title: Phase I/II study of pilaralisib (SAR245408) in combination with trastuzumab or trastuzumab plus paclitaxel in trastuzumab-refractory HER2-positive metastatic breast cancer.
abstract: This phase I/II dose-escalation study investigated the maximum tolerated dose (MTD), safety, pharmacokinetics, and efficacy of the pan-class I phosphoinositide 3-kinase inhibitor pilaralisib in combination with trastuzumab (Arm 1) or trastuzumab plus paclitaxel (Arm 2) in patients with HER2-positive metastatic breast cancer. Patients had progressed on prior trastuzumab (Arms 1 and 2) and received prior taxane (Arm 2). The MTD of pilaralisib was determined using a 3 + 3 dose-escalation design (starting dose 200 mg once daily). Forty-two patients were enrolled (21 in each arm). Five patients had a dose-limiting toxicity (DLT; three in Arm 1 and two in Arm 2). Dose-limiting toxicities were rash (three patients) and neutropenia (two patients). The MTD of pilaralisib was determined at 400 mg once daily in both arms. The most frequently reported treatment-related adverse events (AEs) were diarrhea (23.8 % in Arm 1 vs. 66.7 % in Arm 2), fatigue (14.3 vs. 42.9 %), and rash (33.3 vs. 38.1 %). The most frequently reported treatment-related grade ≥3 AEs were erythematous rash (9.5 %) in Arm 1 and diarrhea, peripheral neuropathy, and neutropenia (14.3 % each) in Arm 2. Steady-state pilaralisib exposure was similar to previous studies with pilaralisib monotherapy. No responses occurred in Arm 1; four of 20 evaluable patients (20 %) in Arm 2 had a partial response. Observed PIK3CA mutations in cell-free circulating DNA did not correlate with response. Pilaralisib in combination with trastuzumab with or without paclitaxel had an acceptable safety profile in metastatic HER2-positive breast cancer, with clinical activity in the paclitaxel arm.
authors.affiliation: Dana-Farber Cancer Institute, 450 Brookline Ave., Boston, MA, 02215, USA, stolaney@partners.org.
authors.forename: Sara
authors.initials: S
authors.lastname: Tolaney
authors.forename: Howard
authors.initials: H
authors.lastname: Burris
authors.forename: Elaina
authors.initials: E
authors.lastname: Gartner
authors.forename: Ingrid A
authors.initials: IA
authors.lastname: Mayer
authors.forename: Cristina
authors.initials: C
authors.lastname: Saura
authors.forename: Matthew
authors.initials: M
authors.lastname: Maurer
authors.forename: Eva
authors.initials: E
authors.lastname: Ciruelos
authors.forename: Agustin A
authors.initials: AA
authors.lastname: Garcia
authors.forename: Frank
authors.initials: F
authors.lastname: Campana
authors.forename: Bin
authors.initials: B
authors.lastname: Wu
authors.forename: Yi
authors.initials: Y
authors.lastname: Xu
authors.forename: Jason
authors.initials: J
authors.lastname: Jiang
authors.forename: Eric
authors.initials: E
authors.lastname: Winer
authors.forename: Ian
authors.initials: I
authors.lastname: Krop
mesh_terms: D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage* / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D017239:Paclitaxel / Q000008:administration & dosage* / Q000009:adverse effects; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011810:Quinoxalines / Q000008:administration & dosage*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D013449:Sulfonamides / Q000008:administration & dosage*; D000068878:Trastuzumab
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D017239:Paclitaxel; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011810:Quinoxalines; D018719:Erb-b2 Receptor Tyrosine Kinases; D013449:Sulfonamides; D000068878:Trastuzumab; C581157:XL147