Solid Tumors
Conditions
Brief summary
The main objectives of this trial are to determine the recommended dose of ridaforolimus for pediatric participants with advanced solid tumors by measuring the number of participants experiencing dose-limiting toxicities (DLTs) while on different doses of ridaforolimus, and to characterize the pharmacokinetics of ridaforolimus in these participants. The primary hypotheses of this study are that 1) the DLTs observed will be dose-dependent and allow for definition of a maximum tolerated dose (MTD) and 2) at a safe and well tolerated dose, ridaforolimus geometric mean (GM) Day-5 blood area under the concentration-time curve at 24 hours (AUC0-24) exceeds 75% (or 1304-ng\*hr/mL) of the estimated GM Day-5, 40-mg AUC0-24 in adults. Study-related visits concluded in August 2013. Participants who did not have disease progression, adequately tolerated therapy, and continued to meet eligibility criteria for 6 months after the enrollment period had been completed could continue treatment in an extension phase until they met discontinuation criteria or voluntarily withdrew.
Interventions
DRUGRidaforolimus
Oral administration of 10 mg enteric-coated tablets at doses of 22 mg/m\^2, 28 mg/m\^2, or 33 mg/m\^2 based on body surface area (BSA), once daily for 5 consecutive days each week in consecutive 28-day cycles.
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
6 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
* Histologic or cytologic diagnosis of a malignant solid tumor, including tumors of the central nervous system and lymphoma, that have progressed despite standard therapy or for which no effective standard therapy is known. Participants who have received standard therapy and continue to have biopsy-proven residual stable disease are eligible * Measurable or non-measurable disease * Must be able to swallow tablets * Performance Status: Lansky Play Scale ≥70 for children \<10 years of age; Karnofsky score ≥70 for children ≥10 to \<16 years; or Eastern Cooperative Oncology Group (ECOG) Status 0-2 for patients age 16 and older * Adequate organ function * For females of reproductive potential, a negative pregnancy test must be documented within 72 hours of receiving the first dose of study medication * Participants of reproductive potential must agree to use (or have their partner use) adequate contraception throughout the study, starting with Visit 1 through 30 days after the last dose of study drug
Exclusion criteria
* Currently receiving any other investigational agents or using any investigational devices * Leukemia * Participant previously received ridaforolimus, rapamycin, or other rapamycin analogs * History of allergic reactions attributed to compounds of similar chemical or biologic composition to ridaforolimus * Persistent acute toxicity from previous therapy ≥Grade 2 (excluding alopecia, neuropathy, or hearing loss) * Uncontrolled intercurrent illness despite adequate therapy * Pregnant or breastfeeding * Requirement for concurrent treatment with medications that are inducers or inhibitors of cytochrome P450 (CYP3A) * Poorly controlled Type 1 or 2 diabetes
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Experiencing a Dose Limiting Toxicity (DLT) According to National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE v.4.0) | Cycle 1 (cycle = 28 days) | DLT defined using NCI-CTCAE v.4.0 as any of the following events occurring during the first 28-day cycle that were possibly, probably, or definitely study drug-related: Grade 4 neutropenia for ≥5 days; Grade 3-4 neutropenia associated with fever, antibiotics, or hospitalization for infection; Grade 4 thrombocytopenia for ≥5 days or requiring platelet transfusion; ≥Grade 3 hyperglycemia for ≥5 days despite management; ≥Grade 3 diarrhea for \>24 hours despite management; ≥Grade 3 nausea or vomiting despite management; any other Grade ≥3 non-hematological toxicity persisting despite management (except alopecia, transient electrolyte abnormalities, transient Grade 3 liver function test elevations, and Grade 3 neurotoxicity for participants with baseline Grade 3 neurotoxicity); inability to complete DLT assessment period, interruption in dosing for \>10 dosing days during DLT assessment period, or any delay in the initiation of the next cycle for \>10 dosing days due to any related toxicity. |
| Area Under the Concentration-Time Curve of Ridaforolimus From Time 0 to 24 Hours (AUC0-24 hr) | Day 5 of Cycle 1 [28-day cycle]: pre-dose (0.0 hours) and 0.5, 1.0, 2.0, 4.0, 8.0, and 24.0 hours after administration of ridaforolimus | AUC is a measure of the amount of drug in the blood over time. Whole blood samples were collected pre-dose (within 5 minutes of ridaforolimus administration) and post-dose at specified time points on Day 5 of the first week of Cycle 1 to determine AUC0-24 hr. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Ridaforolimus 22 mg/m^2 Participants received 22 mg/m\^2 of ridaforolimus administered orally for 5 consecutive days each week (2 days rest) in consecutive 28-day cycles for up to six months. Eligible participants could receive additional treatment in an extension phase of the study. | 4 |
| Ridaforolimus 28 mg/m^2 Participants received 28 mg/m\^2 of ridaforolimus administered orally for 5 consecutive days each week (2 days rest) in consecutive 28-day cycles for up to six months. Eligible participants could receive additional treatment in an extension phase of the study. | 3 |
| Ridaforolimus 33 mg/m^2 Participants received 33 mg/m\^2 of ridaforolimus administered orally for 5 consecutive days each week (2 days rest) in consecutive 28-day cycles for up to six months. Eligible participants could receive additional treatment in an extension phase of the study. | 13 |
| Total | 20 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Treatment Phase | Adverse Event | 0 | 0 | 1 |
| Treatment Phase | Progressive Disease | 4 | 3 | 10 |
Baseline characteristics
| Characteristic | Ridaforolimus 22 mg/m^2 | Ridaforolimus 28 mg/m^2 | Ridaforolimus 33 mg/m^2 | Total |
|---|---|---|---|---|
| Age, Continuous | 13.0 Years STANDARD_DEVIATION 5.7 | 14.7 Years STANDARD_DEVIATION 2.5 | 12.2 Years STANDARD_DEVIATION 3.3 | 12.8 Years STANDARD_DEVIATION 3.2 |
| Sex: Female, Male Female | 3 Participants | 1 Participants | 8 Participants | 12 Participants |
| Sex: Female, Male Male | 1 Participants | 2 Participants | 5 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 4 | 1 / 3 | 1 / 13 |
| other Total, other adverse events | 4 / 4 | 3 / 3 | 13 / 13 |
| serious Total, serious adverse events | 3 / 4 | 2 / 3 | 7 / 13 |
Outcome results
Primary
Area Under the Concentration-Time Curve of Ridaforolimus From Time 0 to 24 Hours (AUC0-24 hr)
AUC is a measure of the amount of drug in the blood over time. Whole blood samples were collected pre-dose (within 5 minutes of ridaforolimus administration) and post-dose at specified time points on Day 5 of the first week of Cycle 1 to determine AUC0-24 hr.
Time frame: Day 5 of Cycle 1 [28-day cycle]: pre-dose (0.0 hours) and 0.5, 1.0, 2.0, 4.0, 8.0, and 24.0 hours after administration of ridaforolimus
Population: Participants who received all 5 ridaforolimus doses in the first week of 28-day Cycle 1 were analyzed.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Ridaforolimus 22 mg/m^2 | Area Under the Concentration-Time Curve of Ridaforolimus From Time 0 to 24 Hours (AUC0-24 hr) | 1340 hr*ng/mL | Geometric Coefficient of Variation 31.7 |
| Ridaforolimus 28 mg/m^2 | Area Under the Concentration-Time Curve of Ridaforolimus From Time 0 to 24 Hours (AUC0-24 hr) | 2330 hr*ng/mL | Geometric Coefficient of Variation 36.2 |
| Ridaforolimus 33 mg/m^2 | Area Under the Concentration-Time Curve of Ridaforolimus From Time 0 to 24 Hours (AUC0-24 hr) | 2280 hr*ng/mL | Geometric Coefficient of Variation 29.8 |
Primary
Number of Participants Experiencing a Dose Limiting Toxicity (DLT) According to National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE v.4.0)
DLT defined using NCI-CTCAE v.4.0 as any of the following events occurring during the first 28-day cycle that were possibly, probably, or definitely study drug-related: Grade 4 neutropenia for ≥5 days; Grade 3-4 neutropenia associated with fever, antibiotics, or hospitalization for infection; Grade 4 thrombocytopenia for ≥5 days or requiring platelet transfusion; ≥Grade 3 hyperglycemia for ≥5 days despite management; ≥Grade 3 diarrhea for \>24 hours despite management; ≥Grade 3 nausea or vomiting despite management; any other Grade ≥3 non-hematological toxicity persisting despite management (except alopecia, transient electrolyte abnormalities, transient Grade 3 liver function test elevations, and Grade 3 neurotoxicity for participants with baseline Grade 3 neurotoxicity); inability to complete DLT assessment period, interruption in dosing for \>10 dosing days during DLT assessment period, or any delay in the initiation of the next cycle for \>10 dosing days due to any related toxicity.
Time frame: Cycle 1 (cycle = 28 days)
Population: Participants who completed the first 28-day cycle of therapy with adequate drug exposure (\>75% of planned study drug doses, exclusive of doses missed due to related toxicity), or who discontinued from the study due to a related DLT, were evaluable for DLT.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ridaforolimus 22 mg/m^2 | Number of Participants Experiencing a Dose Limiting Toxicity (DLT) According to National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE v.4.0) | 0 Participants |
| Ridaforolimus 28 mg/m^2 | Number of Participants Experiencing a Dose Limiting Toxicity (DLT) According to National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE v.4.0) | 0 Participants |
| Ridaforolimus 33 mg/m^2 | Number of Participants Experiencing a Dose Limiting Toxicity (DLT) According to National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE v.4.0) | 1 Participants |