MEK162 for Patients With RAS/RAF/MEK Activated Tumors
- Registration Number
- NCT01885195
- Lead Sponsor
- Pfizer
- Brief Summary
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
- Detailed Description
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.
All patients will be followed for survival status every 3 months for 2 years after the last patient has enrolled in the study regardless of treatment discontinuation reason (except if consent is withdrawn or patient is lost to follow-up.)
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 110
- 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 1.1. or other appropriate hematological guidelines.
- Patient has an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1
- Patient has received prior treatment with MEK162.
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description MEK162 MEK162 MEK162 will be dosed on a flat scale of 45 mg twice daily on a continuous dosing schedule.
- Primary Outcome Measures
Name Time Method Clinical Benefit Rate (CBR) for Solid Tumors at Week 16 as Per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 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 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 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.
- Secondary Outcome Measures
Name Time Method 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) ORR: percentage of participants with a best overall response (BOR) of CR or PR as assessed per RECIST version 1.1. BOR: the best response recorded from the start of the treatment until disease progression (PD). 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 mm; PR: at least a 30 % decrease in sum of diameter of all target lesions, taking as reference the baseline sum of 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.
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) Adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. As per NCI-CTCAE version 4.03, severity was graded as Grade 1: asymptomatic/mild symptoms, clinical/diagnostic observations only, intervention not indicated; Grade 2: moderate, minimal, local/noninvasive intervention indicated, limiting age-appropriate instrumental activities of daily life (ADL); Grade 3: severe/medically significant but not immediately life-threatening, hospitalization/prolongation of existing hospitalization indicated, disabling, limiting self-care ADL; Grade 4: life-threatening consequence, urgent intervention indicated. Treatment-emergent adverse events were defined as new or worsening events that were collected from first study treatment date to last treatment date +30 days. AEs of all grades were reported.
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) Number of Participants With Shift From Baseline in Cardiac Imaging were reported.
ORR for Hematologic Tumors: Multiple Myeloma From the start of the treatment until disease progression (maximum up to 19.4 months) ORR: percentage of participants with sCR, CR, VGPR or PR. For hematologic tumors (multiple myeloma), sCR: negative immunofixation on the serum, urine, disappearance of any soft tissue plasmacytomas and \<5% plasma cells in bone marrow plus normal FLC ratio and absence of clonal cells in bone marrow by immunohistochemistry or immunofluorescence; CR: CR: negative immunofixation on the serum, urine, disappearance of any soft tissue, plasmacytomas and \<5% plasma cells in bone marrow; VGPR: serum and urine M-component detectable by immunofixation but not on electrophoresis or greater than equal to \>=90% reduction in serum M-component plus urine M-component \<100 mg per 24hour (hr); PR: \>50% reduction of serum M-protein and reduction in 24 hr urinary M-protein by \>90% or to \<200 mg/24 hr.
ORR for Hematologic Tumors: Acute Myeloid Leukemia From the start of the treatment until disease progression (maximum up to 19.4 months) ORR: 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.
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) PFS was defined as the time from the date of first dose to the date of first documented PD or relapse or death due to any cause. PD: at least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Unequivocal progression of existing non-target lesions. Appearance of \>=1 new target or non-target lesions was also considered progression. PFS data was censored at date of last adequate tumor assessment.
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) ECG abnormalities criteria included: 1) QTc interval adjusted according to Bazett formula (QTcF) in millisecond (msec): greater than equal to (\>=) 450 to less than (\<) 480, \>=480 to \<500, \>=500, increase from baseline \>=30, increase from baseline \>=60; 2) QTc interval adjusted according to Fridericia formula (QTcB) (msec): \>=450 to \<480, \>=480 to \<500, \>=500, increase from baseline \>=30, increase from baseline \>=60. 3) QT (msec): \>=450 to \<480, \>=480 to \<500, \>=500, increase from baseline \>=30, increase from baseline \>=60.
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) Laboratory parameters included hematological and biochemistry parameters. Hematological parameters included neutrophils, platelets, prothrombin time, activated partial thromboplastin time, INR, fibrinogen. Number of participants with hematological abnormalities by grades (as per Common Terminology Criteria for Adverse Events (CTCAE version 4.03) were reported. Grade 1= mild; Grade 2= moderate; Grade 3= severe and Grade 4= life-threatening or disabling. Participants with a grade shift of 3 or more from baseline are reported in this outcome measure.
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) Laboratory parameters included hematological and biochemistry parameters. Biochemistry parameters included: creatinine, phosphorus, albumin, gamma-glutamyl transferase, aspartate transaminase, alanine aminotransferase, alkaline phosphatase, total bilirubin, uric acid, amylase, lipase, creatine kinase, total cholesterol and triglycerides. Number of participants with biochemistry test abnormalities by grades (CTCAE version 4.03) were reported. Grade 1= mild; Grade 2= moderate; Grade 3= severe and Grade 4= life-threatening or disabling. Participants with a grade shift of 3 or more from baseline are reported in this outcome measure.
Overall Survival (OS) From the date of first dose to the date of death due to any cause (maximum up to 19.4 months) OS was defined as the time from the date of first dose to the date of death due to any cause. If a participant was not known to have died, survival time was censored at the date of last contact.
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) DOR was defined as the time from the first documented response (CR or PR) to the date of first documented disease progression, relapse or death due to any cause. 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 \<10 mm; PR: at least a 30% decrease in sum of diameter of all target lesions, taking as reference the baseline sum of 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. The DOR was determined only in participants whose best response was PR or greater.
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) Vital signs included hypertension, hypotension and weight decreased were reported. As per NCI-CTCAE version 4.03, severity was graded as Grade 1: asymptomatic/mild symptoms, clinical/diagnostic observations only, intervention not indicated; Grade 2: moderate, minimal, local/noninvasive intervention indicated, limiting age-appropriate instrumental activities of daily life (ADL); Grade 3: severe/medically significant but not immediately life-threatening, hospitalization/prolongation of existing hospitalization indicated, disabling, limiting self-care ADL; Grade 4: life-threatening consequence, urgent intervention indicated. Participants with grade 3 or higher vital sign abnormality are reported.
Trial Locations
- Locations (68)
Texas Oncology Austin Midtown
🇺🇸Dallas, Texas, United States
Glacier View Research Institute - Cancer Oncology Dept
🇺🇸Kalispell, Montana, United States
Texas Oncology Texas Oncology - Midland
🇺🇸Dallas, Texas, United States
Indiana University Indiana Univ. - Purdue Univ.
🇺🇸Indianapolis, Indiana, United States
Cleveland Clinic Foundation Cleveland Clinic (19)
🇺🇸Cleveland, Ohio, United States
Comprehensive Cancer Centers of Nevada CCC of Nevada (21)
🇺🇸Las Vegas, Nevada, United States
Cancer Specialists of North Florida
🇺🇸Jacksonville, Florida, United States
Arizona Oncology Associates PC- NAHOA
🇺🇸Sedona, Arizona, United States
Oncology Specialists, SC Onc Specialists
🇺🇸Park Ridge, Illinois, United States
Medical Oncology & Hematology Associates of Northern VA Med Onc Hem Northern VA
🇺🇸Reston, Virginia, United States
Metro MN CCOP - Coon Rapids
🇺🇸Coon Rapids, Minnesota, United States
Maryland Oncology Hematology, P.A. Oncology Hematology
🇺🇸Rockville, Maryland, United States
Whittingham Cancer Center Norwalk Hospital
🇺🇸Norwalk, Connecticut, United States
Cancer and Hematology Centers of West Michigan Dept. of Oncology
🇺🇸Grand Rapids, Michigan, United States
Cancer Centers of Florida PA Cancer Centers of FL-Orlando-4
🇺🇸Ocoee, Florida, United States
New Mexico Cancer Care Alliance Oncology Dept
🇺🇸Albuquerque, New Mexico, United States
Illinois Cancer Care IL. Cancer Care
🇺🇸Peoria, Illinois, United States
Tyler Cancer Center Dept.ofTylerCancerCtr. (2)
🇺🇸Tyler, Texas, United States
Virginia Cancer Specialists, PC Virginia Cancer Specialists
🇺🇸Fairfax, Virginia, United States
Intermountain Medical Center Intermountain Healthcare
🇺🇸Murray, Utah, United States
Oncology Consultants Oncology Group
🇺🇸Houston, Texas, United States
Deke Slayton Cancer Center Deke Slayton Cancer Center (2)
🇺🇸Webster, Texas, United States
MD Anderson Cancer Center/University of Texas MD Anderson Cancer Center (3)
🇺🇸Houston, Texas, United States
Northwest Medical Specialties NW Medical Specialties
🇺🇸Tacoma, Washington, United States
Kadlec Clinic Hematology and Oncology Kadlec Clinic Hematology & Onc
🇺🇸Kennewick, Washington, United States
Arizona Oncology Associates AZ Oncology Assoc.
🇺🇸Phoenix, Arizona, United States
Arizona Oncology Associates HOPE Division
🇺🇸Phoenix, Arizona, United States
University of South Alabama / Mitchell Cancer Institute Univ South Alabama
🇺🇸Mobile, Alabama, United States
Alaska Oncology and Hematology AOH (2)
🇺🇸Anchorage, Alaska, United States
PCR Oncology
🇺🇸Pismo Beach, California, United States
Rocky Mountain Cancer Centers USOR
🇺🇸Boulder, Colorado, United States
Hematology Oncology PC Stamford Hospital
🇺🇸Stamford, Connecticut, United States
Memorial Cancer Institute Memorial Healthcare System
🇺🇸Hollywood, Florida, United States
Ocala Oncology Center Dept. of Ocala Oncology Center
🇺🇸Ocala, Florida, United States
Mt. Sinai Comprehensive Cancer Center
🇺🇸Miami Beach, Florida, United States
Lurie Children's Hospital of Chicago Developmental Therapeutics
🇺🇸Chicago, Illinois, United States
University of Iowa Hospitals & Clinics Regulatory Contact 2
🇺🇸Iowa City, Iowa, United States
Washington University School of Medicine Washington University (16)
🇺🇸Saint Louis, Missouri, United States
Cancer Institute of New Jersey CINJ
🇺🇸New Brunswick, New Jersey, United States
Duke University Medical Center Seeley G. Mudd Bldg.
🇺🇸Durham, North Carolina, United States
Sanford Research/USD-Fargo Sanford Hematology Oncology
🇺🇸Fargo, North Dakota, United States
St. Charles Cancer Center
🇺🇸Bend, Oregon, United States
Willamette Valley Clinical Studies Cancer Institute & Res. Ctr.
🇺🇸Eugene, Oregon, United States
St. Luke's Hospital and Health Network St Luke's (2)
🇺🇸Bethlehem, Pennsylvania, United States
Abington Hematology Oncology Associates, Inc Abington Hem Onc Assoc (5)
🇺🇸Willow Grove, Pennsylvania, United States
West Penn Allegheny Oncology Network
🇺🇸Natrona Heights, Pennsylvania, United States
Chattanooga Oncology and Hematology Assoicates, PC Chattanooga Oncology
🇺🇸Chattanooga, Tennessee, United States
Texas Oncology Presbyterian Hospital (3)
🇺🇸Dallas, Texas, United States
Texas Oncology Texas Oncology - Denton
🇺🇸Dallas, Texas, United States
The West Clinic Dept. of the West Clinic
🇺🇸Memphis, Tennessee, United States
Sammons Cancer Center - Texas Oncology Sammons Cancer Center (10)
🇺🇸Dallas, Texas, United States
Cancer Care Centers of South Texas / HOAST CCC of So. TX-San Antonio (3)
🇺🇸San Antonio, Texas, United States
Florida Cancer Specialists Florida Cancer Specialists (31
🇺🇸Fort Myers, Florida, United States
Highlands Oncology Group Highlands Oncology Group (22)
🇺🇸Fayetteville, Arkansas, United States
New York Oncology Hematology, P.C. NYOH Latham
🇺🇸Troy, New York, United States
Eastern Connecticut Hematology & Oncology Associates Dept. of ECHO
🇺🇸Norwich, Connecticut, United States
Sarah Cannon Research Institute Sarah Cannon Research Inst (51
🇺🇸Nashville, Tennessee, United States
Providence Regional Cancer System
🇺🇸Lacey, Washington, United States
University Cancer & Blood Center, LLC
🇺🇸Athens, Georgia, United States
Ohio State University Medical Center Comprehensive Cancer Center
🇺🇸Columbus, Ohio, United States
MultiCare Health System Institute for Research & Innovation MultiCare
🇺🇸Tacoma, Washington, United States
University of California Davis Cancer Center UC Davis Cancer (3)
🇺🇸Sacramento, California, United States
Yale University School of Medicine Yale Cancer Center
🇺🇸New Haven, Connecticut, United States
Northwest Cancer Specialists Vancouver Cancer Center
🇺🇸Portland, Oregon, United States
Research Medical Center Research Med Center (2)
🇺🇸Kansas City, Missouri, United States
Oregon Health & Science University Oregon Health & Science U (56)
🇺🇸Portland, Oregon, United States
Medical College of Wisconsin Cancer Center
🇺🇸Milwaukee, Wisconsin, United States
University of North Carolina Chapel Hill Physician Office Building
🇺🇸Chapel Hill, North Carolina, United States
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