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MEK162 for Patients With RAS/RAF/MEK Activated Tumors (SIGNATURE)

Primary Purpose

Solid Tumor and Hematologic Malignancies

Status

Completed

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

MEK162

About this trial

This is an interventional treatment trial for Solid Tumor and Hematologic Malignancies focused on measuring RAS, RAF, MEK, NF1, MEK162, signature, papillary thyroid, small intestine, bladder, esophagus, lung cancer, NSCLC, acute myelogenous leukemia, AML

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

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

Exclusion Criteria:

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

Sites / Locations

University of South Alabama / Mitchell Cancer Institute Univ South Alabama
Alaska Oncology and Hematology AOH (2)
Arizona Oncology Associates AZ Oncology Assoc.
Arizona Oncology Associates HOPE Division
Arizona Oncology Associates PC- NAHOA
Highlands Oncology Group Highlands Oncology Group (22)
PCR Oncology
University of California Davis Cancer Center UC Davis Cancer (3)
Rocky Mountain Cancer Centers USOR
Yale University School of Medicine Yale Cancer Center
Whittingham Cancer Center Norwalk Hospital
Eastern Connecticut Hematology & Oncology Associates Dept. of ECHO
Hematology Oncology PC Stamford Hospital
Florida Cancer Specialists Florida Cancer Specialists (31
Memorial Cancer Institute Memorial Healthcare System
Cancer Specialists of North Florida
Mt. Sinai Comprehensive Cancer Center
Ocala Oncology Center Dept. of Ocala Oncology Center
Cancer Centers of Florida PA Cancer Centers of FL-Orlando-4
University Cancer & Blood Center, LLC
Lurie Children's Hospital of Chicago Developmental Therapeutics
Oncology Specialists, SC Onc Specialists
Illinois Cancer Care IL. Cancer Care
Indiana University Indiana Univ. - Purdue Univ.
University of Iowa Hospitals & Clinics Regulatory Contact 2
Maryland Oncology Hematology, P.A. Oncology Hematology
Cancer and Hematology Centers of West Michigan Dept. of Oncology
Metro MN CCOP - Coon Rapids
Research Medical Center Research Med Center (2)
Washington University School of Medicine Washington University (16)
Glacier View Research Institute - Cancer Oncology Dept
Comprehensive Cancer Centers of Nevada CCC of Nevada (21)
Cancer Institute of New Jersey CINJ
New Mexico Cancer Care Alliance Oncology Dept
New York Oncology Hematology, P.C. NYOH Latham
University of North Carolina Chapel Hill Physician Office Building
Duke University Medical Center Seeley G. Mudd Bldg.
Sanford Research/USD-Fargo Sanford Hematology Oncology
Cleveland Clinic Foundation Cleveland Clinic (19)
Ohio State University Medical Center Comprehensive Cancer Center
St. Charles Cancer Center
Willamette Valley Clinical Studies Cancer Institute & Res. Ctr.
Northwest Cancer Specialists Vancouver Cancer Center
Oregon Health & Science University Oregon Health & Science U (56)
St. Luke's Hospital and Health Network St Luke's (2)
West Penn Allegheny Oncology Network
Abington Hematology Oncology Associates, Inc Abington Hem Onc Assoc (5)
Chattanooga Oncology and Hematology Assoicates, PC Chattanooga Oncology
The West Clinic Dept. of the West Clinic
Sarah Cannon Research Institute Sarah Cannon Research Inst (51
Texas Oncology Presbyterian Hospital (3)
Texas Oncology Texas Oncology - Denton
Texas Oncology Austin Midtown
Texas Oncology Texas Oncology - Midland
Sammons Cancer Center - Texas Oncology Sammons Cancer Center (10)
Oncology Consultants Oncology Group
MD Anderson Cancer Center/University of Texas MD Anderson Cancer Center (3)
Cancer Care Centers of South Texas / HOAST CCC of So. TX-San Antonio (3)
Tyler Cancer Center Dept.ofTylerCancerCtr. (2)
Deke Slayton Cancer Center Deke Slayton Cancer Center (2)
Intermountain Medical Center Intermountain Healthcare
Virginia Cancer Specialists, PC Virginia Cancer Specialists
Medical Oncology & Hematology Associates of Northern VA Med Onc Hem Northern VA
Kadlec Clinic Hematology and Oncology Kadlec Clinic Hematology & Onc
Providence Regional Cancer System
MultiCare Health System Institute for Research & Innovation MultiCare
Northwest Medical Specialties NW Medical Specialties
Medical College of Wisconsin Cancer Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

MEK162

Arm Description

MEK162 will be dosed on a flat scale of 45 mg twice daily on a continuous dosing schedule.

Outcomes

Primary Outcome Measures

Clinical Benefit Rate (CBR) for Solid Tumors at Week 16 as Per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1

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

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

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

Overall Response Rate (ORR) as Per RECIST Version 1.1

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.

ORR for Hematologic Tumors: Multiple Myeloma

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

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

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.

Overall Survival (OS)

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

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 Treatment Emergent Adverse Events (TEAEs) Graded According to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03

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 Vital Sign Abnormality of Greater Than or Equal to (>=) Grade 3 as Per CTCAE v4.03

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.

Number of Participants With Electrocardiogram (ECG) Abnormalities

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

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

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.

Number of Participants With Shift From Baseline in Cardiac Imaging

Number of Participants With Shift From Baseline in Cardiac Imaging were reported.

Full Information

NCT ID

NCT01885195

First Posted

June 20, 2013

Last Updated

February 2, 2021

Sponsor

Pfizer

1. Study Identification

Unique Protocol Identification Number

NCT01885195

Brief Title

MEK162 for Patients With RAS/RAF/MEK Activated Tumors

Acronym

SIGNATURE

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

February 2021

Overall Recruitment Status

Completed

Study Start Date

October 10, 2013 (Actual)

Primary Completion Date

October 1, 2015 (Actual)

Study Completion Date

April 11, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Pfizer

4. Oversight

Data Monitoring Committee

5. Study Description

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.)

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Solid Tumor and Hematologic Malignancies

Keywords

RAS, RAF, MEK, NF1, MEK162, signature, papillary thyroid, small intestine, bladder, esophagus, lung cancer, NSCLC, acute myelogenous leukemia, AML

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Single Group Assignment

Allocation

N/A

Enrollment

110 (Actual)

8. Arms, Groups, and Interventions

Arm Title

MEK162

Arm Type

Experimental

Arm Description

MEK162 will be dosed on a flat scale of 45 mg twice daily on a continuous dosing schedule.

Intervention Type

Drug

Intervention Name(s)

MEK162

Intervention Description

MEK162 will be dosed on a flat scale of 45 mg twice daily on a continuous dosing schedule.

Primary Outcome Measure Information:

Title

Clinical Benefit Rate (CBR) for Solid Tumors at Week 16 as Per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1

Description

Time Frame

Week 16

Title

CBR for Hematologic Tumors at Week 16: Multiple Myeloma

Description

Time Frame

Week 16

Title

CBR for Hematologic Tumors at Week 16: Acute Myeloid Leukemia

Description

Time Frame

Week 16

Secondary Outcome Measure Information:

Title

Overall Response Rate (ORR) as Per RECIST Version 1.1

Description

Time Frame

From the start of the treatment until disease progression (maximum up to 19.4 months)

Title

ORR for Hematologic Tumors: Multiple Myeloma

Description

Time Frame

From the start of the treatment until disease progression (maximum up to 19.4 months)

Title

ORR for Hematologic Tumors: Acute Myeloid Leukemia

Description

Time Frame

From the start of the treatment until disease progression (maximum up to 19.4 months)

Title

Progression-free Survival (PFS) as Per RECIST Version 1.1

Description

Time Frame

From the date of first dose to the date of the first documented PD, censored date or death (maximum up to 19.4 months)

Title

Overall Survival (OS)

Description

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.

Time Frame

From the date of first dose to the date of death due to any cause (maximum up to 19.4 months)

Title

Duration of Response (DOR) as Per RECIST Version 1.1

Description

Time Frame

From the first documented response (CR or PR) to the date of the first documented PD or death (maximum up to 19.4 months)

Title

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

Description

Time Frame