A phase I trial of mFOLFOX6 combined with the oral PI3K inhibitor BKM120 in patients with advanced refractory solid tumors

Abstract

Summary Purpose The oral PI3K inhibitor BKM120 has been reported as safe and well tolerated in early phase clinical trials of advanced cancer patients. We performed a phase I trial of BKM120 plus mFOLFOX6 (5-FU/LV + oxaliplatin), a common chemotherapeutic backbone in GI malignancies, to establish the maximum tolerated dose (MTD) and characterize the safety and tolerability of the combination. Methods Patients with advanced solid tumors received oral BKM120 daily combined with standard doses of mFOLFOX6 every 2 weeks of a 28 day cycle. The study utilized a standard 3 + 3 dose escalation schema. Results A total of 17 patients received treatment with BKM120, 13 of which were evaluate for dose limited toxicity (DLT). The most common tumor types were colorectal cancer, cholangiocarcinoma, pancreatic cancer and hepatocellular carcinoma. DLT included grade 3 hyperglycemia, grade 3 AST/ALT elevation, grade 4 neutropenia and grade 4 thrombocytopenia. A total of 76 % of patients experienced treatment related grade 3/4 adverse events (AEs), the most common of which were neutropenia, fatigue, leukopenia, hyperglycemia and thrombocytopenia. One patient demonstrated an unconfirmed partial response and three patients had stable disease. Discussion The MTD of BKM120 in combination with standard doses of mFOLFOX6 was 40 mg daily, which is well below the 100 mg daily dose proven effective and tolerable both as a single agent and in combination with other chemotherapeutics. In addition, the regimen of BKM120 with mFOLFOX6 in patients with refractory solid tumors resulted in increased toxicity than would be expected from either the PI3K inhibitor or the chemotherapy backbone alone.

Cryptotanshinone induces cell cycle arrest and apoptosis through the JAK2/STAT3 and PI3K/Akt/NFkB pathways in cholangiocarcinoma cells

“…Studies have shown that targeted therapy on JAK2/STAT3 or PI3K/Akt pathway could be effective for several cancers, such as endometrial cancer and ovarian cancer 43–45. Researchers have reported that the resistance of CCA to chemotherapy could be related to the PI3K/Akt signaling, and that targeted inhibition on PI3K/Akt signaling pathway may increase sensitivity to chemotherapeutic agents 46. In addition, it has been reported that CTS could reverse chemotherapy resistance in colon cancer and lung cancer cells 47,48.…”

Targeting PI3K in cancer: mechanisms and advances in clinical trials

“…The MTD was 80 mg/d in a phase I study of buparlisib in patients with advanced acute leukemias [109]. A phase I trial in patients with advanced solid tumors suggested that the MTD of buparlisib in combination with standard doses of mFOLFOX6 (every 2 weeks of a 28-day cycle) was 40 mg daily; increased toxicity was observed compared to that expected from either buparlisib or mFOLFOX6 alone [110]. This trial concluded that further studies of buparlisib in combination with mFOLFOX6 are not recommended in gastrointestinal tumor.…”

The landscape of targeted therapies for cholangiocarcinoma: current status and emerging targets

“…More recently, increased efficacy was attained in-vitro by dual inhibition of the PI3K/AKT/MTOR and RAF/MEK/ERK pathway, which overcame resistance pathways [74]. A phase I trial of mFOLFOX6 and the oral PI3K inhibitor BKM120 in patients with advanced solid tumors (4/17 CCA) reported high toxicity rates, with 76 % of the patients experiencing a grade 3/4 AE [75]. The most common AEs were neutropenia, fatigue, leukopenia, hyperglycemia and thrombocytopenia.…”