SNPMiner Trials: Clinical Trial Report
Report for Clinical Trial NCT03878719
Developed by Shray Alag, 2019.
SNP Clinical Trial Gene
This is a multicenter Phase 1b, open-label study to evaluate the pharmacokinetic, safety and
efficacy of binimetinib and encorafenib co-administered to adolescent patients with BRAF
V600-mutant advanced/metastatic melanoma. The study consists of a Safety Run-in Phase to
determine the RDE (recommended dose in expansion), followed by an Expansion Phase.
Name: binimetinib
Description: taken orallyType: Drug
Safety Run-in Phase Expansion Phase
Name: encorafenib
Description: taken orallyType: Drug
Safety Run-in Phase Expansion Phase
Primary Outcomes
Measure: Pharmacokinetic (PK) parameter (time to reach the maximum observed plasma concentration Cmax [Tmax]) for binimetinib
Time: Day 1 and Day 15 of Cycle 1, 28 day cycles
Measure: PK parameter (Cmax) for binimetinib
Time: Day 1 and Day 15 of Cycle 1, 28 day cycles
Measure: PK parameter (time of last PK sample [Tlast]) for binimetinib
Time: Day 1 and Day 15 of Cycle 1, 28 day cycles
Measure: PK parameter (area under the plasma concentration-time curve from time zero to Tlast [AUClast]) for binimetinib
Time: Day 1 and Day 15 of Cycle 1, 28 day cycles
Measure: PK parameter (Tmax) for binimetinib's active metabolite (AR00426032)
Time: Day 1 and Day 15 of Cycle 1, 28 day cycles
Measure: PK parameter (Cmax) for AR00426032
Time: Day 1 and Day 15 of Cycle 1, 28 day cycles
Measure: PK parameter (Tlast) for AR00426032
Time: Day 1 and Day 15 of Cycle 1, 28 day cycles
Measure: PK parameter (AUClast) for AR00426032
Time: Day 1 and Day 15 of Cycle 1, 28 day cycles
Measure: PK parameter (Tmax) for encorafenib
Time: Day 1 and Day 15 of Cycle 1, 28 day cycles
Measure: PK parameter (Cmax) for encorafenib
Time: Day 1 and Day 15 of Cycle 1, 28 day cycles
Measure: PK parameter (Tlast) for encorafenib
Time: Day 1 and Day 15 of Cycle 1, 28 day cycles
Measure: PK parameter (AUClast) for encorafenib
Time: Day 1 and Day 15 of Cycle 1, 28 day cycles
Measure: PK parameter (Tmax) for encorafenib's metabolite (LHY746)
Time: Day 1 and Day 15 of Cycle 1, 28 day cycles
Measure: PK parameter (Cmax) for LHY746
Time: Day 1 and Day 15 of Cycle 1, 28 day cycles
Measure: PK parameter (Tlast) for LHY746
Time: Day 1 and Day 15 of Cycle 1, 28 day cycles
Measure: PK parameter (AUClast) for LHY746
Time: Day 1 and Day 15 of Cycle 1, 28 day cycles
Measure: PK parameter (trough concentration [Ctrough]) for binimetinib
Time: at time zero Day 15 of Cycle 1, 28 day cycles
Measure: PK parameter (trough concentration [Ctrough]) for binimetinib
Time: at time zero Day 1 of Cycle 2, 28 day cycles
Measure: PK parameter (trough concentration [Ctrough]) for binimetinib
Time: at time zero Day 1 of Cycle 3, 28 day cycles
Measure: PK parameter (Ctrough) for AR00426032
Time: at time zero Day 15 of Cycle 1, 28 day cycles
Measure: PK parameter (Ctrough) for AR00426032
Time: at time zero Day 1 of Cycle 2, 28 day cycles
Measure: PK parameter (Ctrough) for AR00426032
Time: at time zero Day 1 of Cycle 3, 28 day cycles
Measure: PK parameter (Ctrough) for encorafenib
Time: at time zero Day 15 of Cycle 1, 28 day cycles
Measure: PK parameter (Ctrough) for encorafenib
Time: at time zero Day 1 of Cycle 2, 28 day cycles
Measure: PK parameter (Ctrough) for encorafenib
Time: at time zero Day 1 of Cycle 3, 28 day cycles
Measure: PK parameter (Ctrough) for LHY746
Time: at time zero Day 15 of Cycle 1, 28 day cycles
Measure: PK parameter (Ctrough) for LHY746
Time: at time zero Day 1 of Cycle 2, 28 day cycles
Measure: PK parameter (Ctrough) for LHY746
Time: at time zero Day 1 of Cycle 3, 28 day cycles
Secondary Outcomes
Measure: Incidence and severity of adverse events (AEs)
Time: From informed consent up to 30 days following last dose of study drug
Measure: Incidence of dose-limiting toxicities (DLTs)
Time: Duration of treatment for safety run-in phase, approximately 6 months, 28 day cycles
Description: Five-point Hedonic scale from 1 to 5, 5=really good
Measure: Palatability score for the pediatric formulations as assessed by an age-appropriate questionnaire for binimetinib
Time: Through Cycle 3 Day 1 in patients receiving the pediatric formulations in the Expansion Phase, 28 day cycles
Description: Five-point Hedonic scale from 1 to 5, 5=really good
Measure: Palatability score for the pediatric formulations as assessed by an age-appropriate questionnaire for encorafenib
Time: Through Cycle 3 Day 1 in patients receiving the pediatric formulations in the Expansion Phase, 28 day cycles
Measure: Objective response rate (ORR) assessed by the investigator, based on Response Criteria Evaluation in Solid Tumors (RECIST) v1.1
Time: Duration of treatment, approximately 6 months, 28 day cycles
Measure: Duration of response (DOR)
Time: Duration of treatment, approximately 6 months, 28 day cycles
Measure: Time to response
Time: Duration of treatment, approximately 6 months, 28 day cycles
Measure: Progression-free survival (PFS)
Time: Duration of treatment, approximately 6 months, 28 day cycles
Measure: One-year survival rate
Time: From first dose up to 1 year after treatment initiation
Measure: Change from Baseline in bone densitometry based on dual energy X-ray absorptiometry (DEXA) scan.
Time: Duration of treatment, approximately 6 months, 28 day cycles
Measure: Change from Baseline in calcium-phosphorus product (Ca × P)
Time: Duration of treatment, approximately 6 months, 28 day cycles
Purpose: Treatment
Allocation: Non-Randomized
Single Group Assignment
There are 2 SNPs
SNPs
1 V600E
- Histologically confirmed diagnosis of locally advanced, unresectable or metastatic
cutaneous melanoma or unknown primary melanoma American Joint Committee on Cancer
Stage IIIB, IIIC, or IV.
- Presence of BRAF V600E or V600K mutation in tumor tissue as determined by a local or
central laboratory
- Adequate cardiac function:
- Left ventricular ejection fraction (LVEF) ≥ 50% as determined by ECHO or
multi-gated acquisition (MUGA) scan and above the institutional lower limit of
normal (LLN);
- Triplicate average baseline QTcF value ≤ 450 ms.
- Adequate bone marrow, organ function, and laboratory parameters:
- Absolute neutrophil count (ANC) ≥ 1.5 × 10⁹/L;
- Hemoglobin ≥ 9 g/dL with or without transfusions;
- Platelets ≥ 75 × 10⁹/L without transfusions;
- Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) ≤ 2.5 ×
upper limit of normal (ULN); in patients with liver metastases ≤ 5 × ULN;
- Total bilirubin ≤ 1.5 × ULN and < 2 mg/dL; OR total bilirubin >1.5 × ULN with
indirect bilirubin < 1.5 × ULN;
- Creatinine ≤ 1.5 × institutional ULN for age, or calculated creatinine clearance
≥ 70 mL/min/1.73 --- V600E ---
2 V600K
- Histologically confirmed diagnosis of locally advanced, unresectable or metastatic
cutaneous melanoma or unknown primary melanoma American Joint Committee on Cancer
Stage IIIB, IIIC, or IV.
- Presence of BRAF V600E or V600K mutation in tumor tissue as determined by a local or
central laboratory
- Adequate cardiac function:
- Left ventricular ejection fraction (LVEF) ≥ 50% as determined by ECHO or
multi-gated acquisition (MUGA) scan and above the institutional lower limit of
normal (LLN);
- Triplicate average baseline QTcF value ≤ 450 ms.
- Adequate bone marrow, organ function, and laboratory parameters:
- Absolute neutrophil count (ANC) ≥ 1.5 × 10⁹/L;
- Hemoglobin ≥ 9 g/dL with or without transfusions;
- Platelets ≥ 75 × 10⁹/L without transfusions;
- Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) ≤ 2.5 ×
upper limit of normal (ULN); in patients with liver metastases ≤ 5 × ULN;
- Total bilirubin ≤ 1.5 × ULN and < 2 mg/dL; OR total bilirubin >1.5 × ULN with
indirect bilirubin < 1.5 × ULN;
- Creatinine ≤ 1.5 × institutional ULN for age, or calculated creatinine clearance
≥ 70 mL/min/1.73 --- V600E --- --- V600K ---
HPO Nodes
HPO:Cutaneous melanoma
Genes 11
BRAF HRAS XPC CDKN2A POLH ERCC3 BAP1 CXCR4 MC1R NRAS WRN hr>Melanoma
Genes 64
RAD51 RAD51C TYR RAD51D CDKN2A KRAS CDKN2B RAF1 CDKN2D MRE11 CYSLTR2 ERCC2 KLLN PTPN11 ERCC3 BRIP1 ERCC4 ERCC5 ERCC6 SF3B1 NRAS MGMT BRCA1 MBTPS2 BRAF ACD BRCA2 PIK3CA CXCR4 CTSC POLH POT1 MC1R MITF WRN CHEK2 HRAS BARD1 NBN AKT1 SLC45A2 GNA11 TRPV3 XPA OCA2 XPC GNAQ PTEN MDM2 TERT DDB2 RNF43 PALLD PALB2 TERF2IP SEC23B TP53 SDHB SDHC SDHD SMAD4 BAP1 CDK4 RAD50 hr>