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.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
139
University of California San Diego - Moores Cancer Center Dept Onc
La Jolla, California, United States
H. Lee Moffitt Cancer Center & Research Institute H. Lee Moffitt SC
Tampa, Florida, United States
Northwestern Memorial Hospital
Chicago, Illinois, United States
Massachusetts General Hospital CCPO
Boston, Massachusetts, United States
Memorial Sloan Kettering Cancer Center Onc. Dept
New York, New York, United States
Montefiore Medical Center SC
The Bronx, New York, United States
University of Texas/MD Anderson Cancer Center Dept. of Onc.
Houston, Texas, United States
University of Utah / Huntsman Cancer Institute Huntsman (3)
Salt Lake City, Utah, United States
Array BioPharma Investigative Site
Parkville, Victoria, Australia
Array BioPharma Investigative Site
Villejuif, France
...and 6 more locations
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.
Time frame: during the first cycle (28 days) of treatment with BYL719 and MEK162
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.
Time frame: 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).
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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
Time frame: Assessed every 4 weeks for 3 months and every 3 months for 6 months followed by every 6 months thereafter until disease progression
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