Advanced Cancer Refractory, Advanced Cancer Relapsed
Conditions
Brief summary
A 2-period, crossover study to assess the effects of MK0683 (vorinostat) on the QTc interval in patients with relapsed or refractory advanced cancer.
Detailed description
Merck Duration of Treatment : vorinostat; treatment will continue until disease progression or intolerable toxicity is reached
Interventions
DRUGvorinostat
A 2-part, crossover study. Part 1: Arm A: Single dose of vorinostat 800 mg capsules (Period 1) crossing over to Single dose of vorinostat Placebo capsules (Period 2) Arm B: Single dose of vorinostat Placebo capsules (Period 1) crossing over to Single dose of vorinostat 800 mg capsules (Period 2). Part 2: All patients will receive 400 mg vorinostat capsules once daily. Treatment will continue until disease progression or intolerable toxicity.
DRUGComparator: placebo (unspecified)
A 2-part, crossover study. Part 1: Arm A: Single dose of vorinostat Placebo capsules (Period 2) Arm B: Single dose of vorinostat Placebo capsules (Period 1).
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patient has a histologically-confirmed metastatic or locally advanced solid tumor that has failed to respond to standard therapy, progressed despite standard therapy or for which standard therapy does not exist * Patient has life expectancy of greater than 3 months * Patient is able to swallow capsules
Exclusion criteria
* Patient has had chemotherapy, radiotherapy or biological therapy 2 weeks prior to taking study drug * Patient is currently participating or has participated in a study with an investigational compound or device within 30 days of signing informed consent * Patient has active CNS metastases and/or carcinomatous meningitis * Patient has primary central nervous system tumor * Patient has a history of drug or alcohol abuse * Patient has Hepatitis B or C * Patient is HIV positive * Patient has active infection or has received intravenous antibiotics, antiviral or antifungal agents 2 weeks before taking study drug
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in QTcF at 0.5 Hours | Baseline and 0.5 hours | The Fridericia correction of the QT interval (QTcF) was determined at each time point from five replicate measurements. The change from baseline in QTcF was calculated by subtracting the QTcF value at each timepoint from the QTcF baseline (predose) value. |
| Change From Baseline in QTcF at 1 Hour | Baseline and 1 hour | Fridericia correction of the QT interval (QTcF) was determined at each time point from five replicate measurements. The change from baseline in QTcF was calculated by subtracting the QTcF value at each timepoint from the QTcF baseline (predose) value. |
| Change From Baseline in QTcF at 2 Hours | Baseline and 2 hours | The Fridericia correction of the QT interval (QTcF) was determined at each time point from five replicate measurements. The change from baseline in QTcF was calculated by subtracting the QTcF value at each timepoint from the QTcF baseline (predose) value. |
| Change From Baseline in QTcF at 3 Hours | Baseline and 3 hours | The Fridericia correction of the QT interval (QTcF) was determined at each time point from five replicate measurements. The change from baseline in QTcF was calculated by subtracting the QTcF value at each timepoint from the QTcF baseline (predose) value. |
| Change From Baseline in QTcF at 4 Hours | Baseline and 4 hours | The Fridericia correction of the QT interval (QTcF) was determined at each time point from five replicate measurements. The placebo-corrected change from baseline in QTcF was calculated by subtracting the QTcF change from baseline for placebo at each timepoint from the QTcF change from baseline for vorinostat at each timepoint. |
| Change From Baseline in QTcF at 8 Hours | Baseline and 8 hours | The Fridericia correction of the QT interval (QTcF) was determined at each time point from five replicate measurements. The change from baseline in QTcF was calculated by subtracting the QTcF value at each timepoint from the QTcF baseline (predose) value. |
| Change From Baseline in QTcF at 12 Hours | Baseline and 12 hours | The Fridericia correction of the QT interval (QTcF) was determined at each time point from five replicate measurements. The change from baseline in QTcF was calculated by subtracting the QTcF value at each timepoint from the QTcF baseline (predose) value. |
| Change From Baseline in QTcF at 24 Hours | Baseline and 24 hours | The Fridericia correction of the QT interval (QTcF) was determined at each time point from five replicate measurements. The change from baseline in QTcF was calculated by subtracting the QTcF value at each timepoint from the QTcF baseline (predose) value. |
Participant flow
Recruitment details
Eric Rubin, M.D., The Cancer Institute of New Jersey, New Brunswick, New Jersey; Pamela Munster, M.D., H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida; Prof. Dr. Simon van Belle, University Hospital of Ghent, Ghent, Belgium. Dosing initiated on 16-Jul-2007 and completed on 05-Feb-2009.
Pre-assignment details
Enrolled patients were assigned to 1 of 2 dose sequences (vorinostat then placebo or placebo then vorinostat) in Part 1 of the study to determine the effect of vorinostat on the QTcF (Fridericia-corrected QT) interval. Following Part 1, active patients continued into Part 2, daily dosing of vorinostat.
Participants by arm
| Arm | Count |
|---|---|
| All Participants All Participants group includes data from all participants throughout Part 1 and Part 2 of the study. | 25 |
| Total | 25 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Part 1, Period 1 | Protocol Violation | 1 | 0 | 0 |
| Part 1, Period 1 | Withdrawal by Subject | 1 | 0 | 0 |
| Part 2 | Adverse Event | 0 | 0 | 3 |
| Part 2 | Death | 0 | 0 | 1 |
| Part 2 | Lack of Efficacy | 0 | 0 | 17 |
| Part 2 | Withdrawal by Subject | 0 | 0 | 3 |
Baseline characteristics
| Characteristic | All Participants |
|---|---|
| Age, Continuous | 59.4 years |
| Cancer Type Anal | 1 Participants |
| Cancer Type Basocellular | 1 Participants |
| Cancer Type Breast | 1 Participants |
| Cancer Type Colon | 3 Participants |
| Cancer Type Gastrointestinal | 1 Participants |
| Cancer Type Lung | 3 Participants |
| Cancer Type Mesothelioma | 3 Participants |
| Cancer Type Mucinous carcinoma | 1 Participants |
| Cancer Type Ovarian | 5 Participants |
| Cancer Type Pancreatic | 1 Participants |
| Cancer Type Soft Tissue | 2 Participants |
| Cancer Type Thyroid | 1 Participants |
| Cancer Type Uterine | 2 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 0 = Normal Activity | 9 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 1 = Symptoms, but ambulatory | 13 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 2 = In bed <50% of the time | 3 Participants |
| Number of Prior Radiation Therapies None | 14 Participants |
| Number of Prior Radiation Therapies One Prior Radiation Therapy | 7 Participants |
| Number of Prior Radiation Therapies Three or More Prior Radiation Therapies | 3 Participants |
| Number of Prior Radiation Therapies Two Prior Radiation Therapies | 1 Participants |
| Number of Prior Systemic Anti-Cancer Therapies One Prior Systemic Anti-Cancer Therapy | 0 Participants |
| Number of Prior Systemic Anti-Cancer Therapies Three or more Prior Systemic Anti-Cancer Therapies | 22 Participants |
| Number of Prior Systemic Anti-Cancer Therapies Two Prior Systemic Anti-Cancer Therapies | 3 Participants |
| Race/Ethnicity, Customized Asian | 1 participants |
| Race/Ethnicity, Customized Black | 2 participants |
| Race/Ethnicity, Customized Hispanic | 1 participants |
| Race/Ethnicity, Customized White | 21 participants |
| Sex: Female, Male Female | 12 Participants |
| Sex: Female, Male Male | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 24 / 25 |
| serious Total, serious adverse events | 11 / 25 |
Outcome results
Primary
Change From Baseline in QTcF at 0.5 Hours
The Fridericia correction of the QT interval (QTcF) was determined at each time point from five replicate measurements. The change from baseline in QTcF was calculated by subtracting the QTcF value at each timepoint from the QTcF baseline (predose) value.
Time frame: Baseline and 0.5 hours
Population: All patients as treated population in Part 1 of the Study;~22 patients had QTcF data from the vorinostat period (One patient with protocol violation, and two patients without predose measurements were excluded) and 23 patients had QTcF data from the placebo period (one patient with protocol violation and one patient who discontinued were excluded)
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Vorinostat | Change From Baseline in QTcF at 0.5 Hours | 1.78 milliseconds |
| Placebo | Change From Baseline in QTcF at 0.5 Hours | -1.22 milliseconds |
90% CI: [-0.28, 6.28]
Primary
Change From Baseline in QTcF at 12 Hours
The Fridericia correction of the QT interval (QTcF) was determined at each time point from five replicate measurements. The change from baseline in QTcF was calculated by subtracting the QTcF value at each timepoint from the QTcF baseline (predose) value.
Time frame: Baseline and 12 hours
Population: All patients as treated population in Part 1 of the Study;~22 patients had QTcF data from the vorinostat period (One patient with protocol violation, and two patients without predose measurements were excluded) and 23 patients had QTcF data from the placebo period (one patient with protocol violation and one patient who discontinued were excluded)
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Vorinostat | Change From Baseline in QTcF at 12 Hours | 1.35 milliseconds |
| Placebo | Change From Baseline in QTcF at 12 Hours | -1.31 milliseconds |
90% CI: [-0.7, 6.02]
Primary
Change From Baseline in QTcF at 1 Hour
Fridericia correction of the QT interval (QTcF) was determined at each time point from five replicate measurements. The change from baseline in QTcF was calculated by subtracting the QTcF value at each timepoint from the QTcF baseline (predose) value.
Time frame: Baseline and 1 hour
Population: All patients as treated population in Part 1 of the Study;~22 patients had QTcF data from the vorinostat period (One patient with protocol violation, and two patients without predose measurements were excluded) and 23 patients had QTcF data from the placebo period (one patient with protocol violation and one patient who discontinued were excluded)
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Vorinostat | Change From Baseline in QTcF at 1 Hour | 0.22 milliseconds |
| Placebo | Change From Baseline in QTcF at 1 Hour | -1.23 milliseconds |
90% CI: [-1.38, 4.72]
Primary
Change From Baseline in QTcF at 24 Hours
The Fridericia correction of the QT interval (QTcF) was determined at each time point from five replicate measurements. The change from baseline in QTcF was calculated by subtracting the QTcF value at each timepoint from the QTcF baseline (predose) value.
Time frame: Baseline and 24 hours
Population: All patients as treated population in Part 1 of the Study;~22 patients had QTcF data from the vorinostat period (One patient with protocol violation, and two patients without predose measurements were excluded) and 23 patients had QTcF data from the placebo period (one patient with protocol violation and one patient who discontinued were excluded)
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Vorinostat | Change From Baseline in QTcF at 24 Hours | 1.53 milliseconds |
| Placebo | Change From Baseline in QTcF at 24 Hours | -4.89 milliseconds |
90% CI: [3.19, 9.82]
Primary
Change From Baseline in QTcF at 2 Hours
The Fridericia correction of the QT interval (QTcF) was determined at each time point from five replicate measurements. The change from baseline in QTcF was calculated by subtracting the QTcF value at each timepoint from the QTcF baseline (predose) value.
Time frame: Baseline and 2 hours
Population: All patients as treated population in Part 1 of the Study;~22 patients had QTcF data from the vorinostat period (One patient with protocol violation, and two patients without predose measurements were excluded) and 23 patients had QTcF data from the placebo period (one patient with protocol violation and one patient who discontinued were excluded)
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Vorinostat | Change From Baseline in QTcF at 2 Hours | 1.09 milliseconds |
| Placebo | Change From Baseline in QTcF at 2 Hours | -1.98 milliseconds |
90% CI: [-0.17, 6.31]
Primary
Change From Baseline in QTcF at 3 Hours
The Fridericia correction of the QT interval (QTcF) was determined at each time point from five replicate measurements. The change from baseline in QTcF was calculated by subtracting the QTcF value at each timepoint from the QTcF baseline (predose) value.
Time frame: Baseline and 3 hours
Population: All patients as treated population in Part 1 of the Study;~22 patients had QTcF data from the vorinostat period (One patient with protocol violation, and two patients without predose measurements were excluded) and 23 patients had QTcF data from the placebo period (one patient with protocol violation and one patient who discontinued were excluded)
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Vorinostat | Change From Baseline in QTcF at 3 Hours | 1.32 milliseconds |
| Placebo | Change From Baseline in QTcF at 3 Hours | -1.52 milliseconds |
90% CI: [-0.4, 6.08]
Primary
Change From Baseline in QTcF at 4 Hours
The Fridericia correction of the QT interval (QTcF) was determined at each time point from five replicate measurements. The placebo-corrected change from baseline in QTcF was calculated by subtracting the QTcF change from baseline for placebo at each timepoint from the QTcF change from baseline for vorinostat at each timepoint.
Time frame: Baseline and 4 hours
Population: All patients as treated population in Part 1 of the Study;~22 patients had QTcF data from the vorinostat period (One patient with protocol violation, and two patients without predose measurements were excluded) and 23 patients had QTcF data from the placebo period (one patient with protocol violation and one patient who discontinued were excluded)
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Vorinostat | Change From Baseline in QTcF at 4 Hours | 4.95 milliseconds |
| Placebo | Change From Baseline in QTcF at 4 Hours | -1.49 milliseconds |
90% CI: [3.21, 9.68]
Primary
Change From Baseline in QTcF at 8 Hours
The Fridericia correction of the QT interval (QTcF) was determined at each time point from five replicate measurements. The change from baseline in QTcF was calculated by subtracting the QTcF value at each timepoint from the QTcF baseline (predose) value.
Time frame: Baseline and 8 hours
Population: All patients as treated population in Part 1 of the Study;~22 patients had QTcF data from the vorinostat period (One patient with protocol violation, and two patients without predose measurements were excluded) and 23 patients had QTcF data from the placebo period (one patient with protocol violation and one patient who discontinued were excluded)
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Vorinostat | Change From Baseline in QTcF at 8 Hours | -3.56 milliseconds |
| Placebo | Change From Baseline in QTcF at 8 Hours | -7.89 milliseconds |
90% CI: [1.05, 7.6]