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Phase Ib, Dose Escalation Study of Oral LDE225 in Combination With BKM120 in Patients With Advanced Solid Tumors

ABSTRACT: The purpose of this study is to determine the maximum dose of LDE225 and BKM120 that can be safely given together to patients and/or the dose that will be used in future studies. This study will also learn more about how the combination of these two investigational drugs may work for patients with certain cancers (specifically metastatic breast cancer, advanced pancreatic adenocarcinoma, metastatic colorectal cancer and recurrent glioblastoma multiforme).

DISEASE(S): Adenocarcinoma,Metastatic Colorectal Cancer,Metastatic Breast Cancer,Triple Negative Metastatic Breast Cancer,Glioblastoma,Advanced Solid Tumors,Preliminary Efficacy,Breast Neoplasms,Dose Escalation,Gastric Cancer,Advanced Pancreatic Adenocarcinoma,Recurrent Glioblastoma Multiforme,Colorectal Neoplasms,Safety,Gastroesophageal Junction Cancer,Stomach Neoplasms,Hormone Receptor Positive (er+/pr+, And Her2-) Metastatic Breast Cancer

PROVIDER: 2123685 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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Project description:We report the RNA sequencing data from the REPEAT study, in which patients with beyond first-line esophagogastric cancer were treated with regorafenib and paclitaxel. For the RNA sequencing, biopsies from metastatic lesions were obtained on baseline (n=21) and fifteen days following treatment initiation (n=13). PURPOSE: Regorafenib monotherapy, a multikinase-inhibitor of angiogenesis, tumor microenvironment, and oncogenesis, showed promising results in gastric cancer. We aimed to assess the tolerability of regorafenib and paclitaxel in advanced esophagogastric cancer (EGC) patients refractory to first-line treatment, and explore potential biomarkers. METHODS: Patients received paclitaxel (80 mg/m2) on days 1, 8, and 15 of a 28-day cycle and regorafenib (80/120/160 mg) on day 1-21 in the dose-escalation cohort, and the maximum-tolerated dose (MTD) in the dose-expansion cohort. Exploratory, overall- (OS) and progression-free survival (PFS) were compared to a propensity-score matched cohort receiving standard second/third line systemic treatment. Paclitaxel pharmacokinetics were assessed using D1 and D15 samples. We performed ELISA measurements of galectin-1, RNA sequencing and shallow whole-genome sequencing of metastatic tumor biopsies for biomarker analyses. RESULTS: In the dose-escalation cohort (n=14), the MTD of regorafenib was 120 mg. Thirty-four patients were enrolled in the dose-expansion cohort. Most common toxicities (all grades; grade ≥3) were fatigue (79%; 4%) and sensory neuropathy (63%; 4%). Best responses achieved were partial response (28%) and stable disease (54%). Median OS and PFS were 7.8 and 4.2 months, respectively (median follow-up 7.8 months). OS (p=0.08) and PFS (p=0.81) were not significantly improved compared to the matched cohort. Paclitaxel concentrations were significantly increased with regorafenib (D15) compared with paclitaxel only (D1; p<0.05); no associations were observed with toxicity or efficacy. An increase in circulating galectin-1 compared to baseline was associated with shorter OS (p<0.01). Enrichment of angiogenesis-related gene expression was observed in short-survivors measured by RNA sequencing. Chromosome 19q13.12-q13.2 amplification was associated with shorter OS (p=0.02) and PFS (p=0.02). CONCLUSION: Treatment with regorafenib and paclitaxel is tolerable and shows promising efficacy in advanced EGC refractory to first-line treatment. Galectin-1 and chromosome 19q13.12-q13.2 amplification could serve as negative predictive biomarkers for treatment response.

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Phase Ib, Dose Escalation Study of Oral LDE225 in Combination With BKM120 in Patients With Advanced Solid Tumors

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