ORR was defined as the percentage of participants in the analysis population who had a complete response (CR: disappearance of all target lesions with no evidence of tumor elsewhere) or a partial response (PR: ≥30% reduction in the total tumor measurement) per Meso-modified RECIST based on independent radiology review. Meso-modified RECIST was created and validated for disease measurement in pleural mesothelioma. The final analysis for ORR per Meso-modified RECIST by independent radiology review was planned and performed at the time of the protocol pre-specified final statistical analysis with a data cut-off of 15-July-2011. Per protocol percentage of participants who had a CR or a PR per Meso-modified RECIST by independent radiology review is reported here as the ORR for all randomized participants who had valid baseline data for ORR analysis available.
Time frame: Up to ~72 months (through pre-specified final statistical analysis cut-off date of 15-July-2011)
Percent Change From Baseline in Lung Cancer Symptom Scale, Modified for Mesothelioma (LCSS-Meso) Dyspnea Score at Week 12
LCSS-Meso provides participant-reported outcome measures of symptom burden and quality of life. LCSS-Meso includes the disease-related item dyspnea or shortness of breath. The LCSS-Meso item dyspnea is measured on a visual analog scale (VAS) using 100 mm and assigned an individual score based on symptom intensity. Dyspnea VAS score ranges from 0 mm (lowest; no dyspnea) to 100 mm (highest; worst dyspnea). Higher scores indicate dyspnea worsening. Baseline measurement was taken before treatment initiation. Per protocol percent change in the LCSS-Meso dyspnea score from baseline to Week 12 post treatment initiation (percent change calculated: \[Week 12 - Baseline\]/Baseline\*100)\] is reported here for all randomized participants who had a valid baseline and ≥1 post-baseline value for the LCSS-Meso dyspnea score available.
Time frame: Baseline, Week 12
Percentage of Participants With ≥50% Change Together With a >10 mm Change From Baseline in the LCSS-Meso Dyspnea Score at Week 12
LCSS-Meso provides participant-reported outcome measures of symptom burden and quality of life. LCSS-Meso includes the disease-related item dyspnea or shortness of breath. The LCSS-Meso item dyspnea is measured on a visual analog scale (VAS) using 100 mm and assigned an individual score based on symptom intensity. Dyspnea VAS score ranges from 0 mm (lowest; no dyspnea) to 100 mm (highest; worst dyspnea). Higher scores indicate dyspnea worsening. Baseline measurement was taken before treatment initiation. Per protocol percentage of participants with ≥50% change (percent change calculated: \[Week 12 - Baseline\]/Baseline\*100) and \>10 mm absolute change in LCSS-Meso dyspnea score from baseline to Week 12 post treatment initiation is reported here for all randomized participants who had a valid baseline and ≥1 post-baseline value for the LCSS-Meso dyspnea score available.
Time frame: Baseline, Week 12
Percent Change From Baseline in Forced Vital Capacity (FVC) at Week 12
Pulmonary function test was conducted using a spirometer for assessment of FVC. FVC is the volume of air forcibly exhaled from the lungs after taking the deepest breath possible. Baseline measurement was taken before treatment initiation. Per protocol percent change in FVC from baseline to Week 12 post treatment initiation (percent change calculated: \[Week 12 - Baseline\]/Baseline\*100)\] is reported here for all randomized participants who had a valid baseline and ≥1 post-baseline value for FVC available.
Time frame: Baseline, Week 12
Percentage of Participants With ≥10% Change From Baseline in FVC at Week 12
Pulmonary function test was conducted using a spirometer for assessment of FVC. FVC is the volume of air forcibly exhaled from the lungs after taking the deepest breath possible. Baseline measurement was taken before treatment initiation. Per protocol percentage of participants with ≥10% change (percent change calculated: \[Week 12 - Baseline\]/Baseline\*100) in FVC from baseline to Week 12 post treatment initiation is reported here for all randomized participants who had a valid baseline and ≥1 post-baseline value for FVC.
Time frame: Baseline, Week 12
| Milestone | Vorinostat | Placebo |
|---|---|---|
| Started | 329 | 332 |
| Treated | 329 | 329 |
| Completed | 1 | 0 |
| Not completed | 328 | 332 |
| Withdrew: Site discontinued | 3 | 6 |
| Withdrew: Other | 0 | 1 |
| Withdrew: Progressive disease | 255 | 285 |
| Withdrew: Adverse event | 34 | 11 |
| Withdrew: Death | 12 | 13 |
| Withdrew: Physician decision | 3 | 3 |
| Withdrew: Withdrawal by subject | 19 | 11 |
| Withdrew: Protocol violation | 2 | 2 |
OS was defined as the time from randomization to death due to any cause. Participants without documented death at the time of final analysis were censored at the date of the last follow up. The final analysis for OS was planned and performed at the time of the protocol pre-specified final statistical analysis with a data cut-off of 15-July-2011. OS analysis is reported here for all randomized participants.
| Weeks | Vorinostat | Placebo |
|---|---|---|
| Overall Survival (OS) | 30.7 (26.71 to 36.14) | 27.1 (23.14 to 31.86) |
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 of a pre-existing condition which is temporally associated with the use of the Sponsor's product is also an AE. Reporting of AEs per NCI CTCAE is based on 5 grades of severity; Grade 1 (mild; no treatment needed), Grade 2 (moderate; minimal treatment needed), Grade 3 (severe, not life threatening; hospitalization needed), Grade 4 (life threatening; urgent treatment needed) and Grade 5 (death).The final analysis for Grade 3 or 4 AEs was planned and performed at the time of the protocol pre-specified final statistical analysis with a data cut-off of 15-July-2011. Per protocol number of participants who experienced Grade 3/4 AEs per NCI CTCAE is reported here for all randomized participants who received ≥1 dose of study treatment.
| Participants | Vorinostat | Placebo |
|---|---|---|
| Number of Participants Who Experienced Adverse Events (AEs) Characterized as Grade 3 or Grade 4 According to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) | 165 | 146 |
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 of a pre-existing condition which is temporally associated with the use of the Sponsor's product is also an AE. The final analysis for participants who experienced an AE was planned and performed at the time of the protocol pre-specified final statistical analysis with a data cut-off of 15-July-2011. Per protocol number of participants who experienced an AE is reported here for all randomized participants who received ≥1 dose of study treatment.
| Participants | Vorinostat | Placebo |
|---|---|---|
| Number of Participants Who Experienced an AE | 327 | 311 |
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 of a pre-existing condition which is temporally associated with the use of the Sponsor's product is also an AE. The final analysis for participants who discontinued study treatment due to an AE was planned and performed at the time of the protocol pre-specified final statistical analysis with a data cut-off of 15-July-2011. Per protocol number of participants who discontinued study treatment due to an AE is reported here for all randomized participants who received ≥1 dose of study treatment. As specified by the protocol, participants who discontinued study treatment due to an AE remained on study until investigator notification to discontinue.
| Participants | Vorinostat | Placebo |
|---|---|---|
| Number of Participants Who Discontinued Study Treatment Due to an AE | 60 | 49 |
PFS was defined as the time from randomization to the first documented progressive disease (PD) per meso-modified-Response Evaluation Criteria in Solid Tumors (Meso-modified RECIST) based on independent radiology review or death due to any cause, whichever occurred first. Meso-modified RECIST was created and validated for disease measurement in pleural mesothelioma. Per meso-modified RECIST, PD was defined as ≥20% increase in the total tumor measurement over the nadir measurement or the appearance of ≥1 new lesions. The final analysis for PFS per Meso-modified RECIST by independent radiology review was planned and performed at the time of the protocol pre-specified final statistical analysis with a data cut-off of 15-July-2011. PFS analysis per Meso-modified RECIST by independent radiology review is reported here for all randomized participants.
| Weeks | Vorinostat | Placebo |
|---|---|---|
| Progression Free Survival (PFS) | 6.3 (6.1 to 7.1) | 6.1 (6.0 to 6.1) |
ORR was defined as the percentage of participants in the analysis population who had a complete response (CR: disappearance of all target lesions with no evidence of tumor elsewhere) or a partial response (PR: ≥30% reduction in the total tumor measurement) per Meso-modified RECIST based on independent radiology review. Meso-modified RECIST was created and validated for disease measurement in pleural mesothelioma. The final analysis for ORR per Meso-modified RECIST by independent radiology review was planned and performed at the time of the protocol pre-specified final statistical analysis with a data cut-off of 15-July-2011. Per protocol percentage of participants who had a CR or a PR per Meso-modified RECIST by independent radiology review is reported here as the ORR for all randomized participants who had valid baseline data for ORR analysis available.
| Percentage of Participants | Vorinostat | Placebo |
|---|---|---|
| Objective Response Rate (ORR) | 0.63 (0.08 to 2.25) | 0.31 (0.01 to 1.71) |
LCSS-Meso provides participant-reported outcome measures of symptom burden and quality of life. LCSS-Meso includes the disease-related item dyspnea or shortness of breath. The LCSS-Meso item dyspnea is measured on a visual analog scale (VAS) using 100 mm and assigned an individual score based on symptom intensity. Dyspnea VAS score ranges from 0 mm (lowest; no dyspnea) to 100 mm (highest; worst dyspnea). Higher scores indicate dyspnea worsening. Baseline measurement was taken before treatment initiation. Per protocol percent change in the LCSS-Meso dyspnea score from baseline to Week 12 post treatment initiation (percent change calculated: \[Week 12 - Baseline\]/Baseline\*100)\] is reported here for all randomized participants who had a valid baseline and ≥1 post-baseline value for the LCSS-Meso dyspnea score available.
| Percent Change | Vorinostat | Placebo |
|---|---|---|
| Percent Change From Baseline in Lung Cancer Symptom Scale, Modified for Mesothelioma (LCSS-Meso) Dyspnea Score at Week 12 | 141.8 (72.9 to 210.8) | 174.7 (40.4 to 308.9) |
LCSS-Meso provides participant-reported outcome measures of symptom burden and quality of life. LCSS-Meso includes the disease-related item dyspnea or shortness of breath. The LCSS-Meso item dyspnea is measured on a visual analog scale (VAS) using 100 mm and assigned an individual score based on symptom intensity. Dyspnea VAS score ranges from 0 mm (lowest; no dyspnea) to 100 mm (highest; worst dyspnea). Higher scores indicate dyspnea worsening. Baseline measurement was taken before treatment initiation. Per protocol percentage of participants with ≥50% change (percent change calculated: \[Week 12 - Baseline\]/Baseline\*100) and \>10 mm absolute change in LCSS-Meso dyspnea score from baseline to Week 12 post treatment initiation is reported here for all randomized participants who had a valid baseline and ≥1 post-baseline value for the LCSS-Meso dyspnea score available.
| Percentage of participants | Vorinostat | Placebo |
|---|---|---|
| Percentage of Participants With ≥50% Change Together With a >10 mm Change From Baseline in the LCSS-Meso Dyspnea Score at Week 12 | 15.05 (11.19 to 19.62) | 16.39 (12.38 to 21.08) |
Pulmonary function test was conducted using a spirometer for assessment of FVC. FVC is the volume of air forcibly exhaled from the lungs after taking the deepest breath possible. Baseline measurement was taken before treatment initiation. Per protocol percent change in FVC from baseline to Week 12 post treatment initiation (percent change calculated: \[Week 12 - Baseline\]/Baseline\*100)\] is reported here for all randomized participants who had a valid baseline and ≥1 post-baseline value for FVC available.
| Percent Change | Vorinostat | Placebo |
|---|---|---|
| Percent Change From Baseline in Forced Vital Capacity (FVC) at Week 12 | -6.0 (-9.82 to -2.09) | -5.6 (-9.2 to -2.0) |
Pulmonary function test was conducted using a spirometer for assessment of FVC. FVC is the volume of air forcibly exhaled from the lungs after taking the deepest breath possible. Baseline measurement was taken before treatment initiation. Per protocol percentage of participants with ≥10% change (percent change calculated: \[Week 12 - Baseline\]/Baseline\*100) in FVC from baseline to Week 12 post treatment initiation is reported here for all randomized participants who had a valid baseline and ≥1 post-baseline value for FVC.
| Percentage of participants | Vorinostat | Placebo |
|---|---|---|
| Percentage of Participants With ≥10% Change From Baseline in FVC at Week 12 | 24.76 (19.08 to 31.17) | 21.63 (16.24 to 27.86) |
Collected over Up to ~77 months (through database cut-off date of 21-November-2011). Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Vorinostat | 288/329 (87.5%) | 133/329 (40.4%) | 303/329 (92.1%) |
| Placebo | 284/332 (85.5%) | 131/329 (39.8%) | 281/329 (85.4%) |
| Event | Vorinostat | Placebo |
|---|---|---|
| Pleural mesothelioma malignant advancedNeoplasms benign, malignant and unspecified (incl cysts and polyps) | 50/329 | 59/329 |
| DyspnoeaRespiratory, thoracic and mediastinal disorders | 11/329 | 25/329 |
| PneumoniaInfections and infestations | 13/329 | 10/329 |
| NauseaGastrointestinal disorders | 12/329 | 0/329 |
| AnaemiaBlood and lymphatic system disorders | 10/329 | 3/329 |
| FatigueGeneral disorders | 8/329 | 2/329 |
| Accidental overdoseInjury, poisoning and procedural complications | 8/329 | 0/329 |
| Tumour painNeoplasms benign, malignant and unspecified (incl cysts and polyps) | 5/329 | 8/329 |
| Atrial fibrillationCardiac disorders | 6/329 | 3/329 |
| VomitingGastrointestinal disorders | 6/329 | 2/329 |
| Event | Vorinostat | Placebo |
|---|---|---|
| NauseaGastrointestinal disorders | 189/329 | 104/329 |
| FatigueGeneral disorders | 153/329 | 128/329 |
| DiarrhoeaGastrointestinal disorders | 142/329 | 58/329 |
| Decreased appetiteMetabolism and nutrition disorders | 133/329 | 85/329 |
| VomitingGastrointestinal disorders | 131/329 | 45/329 |
| DyspnoeaRespiratory, thoracic and mediastinal disorders | 97/329 | 97/329 |
| Tumour painNeoplasms benign, malignant and unspecified (incl cysts and polyps) | 59/329 | 83/329 |
| ConstipationGastrointestinal disorders | 80/329 | 69/329 |
| Weight decreasedInvestigations | 67/329 | 26/329 |
| CoughRespiratory, thoracic and mediastinal disorders | 59/329 | 66/329 |
| Age, Continuous(Years) | Vorinostat | Placebo | Total |
|---|---|---|---|
| Mean | 64.2 ± 9.5 | 64.4 ± 9.3 | 64.3 ± 9.4 |
| Sex: Female, Male(Participants) | Vorinostat | Placebo | Total |
|---|---|---|---|
| Female | 46 | 62 | 108 |
| Male | 283 | 270 | 553 |
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Plan to share: Yes — http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
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