A Phase Ib Study of MEK162 Plus BYL719 in Adult Patients With Selected Advanced Solid Tumors

Study Overview
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Brief Summary
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This is a multi-center, open-label, dose-finding, phase Ib study to estimate the maximum tolerated dose(s) (MTD(s)) and/or recommended dose(s) for expansion (RDE(s)) for the orally administered combination of BYL719 and MEK162. This combination will be explored in adult patients with advanced CRC, esophageal cancer, pancreatic cancer, NSCLC, ovarian cancer, or other advanced solid tumors and in adult patients with AML or high risk and very high risk MDS, with documented RAS or BRAF mutations. Dose escalation will be guided by a Bayesian logistic regression model with overdose control. At MTD or RDE, four expansion arms will be opened in order to further assess the safety and preliminary activity of the combination of BYL719 and MEK162 in specific patient populations.

Official Title
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A Phase Ib Open-label, Multi-center, Dose Escalation and Expansion Study of Orally Administered MEK162 Plus BYL719 in Adult Patients With Selected Advanced Solid Tumors

Conditions
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Advanced and Selected Solid Tumors, AML, High Risk and Very High Risk MDS

Intervention / Treatment
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* Drug: BYL719
* Drug: MEK162


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically/cytologically confirmed, advanced solid tumors, AML or high risk and very high risk MDS Measurable disease as determined by RECIST 1.1 Exclusion Criteria: Primary CNS tumor or CNS tumor involvement Diabetes mellitus Unacceptable ocular/retinal conditions Clinically significant cardiac disease or impaired cardiac 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: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BYL719 + MEK162<br>BYL719 plus MEK162. Dose escalation with a starting dose for the first cohort of 200mg QD BYL719 and 30mg BID MEK162 | Drug: BYL719<br>* taken orally<br>Drug: MEK162<br>* taken orally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Dose Limiting Toxicities (DLT) | Toxicity will be assessed using the National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE), version 4.0 unless otherwise specified. A DLT is defined as an adverse event or abnormal laboratory value assessed as at least possibly related to the study medication, occurs ≤ 28 days following the first dose of BYL719 and MEK162 (Cycle 1), and meets any of the protocol-specified DLT criteria. | during the first cycle (28 days) of treatment with BYL719 and MEK162 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with adverse events and serious adverse events | All AEs and SAEs will be collected in accordance with the protocol and assessed for relatedness to study drug combination. | Assessed from Cycle 1 Day 1 until treatment discontinuation | 
| Overall response rate | Overall response rate (ORR) is the proportion of patients with a best overall response of Complete Response (CR) or Partial Response (PR). | Assessed every 8 weeks until disease progression | 
| Time to progression | Time to progression (TTP) is the time from date of randomization/start of treatment to the date of event defined as the first documented progression or death due to underlying cancer. If a patient has not had an event, time to progression is censored at the date of last adequate tumor assessment. | Assessed every 8 weeks until disease progression | 
| Progression free survival | Progression-free survival (PFS) is the time from date of randomization/start of treatment to the date of event defined as the first documented progression or death due to any cause. If a patient has not had an event, progression-free survival is censored at the date of last adequate tumor assessment. | Assessed every 8 weeks until disease progression | 
| Time versus plasma concentration profiles of BYL719 and MEK162 | Blood concentrations of MEK162 and its metabolite (AR00426032) and BYL719 will be assessed during the first cycle of treatment. | Assessed during the first cycle of treatment | 
| Correlation of baseline mutation or amplification status (PIK3CA, KRAS, NRAS and BRAF) and clinical anti-tumor activity outcome | Collect baseline genetic mutation/alteration status to investigate the potential relationship to anti-tumor activity. | Assessed at Baseline (pre-treatment) | 
| Clinical benefit rate | The clinical benefit rate is defined as the proportion of patients with complete remission, complete remission with incomplete blood count recovery, partial remission, minor response or stable disease for > 15 weeks | Assessed every 4 weeks for 3 months and every 3 months for 6 months followed by every 6 months thereafter until disease progression | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Advanced solid tumor,, AML, high risk and very high risk MDS, dose escalation,, RAS/BRAF mutation,, PI3K inhibitor,, MEK inhibitor,, BYL719,, MEK162