A Phase Ib, Open-Label, Dose-Escalation Study Of The Safety, Tolerability, and Pharmacokinetics of Cobimetinib and GDC-0994 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
- 24
- 试验地点
- 5
- 主要终点
- Percentage of Participants With at Least One Serious Adverse Event (SAE)
研究概览
简要总结
This is a two-stage dose-escalation study to assess the safety, tolerability and effects of oral dosing of cobimetinib and GDC-0994 administered in combination in patients with histologically confirmed, locally advanced, or metastatic solid tumors for which standard therapies either do not exist or have proven ineffective or intolerable.
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
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- •Histologically or cytologically documented, locally advanced or metastatic solid tumors for which standard therapy either does not exist or has proven ineffective or intolerable
- •Evaluable disease or disease measurable
- •Life expectancy > or = 12 weeks
- •Adequate hematologic and end organ function
- •For female patients of childbearing potential and male patients with partners of childbearing potential, use of an effective form of contraception with continued use for study duration and up to 3 months or more following discontinuation of treatment drug
- •Fluorodeoxyglucose positron emission tomography (FDG-PET) avid disease on baseline scan
- •For enrollment in part 2, patients must meet all of the following:
- •Measurable disease
- •No more than four prior systemic therapies for locally advanced or metastatic cancer
排除标准
- •History of prior significant toxicity from another MEK inhibitor or ERK inhibitor requiring discontinuation of treatment
- •Evidence of visible retinal pathology as assessed by ophthalmologic examination that is considered a risk factor for retinal vein thrombosis
- •History of glaucoma
- •Intraocular pressure > 21 mmHg as measured by tonometry
- •Predisposing factors to retinal vein occlusion (RVO)
- •History of RVO, neurosensory retinal detachment, or neovascular macular degeneration
- •Allergy or hypersensitivity to components of the cobimetinib or GDC-0994 formulation
- •Palliative radiotherapy within 2 weeks prior to first dose of study-drug treatment in Cycle 1
- •Experimental therapy within 4 weeks prior to first dose of study-drug treatment in Cycle 1
- •Major surgical procedure or significant traumatic injury within 4 weeks prior to the first dose of study-drug treatment in Cycle 1, or anticipation of the need for major surgery during the course of study treatment
- •Anti-cancer therapy within 28 days prior to the first dose of study-drug treatment in Cycle 1
- •Current severe, uncontrolled systemic disease
- •History of clinically significant cardiac dysfunction
- •History of symptomatic congestive heart failure or serious cardiac arrhythmia requiring treatment
- •History of myocardial infarction within 6 months prior to the first dose of study-drug treatment in Cycle 1
- •History of congenital long QT syndrome or QTc > 470 msec
- •History of malabsorption or other condition that would interfere with enteral absorption
- •Clinically significant history of liver disease, current alcohol abuse, or current known active infection with HIV, hepatitis B virus, or hepatitis C virus
- •Any condition requiring warfarin or thrombolytic anticoagulants
- •Active autoimmune disease
- •Uncontrolled ascites requiring weekly large volume paracentesis for 3 consecutive weeks prior to enrollment
- •Pregnancy, lactation, or breastfeeding
- •Known brain metastases that are untreated, symptomatic, or require therapy to control symptoms
- •No other history of or ongoing malignancy that would potentially interfere with the interpretation of the Pharmacodynamic (PD) or efficacy assays
研究组 & 干预措施
Not assigned
One participant was assigned to receive intermittent cobimetinib 80 milligrams (mg) + GDC 0994 200 mg) and did receive study drug. However, the participant diary was not returned, and the site was unable to document study dose administration.
干预措施: Cobimetinib (Drug)
Not assigned
One participant was assigned to receive intermittent cobimetinib 80 milligrams (mg) + GDC 0994 200 mg) and did receive study drug. However, the participant diary was not returned, and the site was unable to document study dose administration.
干预措施: GDC-0994 (Drug)
COB 20 mg + GDC 200 mg
Concurrent or intermittent dosing of cobimetinib 20 mg, concurrent with GDC-0994 200 mg for 21 consecutive days, followed by 7 days off.
干预措施: Cobimetinib (Drug)
COB 20 mg + GDC 200 mg
Concurrent or intermittent dosing of cobimetinib 20 mg, concurrent with GDC-0994 200 mg for 21 consecutive days, followed by 7 days off.
干预措施: GDC-0994 (Drug)
COB 40 mg + GDC 200 mg
Concurrent or intermittent dosing of cobimetinib 40 mg, concurrent with GDC-0994 200 mg for 21 consecutive days, followed by 7 days off.
干预措施: Cobimetinib (Drug)
COB 40 mg + GDC 200 mg
Concurrent or intermittent dosing of cobimetinib 40 mg, concurrent with GDC-0994 200 mg for 21 consecutive days, followed by 7 days off.
干预措施: GDC-0994 (Drug)
COB 80 mg + GDC 200 mg
Concurrent or intermittent dosing of cobimetinib 80 mg, concurrent with GDC-0994 200 mg for 21 consecutive days, followed by 7 days off.
干预措施: Cobimetinib (Drug)
COB 80 mg + GDC 200 mg
Concurrent or intermittent dosing of cobimetinib 80 mg, concurrent with GDC-0994 200 mg for 21 consecutive days, followed by 7 days off.
干预措施: GDC-0994 (Drug)
COB 80 mg + GDC 400 mg
Concurrent or intermittent dosing of cobimetinib 80 mg, concurrent with GDC-0994 400 mg for 21 consecutive days, followed by 7 days off.
干预措施: Cobimetinib (Drug)
COB 80 mg + GDC 400 mg
Concurrent or intermittent dosing of cobimetinib 80 mg, concurrent with GDC-0994 400 mg for 21 consecutive days, followed by 7 days off.
干预措施: GDC-0994 (Drug)
COB 100 mg + GDC 200 mg
Concurrent or intermittent dosing of cobimetinib 100 mg, concurrent with GDC-0994 200 mg for 21 consecutive days, followed by 7 days off.
干预措施: Cobimetinib (Drug)
COB 100 mg + GDC 200 mg
Concurrent or intermittent dosing of cobimetinib 100 mg, concurrent with GDC-0994 200 mg for 21 consecutive days, followed by 7 days off.
干预措施: GDC-0994 (Drug)
结局指标
主要结局
Percentage of Participants With at Least One Serious Adverse Event (SAE)
时间窗: Up to 15 months
A SAE is any experience that: results in death, is life-threatening, requires in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, or is medically significant.
Percentage of Participants With at Least One Adverse Event
时间窗: Up to 15 months
An adverse event is any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product, regardless of causal attribution.
Percentage of Participants With at Least One Adverse Event of Special Interest
时间窗: Up to 15 months
AESIs were graded per the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), v4.0. AESIs included the following: Grade ≥ 1 retinal vein occlusion; Grade ≥ 2 visual disturbances (including events suggestive of serous retinopathy); Grade ≥ 3 rash for \> 7 days; Grade ≥ 3 diarrhea for \> 3 days; Grade ≥ 2 left ventricular ejection fraction (LVEF) decrease; Grade 3 hepatotoxicity; any dose-limiting toxicity (DLT); cases of potential drug-induced liver injury that include an elevated alanine aminotransferase (ALT) or aspartate aminotransferase (AST) (AST \> 3 × baseline value \[and above the upper limit of normal, ULN\]) in combination with either an elevated bilirubin ( \> 2 × ULN) or clinical jaundice; or suspected transmission of an infectious agent by either study drug.
Mean Change From Baseline in Pulse Rate
时间窗: Baseline, up to 15 months
Mean Change From Baseline in Systolic Blood Pressure
时间窗: Baseline, up to 15 months
Mean Change From Baseline in Temperature
时间窗: Baseline, up to 15 months
Mean Change From Baseline in Weight
时间窗: Baseline, up to 15 months
Mean Change From Baseline in Diastolic Blood Pressure
时间窗: Baseline, up to 15 months
Number of Participants With Dose-Limiting Toxicities (DLTs)
时间窗: 28 days (Cycle 1)
DLTs include symptoms considered by the investigator to be possibly related to study drug.
Percentage of Participants With Laboratory Abnormalities
时间窗: Up to 15 months
Laboratory abnormalities were graded per the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), v4.0. SGPT/ALT - serum glutamic-pyruvic transaminase/alanine aminotransferase; SGOT/AST - serum glutamic oxaloacetic transaminase/aspartate aminotransferase
Mean Change From Baseline in Lean Body Mass
时间窗: Baseline, Day 15
Mean Change From Baseline in Respiratory Rate
时间窗: Baseline, up to 15 months
次要结局
- Total Exposure (AUC From Time 0 to 24 Hour After Dose) for GDC-0994(0 to 24 hours post-dose (Up to Day 22))
- Total Exposure (AUC From Time 0 to 24 Hour After Dose) for Cobimetinib(0 to 24 hours post-dose (Up to Day 22))
- Maximum Serum Concentration (Cmax) for GDC-0994(Up to Day 22)
- Median Time to Maximum Serum Concentration (Tmax) for Cobimetinib(Up to Day 22)
- Mean Accumulation Ratio(Pre-dose Day 1 Cycle 1, 2, 3, Day 18, 21 Cycle 1; post-dose 0.5, 1, 2, 3, 4, 6 hours Day 1, 18, 21 Cycle 1; Day 2, 15, 19, 22, Cycle 1)
- Maximum Serum Concentration (Cmax) for Cobimetinib(Up to Day 22)
- Mean Terminal Half-life (t1/2)(Up to day 22 of study)
- Change From Baseline in Fluorodeoxyglucose Positron Emission Tomography (FDG-PET)(Baseline, Day 15)
- Change From Baseline in Tumor Tissue Biomarkers(Up to 15 months)
- Median Time to Maximum Serum Concentration (Tmax) for GDC-0994(Up to Day 22)