Phase Ib/II Study of Efficacy and Safety of MEK162 and Panitumumab, in Adult mCRC Patients With Mutant or Wild-type RAS Tumors

Study Overview
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Brief Summary
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The primary purpose of the phase Ib is to estimate the MTD/RPD2 and of the phase II is to assess the anti-tumor activity of MEK162 in combination with panitumumab.

Official Title
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A Phase Ib/II, Open-label, Multi-center, Dose Escalation Study of MEK162 in Combination With Panitumumab in Adult Patients With Mutant RAS or Wild-type RAS Metastatic Colorectal Cancer

Conditions
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Metastatic Colorectal Cancer

Intervention / Treatment
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* Drug: MEK162
* Drug: Panitumumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years Metastatic colorectal cancer Progression on or following standard therapy, or no standard therapy (phase Ib). Progression on or following at least 2-prior fluoropyrimidine-containing chemotherapy regimens (phase II) Written documentation of mutant or wild-type RAS Life expectancy ≥ 3 months ECOG performance status ≤ 2 Exclusion Criteria: Phase II arms 1 and 4 only: previous treatment with cetuximab, panitumumab, and/or other EGFR inhibitors Previous treatment with MEK-inhibitors History of severe infusion reactions to monoclonal antibodies. Symptomatic or untreated leptomeningeal disease Symptomatic brain metastasis Current evidence of retinal disease; history of CSR, RVO or ophthalmopathy as assessed by ophthalmologic examination at baseline that would be considered a risk factor for CSR/RVO and history of keratitis. Acute or chronic pancreatitis Clinically significant cardiac disease Not adequate hematologic, renal and hepatic function

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase Ib: Dose escalation<br>Phase Ib: Dose escalation. | Drug: MEK162<br>* Tablet for oral use, 45 mg (three 15 mg tablets), BID<br>Drug: Panitumumab<br>* Intravenous infusion, 20mg/ml concentrate solution for infusion, Q2W (Days 1 and 15 of every cycle)<br>|
| Experimental: Phase II: Patients with mutant RAS mCRC<br>Patients with mutant RAS mCRC who have not been pretreated with an EGFR inhibitor (EGFRi), including EGFR tyrosine kinase inhibitor therapy and/or anti-EGFR monoclonal antibody therapy. | Drug: MEK162<br>* Tablet for oral use, 45 mg (three 15 mg tablets), BID<br>Drug: Panitumumab<br>* Intravenous infusion, 20mg/ml concentrate solution for infusion, Q2W (Days 1 and 15 of every cycle)<br>|
| Experimental: Phase II: Patients with acquired mutant RAS mCRC<br>Patients with acquired mutant RAS mCRC who have been pretreated with anti-EGFR monoclonal antibody therapy, but have not been pre-treated with EGFR tyrosine kinase inhibitor therapy. | Drug: MEK162<br>* Tablet for oral use, 45 mg (three 15 mg tablets), BID<br>Drug: Panitumumab<br>* Intravenous infusion, 20mg/ml concentrate solution for infusion, Q2W (Days 1 and 15 of every cycle)<br>|
| Experimental: Phase II: Patients with WT RAS mCRC (pretreated)<br>Patients with WT RAS mCRC who have been pretreated with an EGFRi, including EGFR tyrosine kinase inhibitor therapy and/or anti-EGFR monoclonal antibody therapy. | Drug: MEK162<br>* Tablet for oral use, 45 mg (three 15 mg tablets), BID<br>Drug: Panitumumab<br>* Intravenous infusion, 20mg/ml concentrate solution for infusion, Q2W (Days 1 and 15 of every cycle)<br>|
| Experimental: Phase II: Patients with WT RAS mCRC (not pretreated)<br>Patients with WT RAS mCRC who have not been pretreated with an EGFRi, including EGFR tyrosine kinase inhibitor therapy and/or anti-EGFR monoclonal antibody therapy. | Drug: MEK162<br>* Tablet for oral use, 45 mg (three 15 mg tablets), BID<br>Drug: Panitumumab<br>* Intravenous infusion, 20mg/ml concentrate solution for infusion, Q2W (Days 1 and 15 of every cycle)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Dose-limiting Toxicities (DLT): Phase 1b | DLT was defined as an adverse event or clinically significant abnormal laboratory value assessed as unrelated to disease, disease progression, inter-current illness, or concomitant medications that occurred within the first 28 days of treatment (Cycle 1) with binimetinib and panitumumab and met any of the specified criteria. | Within the first 28 days of treatment with binimetinib and panitumumab (Cycle 1) | 
| Overall Response Rate (ORR) as Per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 Based on Local Radiology Assessment: Phase 2 | ORR: percentage of participants with a best overall response (BOR) of complete response (CR) or partial response (PR) as assessed per RECIST version 1.1. BOR: the best response recorded from the start of the treatment until CR or PR. CR: disappearance of all non-nodal target lesions and of all non-target lesions. In addition, any pathological lymph nodes assigned as target lesions/ non-target lesions must have a reduction in short axis to <10 mm. PR: at least a 30 percent (%) decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. | From the start of the treatment until CR or PR (approximately up to 11 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAE) | An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent are events between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pretreatment state. | Baseline (Day 1) up to 28 days after last dose of study drug (approximately up to 12 months) | 
| Number of Participants With Vital Sign Abnormalities | Vital sign abnormalities criteria included: 1) Systolic blood pressure (SBP) in millimeters of mercury (mmHg): greater than or equal to (>=)180 mmHg or less than equal to (<=) 90 mmHg with increase or decrease from baseline of >=20 mmHg with high and low post baseline values; 2) Diastolic blood pressure (DBP) (mmHg): >=105 mmHg or <=50 mmHg with increase or decrease from baseline of >=15 mmHg with high and low post baseline values; 3) Pulse rate in beats per minutes (bpm): >=120 bpm or <=50 bpm with increase or decrease from baseline of >=15 bpm with high and low post baseline values; 4) Weight in kilogram: >=10% increase or decrease from baseline with high and low post baseline values; 5) Oral body temperature in degree Celsius (C) : >=39 degree C or <=35 degree C with high and low post baseline values. Categories, with at least 1 participant having vital sign abnormality in any of the reporting arms, were reported in this outcome measure. | Baseline (Day 1) up to 28 days after last dose of study drug (approximately up to 12 months) | 
| Number of Participants With Electrocardiogram (ECG) Abnormalities | ECG abnormalities criteria included: 1) QTc interval adjusted according to Bazett formula (QTcB) in millisecond (msec): greater than (>) 450, >480, >500, increase from baseline >30, increase from baseline >60; 2) QTc interval adjusted according to Fridericia formula (QTcF) (msec): >450, >480, >500, increase from baseline >30, increase from baseline >60; 3) Heart rate (bpm): RR decrease >25% and to a VR (interval between QRS wave and T wave on ECG) >100; RR (interval between 2 successive R waves on ECG) increase >25% and to a VR <50; 4) Pulse rate (msec): increase >25% and to a value >200; 5) QT (msec): >450, >480, >500, increase from baseline >30, increase from baseline >60; 6) QRS (msec): increase >25% and to a value >110. Categories, with at least 1 participant having ECG abnormality in any of the reporting arms, were reported in this outcome measure. | Baseline (Day 1) up to 28 days after last dose of study drug (approximately up to 12 months) | 
| Number of Participants With Clinically Significant Laboratory Abnormalities | Following parameters were analyzed for laboratory examination: hematology (hematocrit, erythrocytes); biochemistry (direct bilirubin, blood urea nitrogen, calcium, creatine kinase, triiodothyronine, thyroxine and thyrotropin). Clinical significance of laboratory abnormalities were judged by investigator. | Baseline (Day 1) up to 28 days after last dose of study drug (approximately up to 12 months) | 
| Overall Response Rate (ORR) as Per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 Based on Local Radiology Assessment: Phase 1b | ORR: percentage of participants with a best overall response (BOR) of complete response (CR) or partial response (PR) as assessed per RECIST version 1.1. BOR: the best response recorded from the start of the treatment until CR or PR. CR: disappearance of all non-nodal target lesions and of all non-target lesions. In addition, any pathological lymph nodes assigned as target lesions/ non-target lesions must have a reduction in short axis to <10 mm. PR: at least a 30 percent (%) decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. | From the start of the treatment until disease progression (approximately up to 11 months) | 
| Progression-free Survival (PFS) as Per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 Based on Local Radiology Assessment | PFS: time from date of randomization to date of first documented PD or death due to any cause, whichever occurred first. RECIST 1.1, PD:>=20% increase in sum of diameter of all measured target lesions (TLs), taking as reference smallest sum of diameter of all TLs recorded at or after baseline, sum must also be absolute increase of >=5 mm^2. Unequivocal progression of existing non-TLs. Appearance of new lesions. With no event at time of analysis cut-off or at start of any new anti-neoplastic therapy, PFS was censored at date of last adequate tumor assessment of complete response (CR), partial response (PR) or stable disease (SD). CR:disappearance of all non-nodal TLs/non TLs, any pathological lymph nodes as TLs/non TLs must have reduction in short axis to <10 mm. PR:>=30% decrease in sum of diameter of all TLs, referring baseline sum of diameters. SD:neither sufficient shrinkage to qualify for PR or CR nor increase in lesions qualified for PD. Kaplan-Meier method used for PFS analysis. | From the date of randomization to the date of the first documented PD or death (approximately up to 11 months) | 
| Duration of Response (DOR) as Per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 Based on Local Radiology Assessment | DOR: time from first documented occurrence of response (PR or CR) until date of first documented PD or death due to underlying cancer. RECIST 1.1. CR: disappearance of all non-nodal target lesions and of all non-target lesions. In addition, any pathological lymph nodes assigned as target lesions/ 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 baseline sum of diameters. PD: at least a 20% increase in 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%, sum must also demonstrate an absolute increase of at least 5 mm^2. Unequivocal progression of existing non-target lesions. Appearance of new lesions. Participants with no PD and were still alive, were censored at last adequate tumor assessment. Kaplan-Meier method was used for DOR analysis. | From the first documented occurrence of response (PR or CR) until the date of the first documented PD or death due to the underlying cancer (approximately up to 11 months) | 
| Disease Control Rate (DCR) as Per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 Based on Local Radiology Assessment | DCR was defined as the percentage of participants with a confirmed BOR of CR, PR, or stable disease (SD). RECIST 1.1, BOR was defined as the best response recorded from the start of the treatment until CR, PR or SD. CR: disappearance of all non-nodal target lesions and of all non-target lesions. In addition, any pathological lymph nodes assigned as target lesions/ non-target lesions must have a reduction in short axis to <10 mm. PR: at least a 30 percent (%) decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. 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^2. Unequivocal progression of existing non-target lesions. Appearance of new lesions. | From the start of the treatment until disease progression (approximately up to 11 months) | 
| Overall Survival (OS) | OS was defined as the time from the start of treatment to the date of death due to any cause. If a participant was not known to have died, survival was censored at the date of last known date patient alive. Kaplan-Meier method was used for OS analysis. | From the start of treatment to the date of death due to any cause (approximately up to 11 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MEK162,, panitumumab,, mutant RAS,, wild-type RAS,, metastatic colorectal cancer,, adult mCRC patient