Malignant, Neoplasms
Conditions
Brief summary
This study determines recommended clinical dose, to evaluate the safety, tolerability and pharmacokinetics of MK-1496 in patients with locally advanced and/or metastatic solid tumors who have failed standard therapy or for whom no standard therapy exists, in two dosing schedules in Japan.
Interventions
DRUGMK-1496
MK-1496 (20 to 120 mg), orally, administered on Day 1 of each 21-day cycle
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participant must have 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. * Participant must have Performance Status 0 or 1. * Participant must have adequate organ function.
Exclusion criteria
* Participant has had chemotherapy, radiotherapy, or biological therapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to registration. * Participant has received 4 or greater regimens of chemotherapy (adjuvant therapy and incomplete 1 cycle treatment are not considered as 1 regimen). * Participant has known hypersensitivity to the components of study drug or its analogs. * Participant has had prescription or non-prescription drugs or other products known to be moderate or potent inhibitors/inducers of cytochrome P (CYP)3A4, or substrates of CYP3A4 with narrow therapeutic window.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Dose-limiting Toxicities (DLTs) | Cycle 1 (up to 21 or 28 days, depending on treatment arm) | Dose-limiting toxicities (DLTs) are any adverse events that are not clearly related to disease progression including Grade 4 neutropenia, Grade 3 or 4 febrile neutropenia, thrombocytopenic bleeding or Grade 4 thrombocytopenia, and any Grade 3 or 4 non hematologic toxicity. An adverse event (AE) is any unfavorable and unintended change in the structure and function (Clinical AE) or chemistry (Laboratory AE) of the body temporally associated with the use of study product, whether or not considered related to the use of the product. |
| Number of Participants With Any Clinical or Laboratory Adverse Event | First dose up to 30 days after last dose (up to 2 years) | This is a measure of the number of participants who experienced any adverse event (AE) while on study. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Curve From Hour 0 to Hour 24 (AUC[0-24]) for MK-1496 Single Dose (21-Day Cycle) | Cycle 1, Day 1 (Hour 0 through Hour 24) | AUC\[0-24\] is a measure of the total plasma exposure of drug over a 24-hour period after the initial dose; for this analysis AUC was measured on Day 1 of the first 21-day cycle. AUC\[0-24\] for the 28-day cycle is reported as Outcome Measures 4 and 5. |
| Mean AUC[0-24] of MK-1496 on Day 1 of Multiple Dose Administration (28-Day Cycle) | Cycle 1, Day 1 (Hour 0 through Hour 24) | AUC is a measure of the total plasma exposure of a drug. For this analysis, AUC was measured just prior to dosing and through 24 hours postdose on Day 1 of Weeks 1, 2, and 3 in Cycle 1. The AUC value presented is the mean AUC for all measurements. AUC\[0-24\] for the Day 3 doses is reported as Outcome Measure 5. |
| Mean AUC[0-24] of MK-1496 on Day 3 of Multiple Dose Administration (28-Day Cycle) | Cycle 1, Day 3 (Hour 0 through Hour 24) | AUC is a measure of the total plasma exposure of a drug. For this analysis, AUC was measured just prior to dosing and through 24 hours postdose on Day 3 of Weeks 1, 2, and 3 in Cycle 1. The AUC value presented is the mean AUC for all measurements. AUC\[0-24\] for the Day 1 doses is reported as Outcome Measure 4. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| MK-1496 20 mg (21-Day Cycle) Participants receiving MK-1496 20 mg on Day 1 of each 21-day cycle | 3 |
| MK-1496 40 mg (21-Day Cycle) Participants receiving MK-1496 40 mg on Day 1 of each 21-day cycle | 3 |
| MK-1496 80 mg (21-Day Cycle) Participants receiving MK-1496 80 mg on Day 1 of each 21-day cycle | 3 |
| MK-1496 120 mg (21-Day Cycle) Participants receiving MK-1496 120 mg on Day 1 of each 21-day cycle | 1 |
| MK-1496 20 mg (28-Day Cycle) Participants receiving MK-1496 20 mg on Days 1, 3, 8, 10, 15, and 17 of each 28-day cycle | 3 |
| MK-1496 40 mg (28-Day Cycle) Participants receiving MK-1496 40 mg on Days 1, 3, 8, 10, 15, and 17 of each 28-day cycle | 3 |
| MK-1496 80 mg (28-Day Cycle) Participants receiving MK-1496 80 mg on Days 1, 3, 8, 10, 15, and 17 of each 28-day cycle | 6 |
| MK-1496 100 mg (28-Day Cycle) Participants receiving MK-1496 100 mg on Days 1, 3, 8, 10, 15, and 17 of each 28-day cycle | 2 |
| MK-1496 120 mg (28-Day Cycle) Participants receiving MK-1496 120 mg on Days 1, 3, 8, 10, 15, and 17 of each 28-day cycle | 3 |
| Total | 27 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 |
|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 0 |
| Overall Study | Disease progression | 3 | 3 | 3 | 1 | 3 | 3 | 5 | 0 | 3 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | MK-1496 20 mg (21-Day Cycle) | MK-1496 40 mg (21-Day Cycle) | MK-1496 80 mg (21-Day Cycle) | MK-1496 120 mg (21-Day Cycle) | MK-1496 20 mg (28-Day Cycle) | MK-1496 40 mg (28-Day Cycle) | MK-1496 80 mg (28-Day Cycle) | MK-1496 100 mg (28-Day Cycle) | MK-1496 120 mg (28-Day Cycle) | Total |
|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 65.0 Years | 57.0 Years | 61.0 Years | 56.0 Years | 52.0 Years | 51.0 Years | 62.5 Years | 57.5 Years | 68.0 Years | 61.0 Years |
| Sex: Female, Male Female | 1 Participants | 2 Participants | 1 Participants | 0 Participants | 2 Participants | 2 Participants | 3 Participants | 2 Participants | 1 Participants | 14 Participants |
| Sex: Female, Male Male | 2 Participants | 1 Participants | 2 Participants | 1 Participants | 1 Participants | 1 Participants | 3 Participants | 0 Participants | 2 Participants | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 3 | 3 / 3 | 2 / 3 | 1 / 1 | 3 / 3 | 3 / 3 | 6 / 6 | 2 / 2 | 3 / 3 |
| serious Total, serious adverse events | 0 / 3 | 0 / 3 | 0 / 3 | 1 / 1 | 1 / 3 | 0 / 3 | 2 / 6 | 2 / 2 | 1 / 3 |
Outcome results
Primary
Number of Participants With Any Clinical or Laboratory Adverse Event
This is a measure of the number of participants who experienced any adverse event (AE) while on study.
Time frame: First dose up to 30 days after last dose (up to 2 years)
Population: All participants on study
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MK-1496 20 mg (21-Day Cycle) | Number of Participants With Any Clinical or Laboratory Adverse Event | 3 participants |
| MK-1496 40 mg (21-Day Cycle) | Number of Participants With Any Clinical or Laboratory Adverse Event | 3 participants |
| MK-1496 80 mg (21-Day Cycle) | Number of Participants With Any Clinical or Laboratory Adverse Event | 2 participants |
| MK-1496 120 mg (21-Day Cycle) | Number of Participants With Any Clinical or Laboratory Adverse Event | 1 participants |
| MK-1496 20 mg (28-Day Cycle) | Number of Participants With Any Clinical or Laboratory Adverse Event | 3 participants |
| MK-1496 40 mg (28-Day Cycle) | Number of Participants With Any Clinical or Laboratory Adverse Event | 3 participants |
| MK-1496 80 mg (28-Day Cycle) | Number of Participants With Any Clinical or Laboratory Adverse Event | 6 participants |
| MK-1496 100 mg (28-Day Cycle) | Number of Participants With Any Clinical or Laboratory Adverse Event | 2 participants |
| MK-1496 120 mg (28-Day Cycle) | Number of Participants With Any Clinical or Laboratory Adverse Event | 3 participants |
Primary
Number of Participants With Dose-limiting Toxicities (DLTs)
Dose-limiting toxicities (DLTs) are any adverse events that are not clearly related to disease progression including Grade 4 neutropenia, Grade 3 or 4 febrile neutropenia, thrombocytopenic bleeding or Grade 4 thrombocytopenia, and any Grade 3 or 4 non hematologic toxicity. An adverse event (AE) is any unfavorable and unintended change in the structure and function (Clinical AE) or chemistry (Laboratory AE) of the body temporally associated with the use of study product, whether or not considered related to the use of the product.
Time frame: Cycle 1 (up to 21 or 28 days, depending on treatment arm)
Population: All participants in the first cycle of each dosing schedule (21 or 28 days)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MK-1496 20 mg (21-Day Cycle) | Number of Participants With Dose-limiting Toxicities (DLTs) | 0 participants |
| MK-1496 40 mg (21-Day Cycle) | Number of Participants With Dose-limiting Toxicities (DLTs) | 0 participants |
| MK-1496 80 mg (21-Day Cycle) | Number of Participants With Dose-limiting Toxicities (DLTs) | 0 participants |
| MK-1496 120 mg (21-Day Cycle) | Number of Participants With Dose-limiting Toxicities (DLTs) | 0 participants |
| MK-1496 20 mg (28-Day Cycle) | Number of Participants With Dose-limiting Toxicities (DLTs) | 0 participants |
| MK-1496 40 mg (28-Day Cycle) | Number of Participants With Dose-limiting Toxicities (DLTs) | 0 participants |
| MK-1496 80 mg (28-Day Cycle) | Number of Participants With Dose-limiting Toxicities (DLTs) | 0 participants |
| MK-1496 100 mg (28-Day Cycle) | Number of Participants With Dose-limiting Toxicities (DLTs) | 2 participants |
| MK-1496 120 mg (28-Day Cycle) | Number of Participants With Dose-limiting Toxicities (DLTs) | 2 participants |
Secondary
Area Under the Curve From Hour 0 to Hour 24 (AUC[0-24]) for MK-1496 Single Dose (21-Day Cycle)
AUC\[0-24\] is a measure of the total plasma exposure of drug over a 24-hour period after the initial dose; for this analysis AUC was measured on Day 1 of the first 21-day cycle. AUC\[0-24\] for the 28-day cycle is reported as Outcome Measures 4 and 5.
Time frame: Cycle 1, Day 1 (Hour 0 through Hour 24)
Population: All participants on the 21-day dosing schedule
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MK-1496 20 mg (21-Day Cycle) | Area Under the Curve From Hour 0 to Hour 24 (AUC[0-24]) for MK-1496 Single Dose (21-Day Cycle) | 305 hr*nmol/L | Standard Deviation 246 |
| MK-1496 40 mg (21-Day Cycle) | Area Under the Curve From Hour 0 to Hour 24 (AUC[0-24]) for MK-1496 Single Dose (21-Day Cycle) | 434 hr*nmol/L | Standard Deviation 82.6 |
| MK-1496 80 mg (21-Day Cycle) | Area Under the Curve From Hour 0 to Hour 24 (AUC[0-24]) for MK-1496 Single Dose (21-Day Cycle) | 295 hr*nmol/L | Standard Deviation 193 |
| MK-1496 120 mg (21-Day Cycle) | Area Under the Curve From Hour 0 to Hour 24 (AUC[0-24]) for MK-1496 Single Dose (21-Day Cycle) | 1460 hr*nmol/L | — |
Secondary
Mean AUC[0-24] of MK-1496 on Day 1 of Multiple Dose Administration (28-Day Cycle)
AUC is a measure of the total plasma exposure of a drug. For this analysis, AUC was measured just prior to dosing and through 24 hours postdose on Day 1 of Weeks 1, 2, and 3 in Cycle 1. The AUC value presented is the mean AUC for all measurements. AUC\[0-24\] for the Day 3 doses is reported as Outcome Measure 5.
Time frame: Cycle 1, Day 1 (Hour 0 through Hour 24)
Population: All participants in the first cycle of the 28-day dosing schedule
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MK-1496 20 mg (21-Day Cycle) | Mean AUC[0-24] of MK-1496 on Day 1 of Multiple Dose Administration (28-Day Cycle) | 122 hr*nmol/L | Standard Deviation 85.3 |
| MK-1496 40 mg (21-Day Cycle) | Mean AUC[0-24] of MK-1496 on Day 1 of Multiple Dose Administration (28-Day Cycle) | 302 hr*nmol/L | Standard Deviation 47.7 |
| MK-1496 80 mg (21-Day Cycle) | Mean AUC[0-24] of MK-1496 on Day 1 of Multiple Dose Administration (28-Day Cycle) | 936 hr*nmol/L | Standard Deviation 364 |
| MK-1496 120 mg (21-Day Cycle) | Mean AUC[0-24] of MK-1496 on Day 1 of Multiple Dose Administration (28-Day Cycle) | 2530 hr*nmol/L | Standard Deviation 81.2 |
| MK-1496 20 mg (28-Day Cycle) | Mean AUC[0-24] of MK-1496 on Day 1 of Multiple Dose Administration (28-Day Cycle) | 2320 hr*nmol/L | Standard Deviation 673 |
Secondary
Mean AUC[0-24] of MK-1496 on Day 3 of Multiple Dose Administration (28-Day Cycle)
AUC is a measure of the total plasma exposure of a drug. For this analysis, AUC was measured just prior to dosing and through 24 hours postdose on Day 3 of Weeks 1, 2, and 3 in Cycle 1. The AUC value presented is the mean AUC for all measurements. AUC\[0-24\] for the Day 1 doses is reported as Outcome Measure 4.
Time frame: Cycle 1, Day 3 (Hour 0 through Hour 24)
Population: All participants in the first 28-day cycle
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MK-1496 20 mg (21-Day Cycle) | Mean AUC[0-24] of MK-1496 on Day 3 of Multiple Dose Administration (28-Day Cycle) | 141 hr*nmol/L | Standard Deviation 114 |
| MK-1496 40 mg (21-Day Cycle) | Mean AUC[0-24] of MK-1496 on Day 3 of Multiple Dose Administration (28-Day Cycle) | 366 hr*nmol/L | Standard Deviation 31.1 |
| MK-1496 80 mg (21-Day Cycle) | Mean AUC[0-24] of MK-1496 on Day 3 of Multiple Dose Administration (28-Day Cycle) | 1300 hr*nmol/L | Standard Deviation 379 |
| MK-1496 120 mg (21-Day Cycle) | Mean AUC[0-24] of MK-1496 on Day 3 of Multiple Dose Administration (28-Day Cycle) | 3090 hr*nmol/L | Standard Deviation 222 |
| MK-1496 20 mg (28-Day Cycle) | Mean AUC[0-24] of MK-1496 on Day 3 of Multiple Dose Administration (28-Day Cycle) | 3470 hr*nmol/L | Standard Deviation 1560 |