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

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ClinicalTrials.gov Identifier: NCT01885195
Recruitment Status : Completed
First Posted : June 24, 2013
Results First Posted : February 21, 2021
Last Update Posted : February 21, 2021
Sponsor:
Information provided by (Responsible Party):
Pfizer

Tracking Information
First Submitted Date  ICMJE June 20, 2013
First Posted Date  ICMJE June 24, 2013
Results First Submitted Date  ICMJE February 2, 2021
Results First Posted Date  ICMJE February 21, 2021
Last Update Posted Date February 21, 2021
Actual Study Start Date  ICMJE October 10, 2013
Actual Primary Completion Date October 1, 2015   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 2, 2021)
  • Clinical Benefit Rate (CBR) for Solid Tumors at Week 16 as Per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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.
Original Primary Outcome Measures  ICMJE
 (submitted: June 20, 2013)
Clinical benefit rate associated with MEK162 treatment [ Time Frame: 16 weeks ]
Clinical benefit rate for patients with solid tumors will be assessed using RECIST 1.1 and will include responses of CR or PR or SD. For hematologic tumors other appropriate hematological response criteria will apply
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: February 2, 2021)
  • Overall Response Rate (ORR) as Per RECIST Version 1.1 [ Time Frame: 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.
  • ORR for Hematologic Tumors: Multiple Myeloma [ Time Frame: 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 [ Time Frame: 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 [ 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) ]
    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) [ Time Frame: 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 [ 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) ]
    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 [ Time Frame: 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 Vital Sign Abnormality of Greater Than or Equal to (>=) Grade 3 as Per CTCAE v4.03 [ Time Frame: 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.
  • Number of Participants With Electrocardiogram (ECG) Abnormalities [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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.
  • Number of Participants With Shift From Baseline in Cardiac Imaging [ Time Frame: 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: June 20, 2013)
  • Overall Response (OR) or Partial Response (PR) or greater [ Time Frame: baseline and every 8 weeks until disease progression or end of treatment, assessed up to 24 months ]
    Overall Response (OR) of Partial Response (PR) or greater based on local investigator assessment. For patients with solid tumors, the assessment criteria will be RECIST 1.1 and will include responses of CR and/or PR. For hematologic tumors other appropriate hematological response criteria will apply.
  • Progression-Free Survival (PFS) [ Time Frame: every 8 weeks until death, assessed up to 24 months ]
    Progression free survival (PFS) is defined as the time from the date of first dose to the date of first documented disease progression or relapse or death due to any cause
  • Overall Survival (OS) [ Time Frame: every 8 weeks until death, assessed up to 36 months ]
    Overall survival (OS) is defined as the time from the date of first dose to the date of death due to any cause
  • Duration of Response (DOR) [ Time Frame: baseline and every 8 weeks until disease progression or end of treatment, assessed up to 24 months ]
    The duration of response (PR or greater) applies only to patients whose best response was PR or greater. It is defined as the Ttime from the first documented response to the date first documented disease progression or relapse or death due to any cause
  • Number of participants with adverse events as a measure of Safety and Tolerability [ Time Frame: baseline and every 8 weeks until disease progression or end of treatment, assessed up to 24 months ]
    Safety and tolerability will be will be based on the frequency of adverse events and on the number of laboratory values that fall outside of pre-determined ranges. Other safety data (e.g., electrocardiogram, vital signs) will be considered as appropriate.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE MEK162 for Patients With RAS/RAF/MEK Activated Tumors
Official Title  ICMJE 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
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.)

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Primary Purpose: Treatment
Condition  ICMJE Solid Tumor and Hematologic Malignancies
Intervention  ICMJE Drug: MEK162
MEK162 will be dosed on a flat scale of 45 mg twice daily on a continuous dosing schedule.
Study Arms  ICMJE Experimental: MEK162
MEK162 will be dosed on a flat scale of 45 mg twice daily on a continuous dosing schedule.
Intervention: Drug: MEK162
Publications * Burkart J, Owen D, Shah MH, Abdel-Misih SRZ, Roychowdhury S, Wesolowski R, Haraldsdottir S, Reeser JW, Samorodnitsky E, Smith A, Konda B. Targeting BRAF Mutations in High-Grade Neuroendocrine Carcinoma of the Colon. J Natl Compr Canc Netw. 2018 Sep;16(9):1035-1040. doi: 10.6004/jnccn.2018.7043.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: February 21, 2015)
110
Original Estimated Enrollment  ICMJE
 (submitted: June 20, 2013)
70
Actual Study Completion Date  ICMJE April 11, 2017
Actual Primary Completion Date October 1, 2015   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01885195
Other Study ID Numbers  ICMJE CMEK162AUS11
C4211007 ( Other Identifier: Alias Study Number )
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.
URL: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests
Responsible Party Pfizer
Study Sponsor  ICMJE Pfizer
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Pfizer CT.gov Call Center Pfizer
PRS Account Pfizer
Verification Date February 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP