Advanced and Selected Solid Tumors, AML, High Risk and Very High Risk MDS
Conditions
Keywords
Advanced solid tumor,, AML, high risk and very high risk MDS, dose escalation,, RAS/BRAF mutation,, PI3K inhibitor,, MEK inhibitor,, BYL719,, MEK162
Brief summary
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.
Interventions
DRUGBYL719
taken orally
DRUGMEK162
taken orally
Sponsors
Array BioPharma
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Dose Limiting Toxicities (DLT) | during the first cycle (28 days) of treatment with BYL719 and MEK162 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall response rate | Assessed every 8 weeks until disease progression | Overall response rate (ORR) is the proportion of patients with a best overall response of Complete Response (CR) or Partial Response (PR). |
| Time to progression | Assessed every 8 weeks until disease 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. |
| Progression free survival | Assessed every 8 weeks until disease progression | 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. |
| Number of participants with adverse events and serious adverse events | Assessed from Cycle 1 Day 1 until treatment discontinuation | All AEs and SAEs will be collected in accordance with the protocol and assessed for relatedness to study drug combination. |
| Correlation of baseline mutation or amplification status (PIK3CA, KRAS, NRAS and BRAF) and clinical anti-tumor activity outcome | Assessed at Baseline (pre-treatment) | Collect baseline genetic mutation/alteration status to investigate the potential relationship to anti-tumor activity. |
| Clinical benefit rate | Assessed every 4 weeks for 3 months and every 3 months for 6 months followed by every 6 months thereafter until disease progression | 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 versus plasma concentration profiles of BYL719 and MEK162 | Assessed during the first cycle of treatment | Blood concentrations of MEK162 and its metabolite (AR00426032) and BYL719 will be assessed during the first cycle of treatment. |
Countries
Australia, France, Italy, Spain, Switzerland, United Kingdom, United States
Outcome results
None listed