A Phase Ib, open-label, dose-finding study of alpelisib in combination with paclitaxel in patients with advanced solid tumors

Jordi Rodon, Giuseppe Curigliano, Jean-Pierre Delord, Wael Harb, Analia Azaro, Yu Han, Celine Wilke, Valerie Donnet, Dalila Sellami, Thaddeus Beck

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)31709-31718
Number of pages10
JournalOncotarget
Volume9
Issue number60
DOIs
Publication statusPublished - Aug 3 2018

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Paclitaxel
Hyperglycemia
Neoplasms
Phosphatidylinositol 3-Kinase
Safety
Leukopenia
Standard of Care
Acute Kidney Injury
Diarrhea

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A Phase Ib, open-label, dose-finding study of alpelisib in combination with paclitaxel in patients with advanced solid tumors. / Rodon, Jordi; Curigliano, Giuseppe; Delord, Jean-Pierre; Harb, Wael; Azaro, Analia; Han, Yu; Wilke, Celine; Donnet, Valerie; Sellami, Dalila; Beck, Thaddeus.

In: Oncotarget, Vol. 9, No. 60, 03.08.2018, p. 31709-31718.

Research output: Contribution to journalArticle

Rodon, J, Curigliano, G, Delord, J-P, Harb, W, Azaro, A, Han, Y, Wilke, C, Donnet, V, Sellami, D & Beck, T 2018, 'A Phase Ib, open-label, dose-finding study of alpelisib in combination with paclitaxel in patients with advanced solid tumors', Oncotarget, vol. 9, no. 60, pp. 31709-31718. https://doi.org/10.18632/oncotarget.25854
Rodon, Jordi ; Curigliano, Giuseppe ; Delord, Jean-Pierre ; Harb, Wael ; Azaro, Analia ; Han, Yu ; Wilke, Celine ; Donnet, Valerie ; Sellami, Dalila ; Beck, Thaddeus. / A Phase Ib, open-label, dose-finding study of alpelisib in combination with paclitaxel in patients with advanced solid tumors. In: Oncotarget. 2018 ; Vol. 9, No. 60. pp. 31709-31718.
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AU - Azaro, Analia

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AB - 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.

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