| General information |
| Database: | DB00298 |
| Objective: | MAPK and PI3K/AKT/mTOR pathways play important roles in many tumors. In this study, safety, antitumor activity, and pharmacokinetics of buparlisib (pan class PI3K inhibitor) and trametinib (MEK inhibitor) were evaluated. |
| Authors: | Bedard PL, et al |
| Title: | a phase Ib doseescalation study of the oral panPI3K inhibitor buparlisib (BKM120) in combination with the oral MEK1/2 inhibitor trametinib (GSK1120212) in patients with selected advanced solid tumors. |
| Journal: | Clin Cancer Res. |
| Year: | 2015 |
| PMID: | 25500057 |
| Trial Design |
| Clinical Trial Id: | NCT01155453 |
| Agent: | buparlisib(BKM120), trametinib
|
| Target: | NA
|
| Cancer Type: | advanced solid tumors |
| Cancer Subtype: | advanced solid tumors |
| Therapy Type: | com |
| Therapeutic Combination Type: | 1 |
| Therapeutic Combination Content: | buparlisib (BKM120)+ trametinib (GSK1120212) |
| Study Type: | a openlabel, dosefinding, phase Ib study |
| Key Patients Feature: | adult patients with advanced solid tumors harboring RAS or BRAF mutations such as colorectal cancer, melanoma, non small cell lung cancer, triplenegative breast cancer (TNBC), or pancreatic cancer. |
| Biomarker: | RAS or BRAFmutant |
| Biomark Analysis: | as in the conclusion |
| Control Group Info: | single arm |
| Treatment Info: | Buparlisib capsules and trametinib tablets were coadministered orally once daily in a 28day cycle. First cohort received 30 mg/d of buparlisib + 0.5 mg/d trametinib. Doses were escalated according to an adaptive Bayesian logistic regression model (BLRM) with overdose control principle until MTD and/or RP2D was reached |
| Primary End Point: | incidence rate of doselimiting toxicities (DLT) in cycle 1. |
| Secondary End Point: | safety, pharmacokinetics (PK), efficacy, and predictive/pharmacodynamic (PD) biomarkers. Tumor response was classified according to RECIST version 1.0. |
| Patients Number: | 113 |
| Trial Results |
| DLT_MTD: | MTD was established as buparlisib 70 mg + trametinib 1.5 mg daily [5/15, 33% patients with doselimiting toxicities (DLT)] and recommendedphase II dose (RP2D) buparlisib 60 mg + trametinib 1.5 mg daily (1/10, 10% patients with DLTs). DLTs included stomatitis (8/103, 8%), diarrhea, dysphagia, and creatine kinase (CK) increase (2/103, 2% each). |
| Objective Response Rate: | For all (21) patients with ovarian cancer, overall response rate was 29% [1 complete response, 5 partial responses (PR)]; Minimal activity was observed in patients with non small cell lung cancer (1/17 PR) and pancreatic cancer (best overall response was SD). |
| Disease Control Rate: | disease control rate 76% |
| Median Time to Progression: | NA |
| Median PFS A vs. C: | 7 months |
| Median OS A vs. C: | NA |
| Adverse Event(agent arm): | Treatmentrelated grade 3/4 adverse events (AEs) occurred in 73 patients (65%); mainly CK increase, stomatitis, AST/ALT (aspartate aminotransferase/alanine aminotransferase) increase, and rash. |
| Conclusions: | At RP2D, buparlisib 60 mg + trametinib 1.5 mg daily shows promising antitumor activity for patients with KRASmutant ovarian cancer. Longterm tolerability of the combination at RP2D is challenging, due to frequent dose interruptions and reductions for toxicity. |