Modular Phase II Study to Link Targeted Therapy to Patients With Pathway Activated Tumors: Module 3 - MEK162 for Patients With RAS/RAF/MEK Activated Tumors
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- Pfizer
- 入组人数
- 110
- 试验地点
- 68
- 主要终点
- Clinical Benefit Rate (CBR) for Solid Tumors at Week 16 as Per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1
研究概览
简要总结
The purpose of this signal seeking study is to determine whether treatment with MEK162 demonstrates sufficient efficacy in select pathway-activated solid tumors and/or hematologic malignancies to warrant further study
详细描述
This is a phase II, open label study to determine the efficacy and safety of treatment with MEK162 in patients with a diagnosis of select solid tumors or hematological malignancies that have been pre-identified (prior to study consent) to have activations of the RAS/RAF/MEK pathway and whose disease has progressed on or after standard treatment.
Genomic profiling is becoming more accessible to patients and their physicians. This is a signal-seeking study to match patients with mutations in RAF, RAS, NF1 or MEK to the ATP-noncompetitive MEK 1/2 inhibitor, MEK162. Pre-identification of these mutations or activations in the pathway will be performed locally at a CLIA certified laboratory prior to screening for participation on the trial.
Once the patient has been identified, treating physicians who are qualified investigators may contact Novartis to consider enrollment in this study. For the purpose of this study, genomic profiling is not considered part of screening. Informed consent must be signed before any screening activities take place. Once eligibility (screening criteria met) has been confirmed by Novartis, the patient will initiate therapy with single agent MEK162. The patient may not receive any additional anti-cancer therapy during treatment with MEK162.
Patients will continue to receive study treatment until disease progression (assessed by RECIST 1.1 or appropriate hematologic response criteria), unacceptable toxicity, death or discontinuation from study treatment for any other reason (e.g., withdrawal of consent, start of a new anti-neoplastic therapy or at the discretion of the investigator), otherwise known as End of Treatment. All patients who discontinue from study treatment due to disease progression must have their progression clearly documented.
Disease assessment (per RECIST 1.1 or appropriate hematological response criteria) will be performed every 8 weeks (±4 days) after first dose of study drug (Day 1 of every odd cycle), until disease progression or end of treatment, whichever occurs first. The frequency of disease assessment may be reduced to every 12 weeks for patients who have at least 4 post-baseline disease assessments and are clinically stable (except AML and MM patients). Scans will be assessed locally by the investigator. After discontinuation of treatment, patients, regardless of reason for treatment discontinuation, will be followed for safety for 30 days after the last dose.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
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
- •Patient has a confirmed diagnosis of a select solid tumor (except for primary diagnosis of pancreatic cancer, biliary cancer, colorectal cancer, low grade serous ovarian cancer, melanoma) or hematologic malignancy (except for primary diagnosis of chronic myelomonocytic leukemia).
- •Patients must be pre-identified as having a tumor with a mutation in RAF, RAS, NF1 or MEK at a CLIA certified laboratory
- •Patient must have received at least one prior treatment for recurrent, metastatic and /or locally advanced disease and for whom no standard therapy options are anticipated to result in a durable remission.
- •Patient must have progressive and measurable disease as per RECIST 1.
- •or other appropriate hematological guidelines.
- •Patient has an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1
排除标准
- •Patient has received prior treatment with MEK
- •Patients with primary CNS tumor or CNS tumor involvement
- •History of retinal degenerative disease
- •History or current evidence of central serous retinopathy (CSR) or retinal vein occlusion (RVO)
- •Any ophthalmopathy visible at screening that would be considered a risk factor for CSR or RVO by the ophthalmologist
- •Patients who have neuromuscular disorders that are associated with elevated CK
研究组 & 干预措施
MEK162
MEK162 will be dosed on a flat scale of 45 mg twice daily on a continuous dosing schedule.
干预措施: MEK162 (Drug)
结局指标
主要结局
Clinical Benefit Rate (CBR) for Solid Tumors at Week 16 as Per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1
时间窗: Week 16
CBR: participants with complete response (CR), partial response (PR) or stable disease (SD) for at least 16 weeks. As per RECIST 1.1, CR: disappearance of all target and non-target lesions, normalization of tumor marker level, pathological lymph nodes assigned as target or non-target lesions must have a reduction in short axis to less than (\<) 10 millimeter (mm); PR: at least a 30 percent (%) decrease in sum of diameter of all target lesions, taking as reference the baseline sum of diameters; SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum diameters; PD: at least a 20% increase in sum of diameter of all measured target lesions, taking as reference smallest sum of diameter of all target lesions recorded at or after baseline, sum was also an absolute increase of at least 5 mm. Unequivocal progression of existing non-target lesions. Appearance of \>=1 new target or non-target lesions.
CBR for Hematologic Tumors at Week 16: Multiple Myeloma
时间窗: Week 16
CBR: participants with stringent complete response(sCR), CR, very good partial response(VGPR), PR/SD for at least 16 weeks. For hematologic tumors (multiple myeloma), sCR: negative immunofixation on serum, urine, disappearance of any soft tissue plasmacytomas and \<5% plasma cells in bone marrow plus normal free light chain(FLC) ratio and absence of clonal cells in bone marrow by immunohistochemistry/immunofluorescence; CR: negative immunofixation on the serum, urine, disappearance of any soft tissue, plasmacytomas and \<5% plasma cells in bone marrow; VGPR: serum,urine M-component detectable by immunofixation but not on electrophoresis or\>=90% reduction in serum M-component plus urine M-component \<100 mg/24 hr; PR: \>50% reduction of serum M-protein and reduction in 24hr urinary M-protein by \>90%/to \<200 mg/24 hr; SD: not meeting criteria for CR, VGPR, PRor PD; PD: increase of \>25% from lowest response value in serum M-component, urine M-component and bone marrow plasma cell percentage.
CBR for Hematologic Tumors at Week 16: Acute Myeloid Leukemia
时间窗: Week 16
CBR: participants with complete remission (CR), CR with incomplete blood count recovery (CRi), partial remission (PR) and no resposne for at least 16 weeks. For hematologic tumors (acute myeloid leukemia); CR: as bone marrow- \< 5% blasts, no blasts with auer rods, peripheral blood- neutrophils ≥1.0\*10\^9/L and/or platelets ≥100\*10\^9/L, ≤1% blasts, no evidence of extramedullary disease (such as CNS or soft tissue involvement), transfusion independent; CRi: all the CR criteria were involved but platelet and neutrophil transfusions were also allowed; PR: bone marrow- 50% or greater decrease (absolute range 5-25% blasts), \< 5% of blasts contain auer rods, peripheral blood- neutrophils \<1.0\*10\^9/L and/or platelets \<100\*10\^9/L, no evidence of extramedullary disease; no response: in case a patient did not achieve CR, CRi, PR or relapse for an individual response assessment.
次要结局
- Overall Response Rate (ORR) as Per RECIST Version 1.1(From the start of the treatment until disease progression (maximum up to 19.4 months))
- Number of Participants With Treatment Emergent Adverse Events (TEAEs) Graded According to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03(From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months))
- Number of Participants With Shift From Baseline in Cardiac Imaging(From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months))
- ORR for Hematologic Tumors: Multiple Myeloma(From the start of the treatment until disease progression (maximum up to 19.4 months))
- ORR for Hematologic Tumors: Acute Myeloid Leukemia(From the start of the treatment until disease progression (maximum up to 19.4 months))
- Progression-free Survival (PFS) as Per RECIST Version 1.1(From the date of first dose to the date of the first documented PD, censored date or death (maximum up to 19.4 months))
- Number of Participants With Electrocardiogram (ECG) Abnormalities(From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months))
- Number of Participants With Shift From Baseline in Clinical Laboratory - Hematology Parameters(From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months))
- Number of Participants With Shift From Baseline in Clinical Laboratory - Biochemistry Parameters(From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months))
- Overall Survival (OS)(From the date of first dose to the date of death due to any cause (maximum up to 19.4 months))
- Duration of Response (DOR) as Per RECIST Version 1.1(From the first documented response (CR or PR) to the date of the first documented PD or death (maximum up to 19.4 months))
- Number of Participants With Vital Sign Abnormality of Greater Than or Equal to (>=) Grade 3 as Per CTCAE v4.03(From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months))