Abstract
Phosphatidylinositol 3-kinase (PI3K) pathway activation is associated with resistance to paclitaxel in solid tumors. We assessed the safety and activity of alpelisib, an oral, selective PI3K p110α inhibitor, plus paclitaxel in patients with advanced solid tumors. This Phase Ib, multicenter, open-label, dose-finding study, with a planned dose-expansion phase of alpelisib once daily (QD) plus fixed-dose paclitaxel, recruited patients with advanced solid tumors. For the dose-finding phase, the primary objective was determination of maximum tolerated and/or recommended Phase II dose of alpelisib plus paclitaxel, and the secondary objectives included the assessment of safety for this combination. From March 2014 to August 2016, 19 patients with advanced solid tumors were treated with alpelisib QD (300 mg, n=6; 250 mg, n=4; 150 mg, n=9) plus paclitaxel (80 mg/m2, per standard of care). During dose finding, five of 12 (41.7%) evaluable patients for MTD determination experienced dose-limiting toxicities: alpelisib 300 mg, Grade 2 hyperglycemia (n=1); alpelisib 250 mg, Grade 2 hyperglycemia (n=1), Grade 4 hyperglycemia and Grade 3 acute kidney injury (n=1); and alpelisib 150 mg, Grade 2 hyperglycemia (n=1) and Grade 4 leukopenia (n=1). The MTD of alpelisib when administered with paclitaxel was 150 mg QD. Most frequent all-grade AEs were diarrhea (73.7%; Grade 3/4 10.5%) and hyperglycemia (57.9%; Grade 3/4 31.6%). The planned dose-expansion phase was not initiated. Alpelisib plus paclitaxel has a challenging safety profile in patients with advanced solid tumors. This study was closed following the completion of the dose-finding phase. Clinical trial registration: ClinicalTrials.gov NCT02051751.
Highlights
Paclitaxel, a taxane-based chemotherapy, has been approved as a weekly injection for the treatment of several solid tumors [1], most patients develop resistance and progressive disease [2, 3]
Hyperglycemia is an expected on-target side effect of PI3Kα inhibition given the involvement of PI3Kα in glucose homeostasis regulation and occurs more frequently with a targeted compound like alpelisib compared to pan-Phosphatidylinositol 3-kinase (PI3K) inhibitors or to beta, gamma or delta specific PI3K inhibitors
Analysis supported an maximum tolerated dose (MTD) of alpelisib 150 mg QD when administered with paclitaxel 80 mg/m2 Once weekly Response Evaluation Criteria In Solid Tumors (RECIST) (QW), which had the highest posterior probability of being within the target toxicity interval (16%, 35%) while meeting the escalation with overdose control (EWOC) criterion
Summary
A taxane-based chemotherapy, has been approved as a weekly injection for the treatment of several solid tumors [1], most patients develop resistance and progressive disease [2, 3]. The administration of a PI3K inhibitor has increased sensitivity in paclitaxel-resistant prostate cancer cells [6]. Decreased tumor burden was observed in mice inoculated with ovarian cancer cells and treated with a PI3K inhibitor plus paclitaxel compared with those treated with paclitaxel alone [5]. Activation of the PI3K/mTOR pathway frequently occurs via mutations in PIK3CA, which encodes the class I PI3K p110α catalytic subunit [7]. PIK3CA mutations are among the most frequently observed alterations in solid tumors [8,9,10,11,12]. Administration of paclitaxel plus a PI3K p110α-specific inhibitor is a potential therapeutic strategy by which to delay disease progression in patients with advanced solid tumors
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