MEK162 for Patients With RAS/RAF/MEK Activated Tumors

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

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01885195

Acronym

SIGNATURE

Enrollment

110

Registered

2013-06-24

Start date

2013-10-10

Completion date

2017-04-11

Last updated

2021-02-21

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

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

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.)

Interventions

DRUGMEK162

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

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

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

Design outcomes

Primary

Measure	Time frame	Description
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: 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.
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.

Secondary

Measure	Time frame	Description
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.
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 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.
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 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.
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.
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.
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.

Countries

United States

Participant flow

Pre-assignment details

Participants diagnosed with select solid tumors or hematological malignancies pre-identified (prior to study consent) and had an activation of the v-raf murine sarcoma viral oncogene (RAF)/ RAS oncogene \[rat sarcoma viral oncogene homologue\] (RAS)/mitogen-activated erk kinase (MEK) pathway and whose disease had progressed on or after standard treatment.

Participants by arm

Arm	Count
Binimetinib (MEK162) Participants received an oral dose of 45 mg of binimetinib tablets (3 tablets of 15 mg) twice daily in each cycle starting from Cycle 1 Day 1 (1 cycle =28 days) until disease progression, unacceptable toxicity, death, or discontinuation from the study treatment due to any other reason. Maximum treatment exposure was approximately of 19.4 months.	110
Total	110

Withdrawals & dropouts

Period	Reason	FG000
Overall Study	Adverse Event	29
Overall Study	Death	1
Overall Study	Disease Progression	67
Overall Study	Patient/guardian decision	8
Overall Study	Physician Decision	3
Overall Study	Protocol Deviation	2

Baseline characteristics

Characteristic	Binimetinib (MEK162)
Age, Continuous	60.4 Years STANDARD_DEVIATION 12.29
Sex: Female, Male Female	68 Participants
Sex: Female, Male Male	42 Participants

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	— / —
other Total, other adverse events	110 / 110
serious Total, serious adverse events	50 / 110

Outcome results

Primary

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.

Time frame: Week 16

Population: Full analysis set included all the participants who had received at least 1 dose of study drug. Here, Overall Number of Participants Analyzed signifies participants evaluable for this outcome measure.

Arm	Measure	Value (NUMBER)
Binimetinib (MEK162)	CBR for Hematologic Tumors at Week 16: Acute Myeloid Leukemia	33.3 Percentage of participants

Primary

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.

Time frame: Week 16

Arm	Measure	Value (NUMBER)
Binimetinib (MEK162)	CBR for Hematologic Tumors at Week 16: Multiple Myeloma	0.0 Percentage of participants

Primary

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.

Time frame: Week 16

Arm	Measure	Value (NUMBER)
Binimetinib (MEK162)	Clinical Benefit Rate (CBR) for Solid Tumors at Week 16 as Per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1	23.1 Percentage of participants

Secondary

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.

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)

Arm	Measure	Value (MEDIAN)
Binimetinib (MEK162)	Duration of Response (DOR) as Per RECIST Version 1.1	NA Months

Secondary

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.