Study of LGX818 and Cetuximab or LGX818, BYL719, and Cetuximab in BRAF Mutant Metastatic Colorectal Cancer

Study Overview
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Brief Summary
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This study will assess the safety and efficacy of LGX818 when combined with cetuximab or combined with cetuximab and BYL719 in patients with BRAF mutant metastatic colorectal cancer

Official Title
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A Phase Ib/II Multi-center, Open-label, Dose Escalation Study of LGX818 and Cetuximab or LGX818, BYL719, and Cetuximab in Patients With BRAF Mutant Metastatic Colorectal Cancer

Conditions
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Colorectal Cancer

Intervention / Treatment
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* Drug: LGX818
* Drug: Cetuximab
* Drug: BYL719


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Metastatic colorectal cancer Progression after at least one prior standard of care regimen or be intolerant to irinotecan-based regimens Life expectancy ≥ 3 months ECOG performance status ≤ 2 Exclusion Criteria: Symptomatic or untreated leptomeningeal disease Symptomatic brain metastasis Patients with clinically manifested diabetes Acute or chronic pancreatitis Clinically significant cardiac disease Other protocol-defined inclusion/exclusion criteria may apply.

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: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LGX818 + cetuximab<br> | Drug: LGX818<br> <br> Drug: Cetuximab<br> <br> |
| Experimental: LGX818 + BYL719 + cetuximab<br> | Drug: LGX818<br> <br> Drug: Cetuximab<br> <br> Drug: BYL719<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1b: Number of Participants With Incidence of Dose Limiting Toxicities (DLTs): Cycle 1 | DLTs were defined as an adverse event (AE) or 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 and meets any of the criteria included blood and lymphatic system disorders, investigations (blood, renal, hepatic, metabolic), skin and subcutaneous tissue disorders: rash, HFSR (hand foot skin reaction) and/or photosensitivity, metabolism and nutrition disorders: hyperglycemia, gastrointestinal disorders, cardiac disorders, vascular disorders, general disorders and administration site conditions, tumor lysis syndrome, ophthalmologic and other adverse events: study drug-related fever, alkaline phosphatase elevation. | Cycle 1: Day 1 to Day 28 | 
| Phase 2: Progression Free Survival (PFS) | PFS was defined as the time from the date of randomization to the date of the first documented disease progression or death due to any cause. Participants who did not progress per RECIST (Response Evaluation Criteria in Solid Tumors) version (v) 1.1, were not known to have died prior to the data cut-off, or received any further anticancer therapy were censored at the date of last adequate tumor assessment or the anticancer therapy date, whichever was earlier. | From the date of randomization until the first documentation of disease progression or death due to any cause, censored date, whichever occurred first (maximum up to 43 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment - Emergent Adverse Events of Grade 3 or 4 Severity Based on National Cancer Institute of Common Terminology Criteria (NCI-CTCAE), Version 4.0 | An AE was any untoward medical occurrence attributed to study drug in participants who received study drug. As per NCI-CTCAE v4.0, Grade 1: asymptomatic or mild symptoms, clinical or diagnostic observations only, intervention not indicated; Grade 2: moderate, minimal, local or noninvasive intervention indicated, limiting age-appropriate instrumental activities of daily life (ADL); Grade 3: severe or medically significant but not immediately life-threatening, hospitalization or prolongation of existing hospitalization indicated, disabling, limiting self-care ADL; Grade 4: life-threatening consequence, urgent intervention indicated; Grade 5: death related to study drug. Treatment-emergent AEs are between first dose of study drug and up to 30 days after last dose of study drug, that were absent before treatment or that worsened relative to pretreatment state. Number of participants with any Grade 3 or 4 treatment-emergent AE were reported in this outcome measure. | From screening up to 30 days after the last dose of study treatment (for a maximum duration of 43 months, approximately) | 
| Apparent Total Plasma Clearance (CL/F) of LGX818 (Encorafenib) | Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Clearance was estimated from population pharmacokinetic (PK) modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. | Cycle 1 Day 1: Pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 +/- 2 hours post-dose | 
| Apparent Total Plasma Clearance at Steady State (CL/F, ss) of LGX818 (Encorafenib) | Clearance of a drug at steady state is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Clearance was estimated from population pharmacokinetic (PK) modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. | Cycle 1 Day 8, Cycle 2 Day 1: Pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 +/- 2 hours post-dose | 
| Apparent Total Plasma Clearance (CL/F) of BYL719 (Alpelisib) | Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Clearance was estimated from population pharmacokinetic (PK) modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. | Cycle 1 Day 1: Pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 +/- 2 hours post-dose | 
| Apparent Total Plasma Clearance at Steady State (CL/F, ss) of BYL719 (Alpelisib) | Clearance of a drug at steady state is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Clearance was estimated from population pharmacokinetic (PK) modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. | Cycle 1 Day 8, Cycle 2 Day 1: Pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 +/- 2 hours post-dose | 
| Apparent Terminal Volume of Distribution (Vz/F) of LGX818 (Encorafenib) | Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after oral dose (Vz/F) is influenced by the fraction absorbed. | Cycle 1 Day 1: Pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 +/- 2 hours post-dose | 
| Apparent Terminal Volume of Distribution at Steady State (Vz/F, ss) of LGX818 (Encorafenib) | Volume of distribution at steady state is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after oral dose (Vz/F, ss) is influenced by the fraction absorbed. | Cycle 1 Day 8, Cycle 2 Day 1: Pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 +/- 2 hours post-dose | 
| Apparent Terminal Volume of Distribution (Vz/F) of BYL719 (Alpelisib) | Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after oral dose (Vz/F) is influenced by the fraction absorbed. | Cycle 1 Day 1: Pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 +/- 2 hours post-dose | 
| Apparent Terminal Volume of Distribution at Steady State (Vz/F, ss) of BYL719 (Alpelisib) | Volume of distribution at steady state was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after oral dose (Vz/F, ss) is influenced by the fraction absorbed. | Cycle 1 Day 8, Cycle 2 Day 1: Pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 +/- 2 hours post-dose | 
| Time to Reach Maximum Observed Plasma Concentration (Tmax) of LGX818 (Encorafenib) | Tmax was defined as the time to reach maximum observed plasma concentration of encorafenib. | Cycle 1 Day 1: Pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 +/- 2 hours post-dose | 
| Time to Reach Maximum Plasma Concentration at Steady State (Tmax, ss) of LGX818 (Encorafenib) | Tmax, ss was defined as the time to reach maximum observed plasma concentration of LGX818 (encorafenib) at steady state. | Cycle 1 Day 8, Cycle 2 Day 1: Pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 +/- 2 hours post-dose | 
| Time to Reach Maximum Observed Plasma Concentration (Tmax) of BYL719 (Alpelisib) | Tmax was defined as the time to reach maximum observed plasma concentration of alpelisib. | Cycle 1 Day 1: Pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 +/- 2 hours post-dose | 
| Time to Reach Maximum Plasma Concentration at Steady State (Tmax, ss) of BYL719 (Alpelisib) | Tmax, ss was defined as the time to reach maximum observed plasma concentration of BYL719 (alpelisib) at steady state. | Cycle 1 Day 8, Cycle 2 Day 1: Pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 +/- 2 hours post-dose | 
| Time of Last Observed Plasma Concentration (T-last) of LGX818 (Encorafenib) | T-last was defined as the time to reach last observed plasma concentration of encorafenib. | Cycle 1 Day 1: Pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 +/- 2 hours post-dose | 
| Time of Last Observed Plasma Concentration at Steady State (T-last, ss) of LGX818 (Encorafenib) | T-last, ss was defined as the time to reach last observed plasma concentration of encorafenib at steady state. | Cycle 1 Day 8, Cycle 2 Day 1: Pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 +/- 2 hours post-dose | 
| Time of Last Observed Plasma Concentration (T-last) of BYL719 (Alpelisib) | T-last was defined as the time to reach last observed plasma concentration of alpelisib. | Cycle 1 Day 1: Pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 +/- 2 hours post-dose | 
| Time of Last Observed Plasma Concentration at Steady State (T-last, ss) of BYL719 (Alpelisib) | T-last, ss was defined as the time to reach last observed plasma concentration of alpelisib at steady state. | Cycle 1 Day 8, Cycle 2 Day 1: Pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 +/- 2 hours post-dose | 
| Plasma Trough Concentration at Steady State (Ctrough, ss) of LGX818 (Encorafenib) | Ctrough, ss was defined as plasma trough concentration of encorafenib at steady state. | Cycle 2 Day 1: Pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 +/- 2 hours post-dose | 
| Plasma Trough Concentration at Steady State (Ctrough, ss) of BYL719 (Alpelisib) | Ctrough, ss was defined as plasma trough concentration of alpelisib at steady state. | Cycle 2 Day 1: Pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 +/- 2 hours post-dose | 
| Overall Survival (OS) | OS was defined as the time (in months) from the date of randomization or date of start of treatment to the date of death due to any cause or data censoring date, whichever occurred first. Participants last known to be alive were censored at date of last contact. Analysis was performed using Kaplan-Meier method. | From the date of randomization or date of start of treatment to the date of death due to any cause or data censoring date, whichever occurred first (up to 43 months) | 
| Overall Response Rate (ORR) | Overall response rate as assessed by the investigator per RECIST v1.1, was defined as percentage of participants with a best overall response of complete response (CR) or partial response (PR), were recorded from date of randomization or date of start of treatment until date of first documentation of progressive disease (PD) or death due to any cause. CR was defined as complete disappearance of all target and non-nodal target lesions, and sustained for at least 4 weeks apart before progression. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (<) 10 millimeter (mm). PR defined as at least 30 percent (%) decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters. Only confirmed CR and PR are counted (those confirmed at least 4 weeks). | From date of randomization or date of start of treatment until date of first documentation of PD or death due to any cause (maximum up to 43 months) | 
| Duration of Response (DOR) | DOR: Time between date of the first documented response (CR or PR) and the date of first documented PD or death due to underlying cancer. If PD or death due to underlying cancer not occurred, then participant was censored at the date of last tumor assessment other than unknown. DOR was calculated for responders (confirmed) only. CR: Disappearance of all target, non-target lesions sustained for >=4 weeks and any pathological lymph nodes reduced in short axis to <10mm. PR: >=30% decrease in sum of diameters of target lesions, taking as reference baseline sum of diameter. PD for target lesions: At least a 20% increase in sum of diameters of target lesions, taking as reference smallest sum on study treatment, with absolute increase of >=5 mm, or appearance of >=1 new lesions. PD for non-target lesions: Unequivocal progression of pre-existing lesions/increase in overall tumor burden leading to discontinuation of therapy or appearance of new unequivocal malignant lesion. | From the first documentation of OR (confirmed CR or PR) to first documentation of PD/death due to any cause or censoring date, whichever occurred first (up to 43 months) | 
| Time to Response (TTR) | TTR as assessed by investigator according to RECIST v1.1, was defined as the time (in months) from date of randomization or date of start of treatment until first documented response (CR or PR) or data censoring date, whichever occurred first. CR was defined as complete disappearance of all target and non-target lesions sustained for at least 4 weeks apart before progression. Any pathological lymph nodes (whether target or non-target) reduced in short axis to <10 mm. PR was defined as at least 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters. Participants who did not achieve a confirmed PR or CR, were censored at last adequate tumor assessment date when they did not progress (including deaths not due to underlying disease) or at maximum follow-up (from study start to study end date) when participant had an event for progression-free survival. | From the date of randomization or date of start of treatment until first documented response (CR or PR) or data censoring date, whichever occurred first (maximum up to 43 months) | 
| Phase 1b: Progression Free Survival (PFS) | PFS was defined as the time from date of start of treatment to the date of event defined as the first documented progression or death due to any cause. Participants who did not progress per RECIST v1.1, were not known to have died prior to the data cut-off, or received any further anticancer therapy were censored at the date of last adequate tumor assessment or the anticancer therapy date, whichever was earlier. | From date of start of treatment to the date of event defined as the first documented progression or death due to any cause, censored date, whichever occurred first (maximum up to 43 months) | 
| Phase 2: Number of Participants With Any Variant in Gene Status at Baseline | Gene alterations/expression relevant to the RAF/MEK/ERK (proto-oncogene serine/threonine-protein kinase/ mitogen-activated ERK kinase/ extracellular signal-regulated kinases) and EGFR/PI3K/AKT (epidermal growth factor receptor/ phosphatidylinositol 3-kinase/ protein kinase B) pathways in tumor tissue, baseline molecular status (mutation/amplification/expression) in tumor tissue of potential predictive markers of tumor response or resistance i.e. BRAF (v-raf murine sarcoma viral oncogene homolog B1), HRAS (harvey rat sarcoma protein), KRAS (V-Ki-ras2 kirsten rat sarcoma viral oncogene homolog B1), NRAS (neuroblastoma RAS viral oncogene homolog), PTEN (phosphatase and tensin homolog), PIK3CA (phosphatidylinositol 3-kinase gene), MAP2K1 (mitogen-activated protein kinase 1), MAP2K2 (mitogen-activated protein kinase 2), ARAF, c-MET, RAF1, EGFR was analyzed. | Baseline (Day 1) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Open-label dose escalation, BRAF inhibitor, LGX818, PI3K inhibitor, BYL719, EGFR, cetuximab, metastatic colorectal cancer, KRAS, BRAF, V600