A Phase I Dose Escalation Study of Oral MK-2206 in Patients With Locally Advanced or Metastatic Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 104
- 主要终点
- Number of Participants With Dose Limiting Toxicities (DLTs)
研究概览
简要总结
The primary purpose of this study is to investigate the Dose Limiting Toxicities (DLTs), pharmacokinetics (PK), and pharmacodynamics (PD) of MK-2206 administered orally to participants with advanced solid tumors. The preliminary efficacy of MK-2206 will also be investigated.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Participant must have confirmed locally advanced or metastatic solid tumors that have failed to respond to standard therapy, have gotten worse or have come back after existing therapy
- •Has normal organ function; is no greater than 2 on the ECOG Performance Scale
- •Has a negative blood or urine pregnancy test within 72 hours of receiving the first dose of study drug if participant is female
- •Is able to swallow capsules and has no surgical or bodily condition that will prevent the patient from swallowing and absorbing oral medications on an ongoing basis
排除标准
- •Participant has had chemotherapy, radiotherapy, biological therapy or surgery within 4 weeks of starting the study and has not recovered from adverse events caused by the treatment
- •Is currently participating or has participated in a study with an investigational compound or device within 30 days
- •Has a primary central nervous system tumor
- •Has a history or current evidence of heart disease, slow heart rate or untreated high blood pressure
- •Is a known diabetic who is taking insulin or oral antidiabetic therapy
- •Is pregnant or breastfeeding or planning to become pregnant during the study
- •Is HIV-positive
- •Has known history of Hepatitis B or C or active Hepatitis A
- •Is receiving treatment with oral corticosteroids
研究组 & 干预措施
MK-2206 30 mg QOD
Participants receive 30 mg oral MK-2206 every other day (QOD) in repeating 4-week treatment cycles.
干预措施: MK-2206 (Drug)
MK-2206 60 mg QOD
Participants receive 60 mg oral MK-2206 QOD in repeating 4-week treatment cycles.
干预措施: MK-2206 (Drug)
MK-2206 75 mg QOD
Participants receive 75 mg oral MK-2206 QOD in repeating 4-week treatment cycles.
干预措施: MK-2206 (Drug)
MK-2206 90 mg QOD
Participants receive 90 mg oral MK-2206 QOD in repeating 4-week treatment cycles.
干预措施: MK-2206 (Drug)
MK-2206 90 mg QW
Participants receive 90 mg oral MK-2206 every week (QW) in repeating 4-week treatment cycles.
干预措施: MK-2206 (Drug)
MK-2206 135 mg QW
Participants receive 135 mg oral MK-2206 QW in repeating 4-week treatment cycles.
干预措施: MK-2206 (Drug)
MK-2206 200 mg QW
Participants receive 200 mg oral MK-2206 QW in repeating 4-week treatment cycles.
干预措施: MK-2206 (Drug)
MK-2206 300 mg QW
Participants receive 300 mg oral MK-2206 QW in repeating 4-week treatment cycles.
干预措施: MK-2206 (Drug)
MK-2206 250 mg QW
Participants receive 250 mg oral MK-2206 QW in repeating 4-week treatment cycles.
干预措施: MK-2206 (Drug)
MK-2206 150 mg QW
Participants receive 150 mg oral MK-2206 QW in repeating 4-week treatment cycles.
干预措施: MK-2206 (Drug)
结局指标
主要结局
Number of Participants With Dose Limiting Toxicities (DLTs)
时间窗: Day 1 to Day 28 (Cycle 1)
DLT was any drug-related AE, regardless of grade, leading to a dose modification of MK-2206. Dose-limiting hematologic and nonhematologic toxicities were defined differently and were based on events occurring during the first cycle of study drug administration. Hematologic DLT defined as any Grade (Gr) 4 or greater hematologic toxicity except neutropenia described as follows: Neutropenia that was Gr 4 lasting for ≥7 days, or Gr 3/Gr 4 with fever \>38.5°C and/or infection requiring antibiotic or anti-fungal treatment considered DLT. Gr 4 thrombocytopenia (≤25.0 x 10\^9/L) was also considered DLT. Non-hematologic DLTs were defined as any Gr 3, 4, or 5 nonhematologic toxicity, with the specific exceptions of: Gr 3 nausea, vomiting, diarrhea, or dehydration occurring with inadequate supportive care and lasting \<48 hours; alopecia; inadequately treated hypersensitivity reactions; and Gr 3 elevated transaminases of ≤1 week in duration. A participant could have more than one DLT.
Number of Participants With One or More Adverse Events (AE)
时间窗: Up to 269 days
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 (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition which was temporally associated with the use of the SPONSOR's product, was also an AE. The number of participants that experienced one or more AEs was reported for each dose level group.
Cmax of MK-2206 in Participants Receiving Multiple QW Dosing
时间窗: Days 1 and 22: predose and 2, 4, 6, 10, 24, 48, 96 hours, and 168 hours after MK-2206 dosing
Blood samples were collected for PK analyses during the first cycle of therapy. Samples were centrifuged, plasma was withdrawn and plasma concentrations were analyzed by high performance liquid chromatography with tandem mass spectroscopy. Cmax was calculated for Day 1 and the last day of treatment in Cycle 1 and reported for all dose levels receiving MK-2206 orally QW (90, 135, 200, 300, 250, and 150 mg QW).
C48hr of MK-2206 in Participants Receiving Multiple QW Dosing
时间窗: Days 1 and 22: predose and 48 hours after MK-2206 dosing
Blood samples were collected for PK analyses during the first cycle of therapy. Samples were centrifuged, plasma was withdrawn and plasma concentrations were analyzed by high performance liquid chromatography with tandem mass spectroscopy. C48hr was calculated for Day 1 and the last day of treatment in Cycle 1 and reported for all dose levels receiving MK-2206 orally QW (90, 135, 200, 300, 250, and 150 mg QW).
Area Under the Concentration-time Curve of MK-2206 From Time 0 to 48 Hours (AUC0-48hr) in Participants Receiving Multiple QOD Dosing
时间窗: Days 1 and 27: predose and 0.5, 1, 2, 3, 4, 6, 10, 24, and 48 hours after MK-2206 dosing
Blood samples were collected for PK analyses during the first cycle of therapy. Samples were centrifuged, plasma was withdrawn and plasma concentrations were analyzed by high performance liquid chromatography with tandem mass spectroscopy. AUC 0-48hr was calculated for Day 1 and the last day of treatment in Cycle 1 (Day 27) and reported for all dose levels receiving MK-2206 orally QOD (30, 60, 75, and 90 mg QOD).
Concentration of MK-2206 After 48 Hours (C48hr) in Participants Receiving Multiple QOD Dosing
时间窗: Days 1 and 27: predose and 48 hours after MK-2206 dosing.
Blood samples were collected for PK analyses during the first cycle of therapy. Samples were centrifuged, plasma was withdrawn and plasma concentrations were analyzed by high performance liquid chromatography with tandem mass spectroscopy. C48hr was calculated for Day 1 and the last day of treatment in Cycle 1 (Day 27) and reported for all dose levels receiving MK-2206 orally QOD (30, 60, 75, and 90 mg QOD).
Maximum Concentration (Cmax) of MK-2206 in Participants Receiving Multiple QOD Dosing
时间窗: Days 1 and 27: predose and 0.5, 1, 2, 3, 4, 6, 10, 24, and 48 hours after MK-2206 dosing
Blood samples were collected for PK analyses during the first cycle of therapy. Samples were centrifuged, plasma was withdrawn and plasma concentrations were analyzed by high performance liquid chromatography with tandem mass spectroscopy. Cmax was calculated for Day 1 and the last day of treatment in Cycle 1 (Day 27) and reported for all dose levels receiving MK-2206 orally QOD (30, 60, 75, and 90 mg QOD).
Time to Maximum Concentration (Tmax) of MK-2206 in Participants Receiving Multiple QOD Dosing
时间窗: Days 1 and 27: predose and 0.5, 1, 2, 3, 4, 6, 10, 24, and 48 hours after MK-2206 dosing
Blood samples were collected for PK analyses during the first cycle of therapy. Samples were centrifuged, plasma was withdrawn and plasma concentrations were analyzed by high performance liquid chromatography with tandem mass spectroscopy. Tmax was calculated for Day 1 and the last day of treatment in Cycle 1 and reported for all dose levels receiving MK-2206 orally QOD (30, 60, 75, and 90 mg QOD).
AUC0-168hr in Participants Receiving Multiple QW Dosing
时间窗: Days 1 and 22: predose and 2, 4, 6, 10, 24, 48, 96 hours, and 168 hours after MK-2206 dosing
Blood samples were collected for PK analyses during the first cycle of therapy. Samples were centrifuged, plasma was withdrawn and plasma concentrations were analyzed by high performance liquid chromatography with tandem mass spectroscopy. AUC 0-168 was calculated for Day 1 and the last day of treatment in Cycle 1 and reported for all dose levels receiving MK-2206 orally QW (90, 135, 200, 300, 250, and 150 mg QW).
Tmax of MK-2206 in Participants Receiving Multiple QW Dosing
时间窗: Days 1 and 22: predose and 2, 4, 6, 10, 24, 48, 96 hours, and 168 hours after MK-2206 dosing
Blood samples were collected for PK analyses during the first cycle of therapy. Samples were centrifuged, plasma was withdrawn and plasma concentrations were analyzed by high performance liquid chromatography with tandem mass spectroscopy. Tmax was calculated for Day 1 and the last day of treatment in Cycle 1 and reported for all dose levels receiving MK-2206 orally QW (90, 135, 200, 300, 250, and 150 mg QW).
Apparent Terminal Half-life (t½) of MK-2206 in Participants Receiving Multiple QOD Dosing
时间窗: Day 27: predose and 0.5, 1, 2, 3, 4, 6, 10, 24, and 48 hours after MK-2206 dosing.
Blood samples were collected for PK analyses on Day 27 of the first cycle of therapy. Samples were centrifuged, plasma was withdrawn and plasma concentrations were analyzed by high performance liquid chromatography with tandem mass spectroscopy. t½ (Harmonic mean ± pseudo SD) was calculated and reported for all dose levels receiving MK-2206 orally QOD (30, 60, 75, and 90 mg QOD).
t½ of MK-2206 in Participants Receiving Multiple QW Dosing
时间窗: Day 22: predose and 2, 4, 6, 10, 24, 48, 96 hours, and 168 hours after MK-2206 dosing
Blood samples were collected for PK analyses during the first cycle of therapy. Samples were centrifuged, plasma was withdrawn and plasma concentrations were analyzed by high performance liquid chromatography with tandem mass spectroscopy. t½ (Harmonic mean ± pseudo SD) was calculated for the last day of treatment in Cycle 1 and reported for all dose levels receiving MK-2206 orally QW (90, 135, 200, 300, 250, and 150 mg QW).
次要结局
- Number of Participants With Confirmed Response as Per Response Evaluation Criteria in Solid Tumors (RECIST)(From Cycle 1 Day 1 through the End of Study Visit (up to 6 months))
- Phosphorylated Protein Kinase B (pAkt) Level on Cycle 1 Day 15 (C1D15) After Treatment With MK-2206 at the Maximum Tolerated Dose (MTD)(Baseline, Cycle 1 Day 15)