Tumors
Conditions
Brief summary
This is a clinical study to evaluate the safety and pharmacokinetics of an overseas determined maximum tolerated dose (MTD) of MK-0683 (vorinostat) in a Japanese patient population with solid tumors.
Interventions
DRUGVorinostat
600 mg daily (300 mg twice daily \[b.i.d.\]) for 3 consecutive days followed by 4 days of rest.
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients with histologically or cytologically diagnosed solid tumor in whom no standard therapy is available or the malignancy is refractory to standard therapy
Exclusion criteria
* Patients with history of immunotherapy, radiotherapy, surgery, or chemotherapy during the previous 4 weeks * Any uncontrolled concomitant illness * Pregnant or breast-feeding * Serious drug or food allergy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With a Dose Limiting Toxicity (DLT) | 21 Days (first cycle) | Dose Limiting Toxicity = Drug-related side effects that are serious enough to prevent an increase in dose or level of that treatment |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Curve (AUC(0-infinity)) at Day 3 (600 mg) | Day 3 (600 mg) | Area Under Curve (AUC(0-infinity))=Area under the plasma concentration versus time curve (AUC) from time zero to 24 ｈours. It is obtained from AUC (0 - 12) plus AUC (12 - ∞) |
| Area Under the Curve (AUC(0-infinity) at Day 21 (400 mg) | Day 21 (400 mg) | Area Under Curve (AUC(0-infinity))=Area under the plasma concentration versus time curve (AUC) from time zero to 24 ｈours. It is obtained from AUC (0 - 24) plus AUC (24 - ∞) |
| Area Under the Curve (AUC(0-infinity)) at Day 1 (600 mg and 400 mg) | Day 1 (600 mg and 400 mg) | Area Under Curve (AUC(0-infinity))=Area under the plasma concentration versus time curve (AUC) from time zero to extrapolated infinite time (o- ∞). It is obtained from AUC (0 - t) plus AUC (t - ∞). At 600 mg, t=12 hours and at 400 mg, t=24 hours. |
| Maximum Concentration (Cmax) at Day 3 (600 mg) | Day 3 (600 mg) | — |
| Maximum Concentration (Cmax) at Day 21 (400 mg) | Day 21 (400 mg) | — |
| Maximum Concentration (Cmax) at Day 1 (600 mg and 400 mg) | Day 1 (600 mg and 400 mg) | — |
Participant flow
Recruitment details
Phase I. First participant started on study therapy on 18-Jul-2006. Study was multicenter (total of 3 sites).
Pre-assignment details
Study of 2 doses of vorinostat (MK-0683) in participants with solid tumors who failed standard therapy. \>= 3 participants were enrolled at each dose. In the case of a dose level toxicity, a maximum of 6 participants were enrolled per level. If no safety problems, a total of 10 participants were evaluated for pharmacokinetics.
Participants by arm
| Arm | Count |
|---|---|
| Vorinostat 600 mg 600 mg daily (300 mg twice daily \[b.i.d.\]) for 3 consecutive days followed by 4 days of rest (repeated 3 times over 21 days) | 10 |
| Vorinostat 400 mg 400 mg once daily (400 mg q.d.) continuous daily dosing for 21 days | 6 |
| Total | 16 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 |
| Overall Study | Lack of Efficacy | 9 | 4 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Vorinostat 600 mg | Vorinostat 400 mg | Total |
|---|---|---|---|
| Age, Continuous | 60.2 years STANDARD_DEVIATION 8.4 | 53.3 years STANDARD_DEVIATION 12 | 57.6 years STANDARD_DEVIATION 10.1 |
| Prior chemotherapy regimens | 3.5 Number of prior chemotherapy regimens | 4.5 Number of prior chemotherapy regimens | 4 Number of prior chemotherapy regimens |
| Sex: Female, Male Female | 2 Participants | 2 Participants | 4 Participants |
| Sex: Female, Male Male | 8 Participants | 4 Participants | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 10 / 10 | 6 / 6 |
| serious Total, serious adverse events | 4 / 10 | 0 / 6 |
Outcome results
Primary
Number of Participants With a Dose Limiting Toxicity (DLT)
Dose Limiting Toxicity = Drug-related side effects that are serious enough to prevent an increase in dose or level of that treatment
Time frame: 21 Days (first cycle)
Population: Six (6) participants received vorinostat at 400 mg once daily. Of these, 2 participants did not complete the first cycle resulting in the drug compliance falling below 75%, and thus these participants were excluded from the DLT assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vorinostat 600 mg | Number of Participants With a Dose Limiting Toxicity (DLT) | 0 Participants |
| Vorinostat 400 mg | Number of Participants With a Dose Limiting Toxicity (DLT) | 2 Participants |
Secondary
Area Under the Curve (AUC(0-infinity)) at Day 1 (600 mg and 400 mg)
Area Under Curve (AUC(0-infinity))=Area under the plasma concentration versus time curve (AUC) from time zero to extrapolated infinite time (o- ∞). It is obtained from AUC (0 - t) plus AUC (t - ∞). At 600 mg, t=12 hours and at 400 mg, t=24 hours.
Time frame: Day 1 (600 mg and 400 mg)
Population: Six (6) participants received vorinostat at 400 mg once daily. Of these, one (1) participant had missing Pharmacokinetics Data on Day 1 because the participant vomited after administration on Day 1.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Vorinostat 600 mg | Area Under the Curve (AUC(0-infinity)) at Day 1 (600 mg and 400 mg) | 3.94 μM·hr | Standard Deviation 1.56 |
| Vorinostat 400 mg | Area Under the Curve (AUC(0-infinity)) at Day 1 (600 mg and 400 mg) | 7.75 μM·hr | Standard Deviation 2.79 |
Secondary
Area Under the Curve (AUC(0-infinity) at Day 21 (400 mg)
Area Under Curve (AUC(0-infinity))=Area under the plasma concentration versus time curve (AUC) from time zero to 24 ｈours. It is obtained from AUC (0 - 24) plus AUC (24 - ∞)
Time frame: Day 21 (400 mg)
Population: Six (6) participants received vorinostat at 400 mg once daily. Of these, four (4) participants had missing Pharmacokinetics Data on Day 21 because they did not receive study drug on day 21.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Vorinostat 400 mg | Area Under the Curve (AUC(0-infinity) at Day 21 (400 mg) | 8.3 μM·hr | Standard Deviation 0.04 |
Secondary
Area Under the Curve (AUC(0-infinity)) at Day 3 (600 mg)
Area Under Curve (AUC(0-infinity))=Area under the plasma concentration versus time curve (AUC) from time zero to 24 ｈours. It is obtained from AUC (0 - 12) plus AUC (12 - ∞)
Time frame: Day 3 (600 mg)
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Vorinostat 600 mg | Area Under the Curve (AUC(0-infinity)) at Day 3 (600 mg) | 4.15 μM·hr | Standard Deviation 2.15 |
Secondary
Maximum Concentration (Cmax) at Day 1 (600 mg and 400 mg)
Time frame: Day 1 (600 mg and 400 mg)
Population: Six (6) participants received vorinostat at 400 mg once daily. Of these, one (1) participant had missing Pharmacokinetics Data on Day 1 because the participant vomited after administration on Day 1.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Vorinostat 600 mg | Maximum Concentration (Cmax) at Day 1 (600 mg and 400 mg) | 1.17 μM | Standard Deviation 0.43 |
| Vorinostat 400 mg | Maximum Concentration (Cmax) at Day 1 (600 mg and 400 mg) | 1.62 μM | Standard Deviation 0.52 |
Secondary
Maximum Concentration (Cmax) at Day 21 (400 mg)
Time frame: Day 21 (400 mg)
Population: Six (6) participants received vorinostat at 400 mg once daily. Of these, four (4) participants had missing Pharmacokinetics Data on Day 21 because they did not receive study drug on day 21.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Vorinostat 400 mg | Maximum Concentration (Cmax) at Day 21 (400 mg) | 2.04 μM | Standard Deviation 0.78 |
Secondary
Maximum Concentration (Cmax) at Day 3 (600 mg)
Time frame: Day 3 (600 mg)
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Vorinostat 600 mg | Maximum Concentration (Cmax) at Day 3 (600 mg) | 1.32 μM | Standard Deviation 0.75 |